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Gasparri AM, Pocaterra A, Colombo B, Taiè G, Gnasso C, Gori A, Pozzi F, Smith A, Magni F, Ugolini A, Doglio M, Bonini MC, Mondino A, Corti A, Curnis F. Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth. J Exp Clin Cancer Res 2025; 44:88. [PMID: 40055773 PMCID: PMC11889887 DOI: 10.1186/s13046-025-03352-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many solid tumors, can promote the activation of transforming growth factor-β (TGFβ), a potent immunosuppressive cytokine, by interacting with the RGD sequence of the latency-associated peptide (LAP)/TGFβ complex. We have previously described a chromogranin A-derived peptide, called "peptide 5a", which recognizes the RGD-binding site of both αvβ6 and αvβ8 with high affinity and selectivity, and efficiently accumulates in αvβ6- or αvβ8-positive tumors. This study aims to demonstrate that peptide 5a can inhibit TGFβ activation in tumors and suppress tumor growth. METHODS Peptide 5a was chemically coupled to human serum albumin (HSA) to prolong its plasma half-life. The integrin recognition properties of this conjugate (called 5a-HSA) and its capability to block TGFβ activation by αvβ6+ and/or αvβ8+ cancer cells or by regulatory T cells (Tregs) were tested in vitro. The in vivo anti-tumor effects of 5a-HSA, alone and in combination with S-NGR-TNF (a vessel-targeted derivative of tumor necrosis factor-a), were investigated in various murine tumor models, including pancreatic ductal adenocarcinoma, fibrosarcoma, prostate cancer, and mammary adenocarcinoma. RESULTS In vitro assays showed that peptide 5a coupled to HSA maintains its capability of recognizing αvβ6 and αvβ8 with high affinity and selectivity and inhibits TGFβ activation mediated by αvβ6+ and/or αvβ8+ cancer cells, as well as by αvβ8+ Tregs. In vivo studies showed that systemic administration of 5a-HSA to tumor-bearing mice can reduce TGFβ signaling in neoplastic tissues and promote CD8-dependent anti-tumor responses. Combination therapy studies showed that 5a-HSA can enhance the anti-tumor activity of S-NGR-TNF, leading to tumor eradication. CONCLUSION Peptide 5a is an efficient tumor-homing inhibitor of αvβ6- and αvβ8-integrin that after coupling to HSA, can be used as a drug to block integrin-dependent TGFβ activation in tumors and promote immunotherapeutic responses.
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Affiliation(s)
- Anna Maria Gasparri
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Arianna Pocaterra
- Lymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Taiè
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Chiara Gnasso
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Gori
- Istituto di Scienze e Tecnologie Chimiche (SCITEC-CNR), National Research Council of Italy, Milan, Italy
| | - Federica Pozzi
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Andrew Smith
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Milan, Italy
| | - Fulvio Magni
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Milan, Italy
| | - Alessia Ugolini
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Matteo Doglio
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Chiara Bonini
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Anna Mondino
- Lymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
| | - Flavio Curnis
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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McCurdy JD, Hartley I, Behrenbruch C, Hart A, Tozer P, Ding NS. Management of Perianal Fistulizing Crohn's Disease According to Principles of Wound Repair. Aliment Pharmacol Ther 2025; 61:600-613. [PMID: 39757535 DOI: 10.1111/apt.18466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/14/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Perianal fistulizing Crohn's disease (PFCD) is a challenging and debilitating phenotype of Crohn's disease that can negatively affect quality of life. Studies have begun to uncover the physiologic mechanisms involved in wound repair as it relates to PFCD and how aberrations in these mechanisms may contribute to fistula persistence. AIMS To review the physiologic and pathophysiologic mechanisms of wound repair in PFCD and how specific therapeutic strategies may impact their outcomes. METHODS We reviewed the latest published literature on wound repair as it relates to PFCD. RESULTS Wound repair can be categorised into three overlapping biological phases: localised inflammation, cell recruitment/proliferation and tissue remodelling. Each is tightly regulated since insufficient or excessive activation can result in, respectively, chronic wounds and fibrotic tissue, both of which can impair organ function. In PFCD, the outcomes of wound repair include restitution (complete healing), epithelialisation and chronic wounds. Treatment of PFCD should take into consideration the distinct phases of wound repair. Therefore, the ability to differentiate between each phase of wound repair and their outcomes may help physicians deliver the most effective treatment strategy at the most appropriate time. CONCLUSIONS This review provides a comprehensive overview of the phases of wound repair and specific treatment strategies for each to provide clinicians with a rational framework for managing PFCD.
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Affiliation(s)
- Jeffrey D McCurdy
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Imogen Hartley
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | - Corina Behrenbruch
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | | | | | - Nik S Ding
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
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3
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Che X, Tian X, Wang Z, Zhu S, Ye S, Wang Y, Chen Y, Huang Y, Anwaier A, Yao P, Chen Y, Wu K, Liu Y, Xu W, Zhang H, Ye D. Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC. Cancer Cell Int 2024; 24:363. [PMID: 39501306 PMCID: PMC11539770 DOI: 10.1186/s12935-024-03546-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/24/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated. METHODS We investigated the prognostic implications of ITGA5 with a machine learning model and evaluated biological behaviors of different levels of ITGA5 expression in vitro. Bioinformatic analysis was performed to explain the comprehensive effect of ITGA5 on the TME and drug sensitivity. RESULTS We constructed a machine learning model to elaborate the prognostic implication of ITGA5. As tumorigenesis of ccRCC was tightly relevant with several mutant genes, we investigated the correlation between ITGA5 expression and frequent mutations and found ITGA5 upregulation in VHL mutant ccRCC (P = 0.016). Through overexpressing, silencing, and blocking ITGA5, we verified the role of ITGA5 in promoting ccRCC adverse biological activities; and the potential functions of ITGA5 in ccRCC were bioinformatically demonstrated, summarizing as cell proliferation, migration, and angiogenesis. The localization of ITGA5 primarily in endothelia and macrophages further verified its magnitude in angiogenesis and aroused our excavation in ITGA5 regulation of immune infiltration landscape. Generally, ITGA5-high ccRCC presented an immunosuppressive TME by inducing a lower level of CD8 + T cell infiltration. For the last part we predicted drug sensitivity relevant to ITGA5 and concluded that a joint medication of ITGA5 inhibitors and VEGFR-target drugs (including sunitinib, axitinib, pazopanib, and motesanib) might be a promising therapeutic strategy. CONCLUSION Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy.
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Grants
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- 22401 FDUROP (Fudan Undergraduate Research Opportunities Program)
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- S202310246246 Shanghai Undergraduate Training Program on Innovation and Entrepreneurship (SUTPLE) grant
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- SACA-CY21A06,SACA-CY21B01,SACA-CY23A02,SACA-CY23C04 Shanghai Anti-Cancer Association
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- 2020CXJQ03 Shanghai Municipal Health Bureau
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
- Y-HR2020MS-0948 Beijing Xisike Clinical Oncology Research Foundation
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Affiliation(s)
- Xiangxian Che
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Xi Tian
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Zhenda Wang
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Shuxuan Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Shiqi Ye
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Yue Wang
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Yihan Chen
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Yiyun Huang
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Aihetaimujiang Anwaier
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Peifeng Yao
- School of Informatics, Xiamen University, Xiamen, 361102, People's Republic of China
| | - Yijia Chen
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Keting Wu
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Yifei Liu
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China.
| | - Hailiang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China.
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, People's Republic of China.
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Paulus J, Sewald N. Small molecule- and peptide-drug conjugates addressing integrins: A story of targeted cancer treatment. J Pept Sci 2024; 30:e3561. [PMID: 38382900 DOI: 10.1002/psc.3561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 02/23/2024]
Abstract
Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleavable or non-cleavable linker in peptide-drug conjugates (PDCs) or small molecule-drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody-drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small-molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin αVβ3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin-addressing PDCs and SMDCs while highlighting points of great interest.
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Affiliation(s)
- Jannik Paulus
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
| | - Norbert Sewald
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
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Wang Y, Chen Y, Zhao M. N6-methyladenosine modification and post-translational modification of epithelial-mesenchymal transition in colorectal cancer. Discov Oncol 2024; 15:209. [PMID: 38834851 DOI: 10.1007/s12672-024-01048-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 05/20/2024] [Indexed: 06/06/2024] Open
Abstract
Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic mutations. However, recent studies have revealed the significant role of epigenetic alterations in the progression of colorectal cancer. Epithelial-mesenchymal transition, a critical step in cancer cell metastasis, has been found to be closely associated with the tumor microenvironment and immune factors, thereby playing a crucial role in many kinds of biological behaviors of cancers. In this review, we explored the impact of N6-methyladenosine and post-translational modifications (like methylation, acetylation, ubiquitination, SUMOylation, glycosylation, etc.) on the process of epithelial-mesenchymal transition in colorectal cancer and the epigenetic regulation for the transcription factors and pathways correlated to epithelial-mesenchymal transition. Furthermore, we emphasized that the complex regulation of epithelial-mesenchymal transition by epigenetics can provide new strategies for overcoming drug resistance and improving treatment outcomes. This review aims to provide important scientific evidence for the prevention and treatment of colorectal cancer based on epigenetic modifications.
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Affiliation(s)
- Yingnan Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Yufan Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Miaomiao Zhao
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China.
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Yu J, E T, Zhou M, Niu J, Wang J, Miao R, Dong C, Gao H, Jing C, Liang B. Integrin αvβ6 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon carcinoma. Am J Cancer Res 2024; 14:2608-2625. [PMID: 38859847 PMCID: PMC11162679 DOI: 10.62347/rhdb8792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/15/2024] [Indexed: 06/12/2024] Open
Abstract
The immune escape of colon cancer and its role in the response to immunotherapies such as PD-1/PD-L1 checkpoint inhibitors have long been of great interest. The positive outcomes of immunotherapy are limited by the immunosuppressive nature of the tumor microenvironment. Integrin αvβ6, which can regulate the progression of colon cancer, was recently reported to be involved in the immune suppression of colon cancer. In the present study, we explored the correlation between αvβ6 and PD-L1 expression by immunohistochemistry of colon cancer tissues. Then, the regulation of PD-L1 signaling by αvβ6 in colon cancer cells was demonstrated. We constructed an in vivo model and performed immunophenotyping experiments to analyze further the regulation of the immune response by αvβ6. The role of αvβ6 in the response to anti-PD-1 therapy in colon cancer was also verified. αvβ6-positive tissues exhibited increased PD-L1 expression. Inhibition of αvβ6 not only downregulated constitutive PD-L1 expression but also decreased IFN-γ-induced PD-L1 expression. In addition, αvβ6-induced PD-L1 expression was suppressed by the ERK inhibitor PD98059, and knockdown of the β6-ERK2 binding site had the equivalent effect. αvβ6 decreased CD8+ T cell infiltration and granzyme B expression in CD8+ T cells in colon cancer patients. Furthermore, mice engrafted with αvβ6-expressing colon cancer cells exhibited an unsatisfactory response to anti-PD-1 therapy, and anti-PD-1-induced increases in CD4+ and CD8+ T cell infiltration could be inhibited by αvβ6. These results indicate that αvβ6 mediates immune escape in colon cancer by upregulating PD-L1 through the ERK/MAPK pathway. Moreover, αvβ6 could serve as a marker for the efficacy of anti-PD-1 therapy in colon cancer.
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Affiliation(s)
- Jintao Yu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Tianyu E
- Shandong First Medical UniversityJinan, Shandong, China
| | - Mingliang Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong UniversityJinan, Shandong, China
| | - Jinshen Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Ruizheng Miao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Cunjin Dong
- Department of Medical Affair, Heze Municipal HospitalHeze, Shandong, China
| | - Huijie Gao
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong UniversityJinan, Shandong, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong UniversityJinan, Shandong, China
| | - Benjia Liang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
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Si G, Chen X, Li Y, Yuan X. Exosomes promote pre-metastatic niche formation in colorectal cancer. Heliyon 2024; 10:e27572. [PMID: 38509970 PMCID: PMC10950591 DOI: 10.1016/j.heliyon.2024.e27572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/22/2024] Open
Abstract
It is well known that colorectal cancer (CRC) has a high morbidity rate, a poor prognosis when metastasized, and a greatly shortened 5-year survival rate. Therefore, understanding the mechanism of tumor metastasis is still important. Based on the "seed and soil" theory, the concept of " premetastatic niche (PMN)" was introduced by Kaplan et al. The complex interaction between primary tumors and the metastatic organ provides a beneficial microenvironment for tumor cells to colonize at a distance. With further exploration of the PMN, exosomes have gradually attracted interest from researchers. Exosomes are extracellular vesicles secreted from cells that include various biological information and are involved in communication between cells. As a key molecule in the PMN, exosomes are closely related to tumor metastasis. In this article, we obtained information by conducting a comprehensive search across academic databases including PubMed and Web of Science using relevant keywords. Only recent, peer-reviewed articles published in the English language were considered for inclusion. This study aims to explore in depth how exosomes promote the formation of pre-metastatic microenvironment (PMN) in colorectal cancer and its related mechanisms.
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Affiliation(s)
- Guifei Si
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Xuemei Chen
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Yuquan Li
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Xuemin Yuan
- Department of Gastroenterology, Linyi People's Hospital, Linyi, Shandong, 276000, China
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Brockmueller A, Sajeev A, Koklesova L, Samuel SM, Kubatka P, Büsselberg D, Kunnumakkara AB, Shakibaei M. Resveratrol as sensitizer in colorectal cancer plasticity. Cancer Metastasis Rev 2024; 43:55-85. [PMID: 37507626 PMCID: PMC11016130 DOI: 10.1007/s10555-023-10126-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Lenka Koklesova
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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9
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Kumari S, Kumar S, Muthuswamy S. RNA N6-methyladenosine modification in regulating cancer stem cells and tumor immune microenvironment and its implication for cancer therapy. J Cancer Res Clin Oncol 2023; 149:1621-1633. [PMID: 35796777 DOI: 10.1007/s00432-022-04158-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/15/2022] [Indexed: 11/28/2022]
Abstract
Therapy resistance is a well-known phenomenon in cancer treatment. It can be intrinsic or acquired, accountable for frequent tumor relapse and death worldwide. The interplay between cancer cells and their neighboring environment can activate complex signaling mechanisms influencing epigenetic changes and maintain cancer cell survival leading to the malignant phenotype. Cancer stem cells (CSCs) are tumor-initiating cells (TICs) and constitute the primary source of drug resistance and tumor recurrence. Studies have shown that cancer cells exhibit dysregulated RNA N6-methyladenosine (m6A) "writers," "erasers," and "readers" levels after acquiring drug resistance. The present review provides novel insight into the role of m6A modifiers involved in CSC generation, cancer cell proliferation, and therapy resistance. m6A RNA modifications in the cross-talk between CSC and the tumor immune microenvironment (TIME) have also been highlighted. Further, we have discussed the therapeutic potential of targeting m6A machinery for cancer diagnosis and the development of new therapies for cancer treatment.
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Affiliation(s)
- Subhadra Kumari
- Department of Life Science, National Institute of Technology, Rourkela, India
| | - Santosh Kumar
- Department of Life Science, National Institute of Technology, Rourkela, India
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10
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Monieri M, Rainone P, Sacchi A, Gori A, Gasparri AM, Coliva A, Citro A, Ferrara B, Policardi M, Valtorta S, Pocaterra A, Alfano M, Sheppard D, Piemonti L, Moresco RM, Corti A, Curnis F. A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins. Int J Biol Sci 2023; 19:156-166. [PMID: 36594095 PMCID: PMC9760430 DOI: 10.7150/ijbs.76148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/15/2022] [Indexed: 11/24/2022] Open
Abstract
Rationale: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "5a"), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Methods: Peptide 5a was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with 18F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single - or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors. Results: In vitro studies showed that 5a can bind both integrins with high affinity and inhibits cell-mediated TGFβ activation. The 5a-IRDye and 5a-NOTA conjugates could bind purified αvβ6/αvβ8 integrins with no loss of affinity compared to free peptide, and selectively recognized various αvβ6/αvβ8 single- or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. In vivo static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence- and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing αvβ8-positive prostate tumors. Conclusions: The results indicate that 5a can home to αvβ6- and/or αvβ8-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to αvβ6/αvβ8 single- or double-positive tumors, or as a tumor-homing inhibitor of these TGFβ activators.
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Affiliation(s)
- Matteo Monieri
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Rainone
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelina Sacchi
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Gori
- Istituto di Scienze e Tecnologie Chimiche, C.N.R., Milan, Italy
| | - Anna Maria Gasparri
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Coliva
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Citro
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Benedetta Ferrara
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Policardi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Valtorta
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Institute of Molecular Bioimaging and Physiology of C.N.R., Segrate, Italy
| | - Arianna Pocaterra
- Division of Immunology Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Alfano
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Dean Sheppard
- Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Rosa Maria Moresco
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Institute of Molecular Bioimaging and Physiology of C.N.R., Segrate, Italy
| | - Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy.,✉ Corresponding authors: Angelo Corti (ORICD: 0000-0002-0893-6191) and Flavio Curnis (ORICD: 0000-0002-7231-9569), Division of Experimental Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy (Tel. +390226434802; E-mail: and )
| | - Flavio Curnis
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,✉ Corresponding authors: Angelo Corti (ORICD: 0000-0002-0893-6191) and Flavio Curnis (ORICD: 0000-0002-7231-9569), Division of Experimental Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy (Tel. +390226434802; E-mail: and )
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11
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Benesch MGK, Wu R, Menon G, Takabe K. High beta integrin expression is differentially associated with worsened pancreatic ductal adenocarcinoma outcomes. Am J Cancer Res 2022; 12:5403-5424. [PMID: 36628277 PMCID: PMC9827087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 11/27/2022] [Indexed: 01/12/2023] Open
Abstract
Outcomes in pancreatic ductal adenocarcinoma (PDAC) are known to be worse in tumors with high integrin β1 expression, but targeted monotherapy against this integrin has not been effective. Seven other beta integrins are expressed in mammalian biology and they are known to have overlapping and compensatory signaling in biological systems. However, their roles in PDAC are poorly understood and have not been systematically compared to integrin β1 biology. In this study, we analyzed the clinical outcomes against beta integrin 1-8 (ITGB1-8) expression in PDAC samples from two large independent cohorts, The Cancer Genome Atlas (TCGA) and GSE21501. Biological function and tumor microenvironment composition were studied using Gene Set Enrichment Analysis and xCell. Expression of all eight beta integrins is significantly increased in PDACs relative to normal pancreatic tissues (all P<0.001). ITGB1, 2, 5, and 6 have similarly enriched gene patterns related to transforming growth factor (TGF)-β, epithelial mesenchymal transition, inflammation, stemness, and angiogenesis pathways. Homologous recombination defects and neoantigens are increased in high-ITGB4, 5, and 6 tumors, with decreased overall survival in high-ITGB1, 5, and 6 tumors compared to low expression tumors (hazard ratios 1.5-2.0). High-ITGB1, 2, and 5 tumors have increased fibroblast infiltration (all P<0.01) while endothelial cells are increased in high-ITGB2 and 3 tumors (all P<0.05). Overall, beta integrin expression does not correlate to immune cell populations in PDACs. Therefore, while all beta integrins are overexpressed in PDACs, they exert differential effects on PDAC biology. ITGB2, 5, and 6 have a similar profile to ITGB1, suggesting that future research in PDAC integrin therapy needs to consider the complementary signaling profiles mediated by these integrins.
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Affiliation(s)
- Matthew GK Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA,Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Gopal Menon
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA,Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan,Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan,Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan,Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
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12
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Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment. Int J Mol Sci 2022; 23:ijms232012346. [PMID: 36293202 PMCID: PMC9603893 DOI: 10.3390/ijms232012346] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/20/2022] Open
Abstract
Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis. This review focuses on an arginine-glycine-aspartic acid (RGD)-dependent integrin αVβ6, its biology, and its role in healthy humans. We examine the implications of αVβ6 in cancer progression and the promotion of epithelial-mesenchymal transition (EMT) by contributing to the activation of transforming growth factor beta TGF-β. Although αvβ6 is crucial for proper function in healthy people, it has also been validated as a target for cancer treatment. This review briefly considers aspects of targeting αVβ6 in the clinic via different therapeutic modalities.
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13
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McGregor CGC, Tandon R, Simmons A. Pathogenesis of Fistulating Crohn's Disease: A Review. Cell Mol Gastroenterol Hepatol 2022; 15:1-11. [PMID: 36184031 PMCID: PMC9667304 DOI: 10.1016/j.jcmgh.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 12/10/2022]
Abstract
Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.
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Affiliation(s)
- Colleen Georgette Chantelle McGregor
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Ruchi Tandon
- Pathology, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Alison Simmons
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
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14
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Huynh TT, Sreekumar S, Mpoy C, Rogers BE. A comparison of 64Cu-labeled bi-terminally PEGylated A20FMDV2 peptides targeting integrin α νβ 6. Oncotarget 2022; 13:360-372. [PMID: 35186193 PMCID: PMC8849274 DOI: 10.18632/oncotarget.28197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/07/2022] [Indexed: 11/25/2022] Open
Abstract
Expression of epithelial-specific integrin ανβ6 is up-regulated in various aggressive cancers and serves as a prognostic marker. Integrin-targeted PET imaging probes have been successfully developed and tested in the clinic. Radiotracers based on the peptide A20FMDV2 derived from foot-and-mouth disease virus represent specific and selective PET ligands for imaging ανβ6-positive cancers. The present study aims to describe the radiolabeling, in vitro and in vivo evaluation of a bi-terminally PEGylated A20FMDV2 conjugated with DOTA or PCTA for 64Cu radiolabeling. Stability studies showed radiolabeled complexes remained stable up to 24 h in PBS and human serum. In vitro cell assays in CaSki cervical cancer cells and BxPC-3 pancreatic cancer cells confirmed that the peptides displayed high affinity for αvβ6 with Kd values of ~50 nM. Biodistribution studies revealed that [64Cu] Cu-PCTA-(PEG28)2-A20FMDV2 exhibited higher tumor uptake (1.63 ± 0.53 %ID/g in CaSki and 3.86 ± 0.58 %ID/g in BxPC-3 at 1 h) when compared to [64Cu]Cu-DOTA-(PEG28)2-A20FMDV2 (0.95 ± 0.29 %ID/g in CaSki and 2.12 ± 0.83 %ID/g in BxPC-3 at 1 h) . However, higher tumor uptake was accompanied by increased radioactive uptake in normal organs. Therefore, both peptides are appropriate for imaging ανβ6-positive lesions although further optimization is needed to improve tumor-to-normal-tissue ratios.
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Affiliation(s)
- Truc T Huynh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.,Department of Chemistry, Washington University, St. Louis, MO, USA
| | - Sreeja Sreekumar
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Cedric Mpoy
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Buck E Rogers
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
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15
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Abstract
Transforming growth factor-β (TGFβ) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFβ exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFβ controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFβ exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFβ to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFβ-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFβ pathway, many of which are currently in clinical evaluation.
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Affiliation(s)
- Daniele V F Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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16
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Tanabe S. Epithelial-Mesenchymal Transition and Cancer Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:1-49. [PMID: 36587300 DOI: 10.1007/978-3-031-12974-2_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Epithelial-mesenchymal transition (EMT), a cellular phenotypic change from epithelial to mesenchymal-like features, is related to the resistance and metastasis of cancer stem cells (CSCs). Several signal transduction mechanisms induce EMT, which causes the gene expression alteration to induce the acquisition of resistance and metastasis in cancer. EMT is characterized with high gene expression of cadherin 2 (N-cadherin) and vimentin, and sparse cell-cell junction. The cells with EMT-phenotype have migration, metastasis and drug-resistance capacity, which are main characteristics of CSCs. It seems that the main population of CSCs exhibits EMT phenotype, whereas some populations consist of phenotypes other than EMT. In this chapter, EMT mechanism, phenotypic features of EMT and CSCs, signal transduction in EMT and CSCs, differences between EMT and CSCs, and the role of EMT in CSCs are described.
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Affiliation(s)
- Shihori Tanabe
- Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, 210-9501, Japan.
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17
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Structural Biology of the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1350:91-100. [PMID: 34888845 DOI: 10.1007/978-3-030-83282-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancers can be described as "rogue organs" (Balkwill FR, Capasso M, Hagemann T, J Cell Sci 125:5591-5596, 2012) because they are composed of multiple cell types and tissues. The transformed cells can recruit and alter healthy cells from surrounding tissues for their own benefit. It is these interactions that create the tumor microenvironment (TME). The TME describes the cells, factors, and extracellular matrix proteins that make up the tumor and the area around it; the biology of the TME influences tumor progression. Changes in the TME can lead to the growth and development of the tumor, the death of the tumor, or tumor metastasis. Metastasis is the process by which cancer spreads from its initial site to a different part of the body. Metastasis occurs when cancer cells enter the circulatory system or lymphatic system after they break away from a tumor. Once the cells leave, they can travel to a different part of the body and form new tumors. Therefore, understanding the TME is critical to fully understand cancer and find a way to successfully combat it. Knowledge of the TME can better inform researchers of the ability of potential therapies to reach tumor cells. It can also give researchers potential targets to kill the tumor. Instead of directly killing the cancer cells, therapies can target an aspect of the TME which could then halt tumor development or lead to tumor death. In other cases, targeting another aspect of the TME could make it easier for another therapy to kill the cancer cells, for example, using nanoparticles with collagenases to target the collagen in the surrounding environment to expose the cancer cells to drugs (Zinger A, et al, ACS Nano 13(10):11008-11021, 2019).The TME can be split simply into cells and the structural matrix. Within these groups are fibroblasts, structural proteins, immune cells, lymphocytes, bone marrow-derived inflammatory cells, blood vessels, and signaling molecules (Spill F, et al, Curr Opin Biotechnol 40:41-48, 2016; Del Prete A, et al, Curr Opin Pharmacol 35:40-47, 2017; Arneth B, Medicina (Kaunas) 56(1), 2019). From structure to providing nutrients for growth, each of these components plays a critical role in tumor maintenance. Together these components impact cancer growth, development, and resistance to therapies (Hanahan D, Coussens LM, Cancer Cell 21:309-322, 2012). In this chapter, we will describe the TME and express the importance of the cellular and structural elements of the TME.
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18
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Hou S, Wang J, Li W, Hao X, Hang Q. Roles of Integrins in Gastrointestinal Cancer Metastasis. Front Mol Biosci 2021; 8:708779. [PMID: 34869579 PMCID: PMC8634653 DOI: 10.3389/fmolb.2021.708779] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Integrins are a large family of heterodimeric transmembrane receptors which mediate cell adhesion and transmit signals to the cell interior. The mechanistic roles of integrins have long been an enigma in cancer, given its complexity in regulating different cellular behaviors. Recently, however, increasing research is providing new insights into its function and the underlying mechanisms, which collectively include the influences of altered integrin expression on the aberrant signaling pathways and cancer progression. Many studies have also demonstrated the potentiality of integrins as therapeutic targets in cancer treatment. In this review, we have summarized these recent reports and put a particular emphasis on the dysregulated expression of integrins and how they regulate related signaling pathways to facilitate the metastatic progression of gastrointestinal cancer, including gastric cancer (GC) and colorectal cancer (CRC), which will address the crucial roles of integrins in gastrointestinal cancer.
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Affiliation(s)
- Sicong Hou
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jiaxin Wang
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Wenqian Li
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Xin Hao
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Qinglei Hang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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19
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Kossatz S, Beer AJ, Notni J. It's Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals. Cancers (Basel) 2021; 13:cancers13235958. [PMID: 34885066 PMCID: PMC8657165 DOI: 10.3390/cancers13235958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Cancer cells often present a different set of proteins on their surface than normal cells. This also applies to integrins, a class of 24 cell surface receptors which mainly are responsible for physically anchoring cells in tissues, but also fulfil a plethora of other functions. If a certain integrin is found on tumor cells but not on normal ones, radioactive molecules (named tracers) that specifically bind to this integrin will accumulate in the cancer lesion if injected into the blood stream. The emitted radiation can be detected from outside the body and allows for localization and thus, diagnosis, of cancer. Only one of the 24 integrins, the subtype αvβ3, has hitherto been thoroughly investigated in this context. We herein summarize the most recent, pertinent research on other integrins, and argue that some of these approaches might ultimately improve the clinical management of the most lethal cancers, such as pancreatic carcinoma. Abstract For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvβ3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvβ3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.
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Affiliation(s)
- Susanne Kossatz
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
- Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | | | - Johannes Notni
- Department of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- TRIMT GmbH, 01454 Radeberg, Germany
- Correspondence: ; Tel.: +49-89-4140-6075; Fax: +49-89-4140-6949
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20
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Xiong J, Yan L, Zou C, Wang K, Chen M, Xu B, Zhou Z, Zhang D. Integrins regulate stemness in solid tumor: an emerging therapeutic target. J Hematol Oncol 2021; 14:177. [PMID: 34715893 PMCID: PMC8555177 DOI: 10.1186/s13045-021-01192-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023] Open
Abstract
Integrins are the adhesion molecules and transmembrane receptors that consist of α and β subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.
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Affiliation(s)
- Jiangling Xiong
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Lianlian Yan
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Cheng Zou
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Kai Wang
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Mengjie Chen
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Bin Xu
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Zhipeng Zhou
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, China.
| | - Dingxiao Zhang
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China. .,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China.
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21
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Greco L, Rubbino F, Morelli A, Gaiani F, Grizzi F, de’Angelis GL, Malesci A, Laghi L. Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers. Int J Mol Sci 2021; 22:11469. [PMID: 34768901 PMCID: PMC8584071 DOI: 10.3390/ijms222111469] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Alessandra Morelli
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Fabio Grizzi
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
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22
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Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov 2021; 21:60-78. [PMID: 34535788 PMCID: PMC8446727 DOI: 10.1038/s41573-021-00284-4] [Citation(s) in RCA: 310] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins. Integrins are key signalling molecules that are present on the surface of subsets of cells and are therefore good potential therapeutic targets. In this Review, Hatley and colleagues discuss the development of integrin inhibitors, particularly the challenges in developing inhibitors for integrins that contain an αv-subunit, and suggest how these challenges could be addressed.
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Affiliation(s)
| | | | | | - R G Jenkins
- National Heart and Lung Institute, Imperial College London, London, UK
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23
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Wang B, Wang S, Wang W, Liu E, Guo S, Zhao C, Niu J, Zhang Z. Hyperglycemia Promotes Liver Metastasis of Colorectal Cancer via Upregulation of Integrin αvβ6. Med Sci Monit 2021; 27:e930921. [PMID: 34408123 PMCID: PMC8383819 DOI: 10.12659/msm.930921] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Diabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC. Material/Methods Overall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of αvβ6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on αvβ6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and β6 expression was detected by western blot in a liver metastasis mouse model. Results CRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher αvβ6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of αvβ6. Hyperglycemia upregulated the expression of β6 and cell surface expression of αvβ6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model. Conclusions Our study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that αvβ6 was involved in this process, suggesting that control of glucose levels and inhibition of αvβ6 can reduce the risk of liver metastasis in diabetic CRC patients.
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Affiliation(s)
- Ben Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Shanjie Wang
- Department of General Surgery, People's Hospital, Zhangqiu District, Jinan, Shandong, China (mainland)
| | - Wenke Wang
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (mainland)
| | - Enyu Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Sen Guo
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Chuanzong Zhao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Jun Niu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
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24
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Kemper M, Schiecke A, Maar H, Nikulin S, Poloznikov A, Galatenko V, Tachezy M, Gebauer F, Lange T, Riecken K, Tonevitsky A, Aigner A, Izbicki J, Schumacher U, Wicklein D. Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:214. [PMID: 34174926 PMCID: PMC8235815 DOI: 10.1186/s13046-021-01946-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/13/2021] [Indexed: 01/10/2023]
Abstract
Background Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis. Methods Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated. Results The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients. Conclusion Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01946-2.
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Affiliation(s)
- Marius Kemper
- Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. .,Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Alina Schiecke
- Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hanna Maar
- Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sergey Nikulin
- Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Andrey Poloznikov
- Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Vladimir Galatenko
- Faculty of Mechanics and Mathematics, Lomonosov Moscow State University, Moscow, Russia
| | - Michael Tachezy
- Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Florian Gebauer
- Department of General, Visceral and Tumor Surgery, University Hospital Cologne, Köln, Germany
| | - Tobias Lange
- Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, Higher School of Economics University, Moscow, Russia
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Medical Faculty, University of Leipzig, Leipzig, Germany
| | - Jakob Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Wicklein
- Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
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25
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Sachindra S, Hellberg T, Exner S, Prasad S, Beindorff N, Rogalla S, Kimura R, Gambhir SS, Wiedenmann B, Grötzinger C. SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model. Front Oncol 2021; 11:684713. [PMID: 34136410 PMCID: PMC8200818 DOI: 10.3389/fonc.2021.684713] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/10/2021] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide 177Lu for targeting of PDAC. METHODS The expression of integrin αvβ6 in PDAC cell lines BxPC-3 and Capan-2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC-3 and Capan-2 cell lines as well as the maximum number of binding sites in these cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan-2 xenograft tumor mouse model. RESULTS RT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC-3 and Capan-2 cells. A competition binding assay revealed high affinity of the tracer with IC50 values of 1.69 nM and 9.46 nM for BxPC-3 and Capan-2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan-2 xenograft tumors (3.13 ± 0.63%IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors. CONCLUSION 177Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy.
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Affiliation(s)
- Sachindra Sachindra
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Teresa Hellberg
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Samantha Exner
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Sonal Prasad
- Berlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nicola Beindorff
- Berlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Stephan Rogalla
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Richard Kimura
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Sanjiv Sam Gambhir
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Molecular Cancer Research Center (MKFZ), Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
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Zheng X, Zhu Y, Wang X, Hou Y, Fang Y. Silencing of ITGB6 inhibits the progression of cervical carcinoma via regulating JAK/STAT3 signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:803. [PMID: 34268416 PMCID: PMC8246156 DOI: 10.21037/atm-21-1669] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/29/2021] [Indexed: 12/03/2022]
Abstract
Background Integrin β6 (ITGB6), a key submonomer of integrin αvβ6, plays an important role in epithelial-to-mesenchymal transition (EMT), wound healing, epithelial-derived tumor growth, fibrosis, and epithelial repair. However, the role of ITGB6 in cervical carcinoma (CC) remains elusive. Methods The expression levels of ITGB6 in CC tissues and cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony-forming, flow cytometry, and Transwell assay, respectively. The expression of related proteins, including EMT markers and the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling markers, were detected using western blotting. Results The ITGB6 expression in CC tissues and cells (C-33A, Hela, SiHa, and Caski) was remarkably higher than that in paracarcinoma tissues and ECT1/E6E7 cells. The data from The Cancer Genome Atlas (TCGA) data set suggested that patients with CC with high ITGB6 expression showed poorer overall survival (OS). Compared with the empty transfection group (si-NC), si-ITGB6 restrained the proliferation, migration, and invasion of SiHa and Hela cells, while promoting cell apoptosis. si-ITGB6 suppression decreased the expression of Snail, vimentin, and N-cadherin, while increasing E-cadherin expression. Further research showed that si-ITGB6 reduced p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 expression in the JAK/STAT3 signaling pathway. Interestingly, proliferation, migration, invasion, and the expressions of the molecular markers of the JAK/STAT3 signaling pathway and EMT pathway induced by ITGB6 were altered by RO8191 (JAK/STAT3 pathway activator). Furthermore, the protein expression levels of Snail, vimentin, N-cadherin, p-STAT3/STAT3, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues were higher than those in adjacent normal tissue, while the expression level of E-cadherin was downregulated in tumor tissues. Conclusions Silencing of ITGB6 restrains cell proliferation, migration and invasion, and promotes apoptosis in CC by inhibiting JAK/STAT signaling pathways. Thus, ITGB6 may perhaps be a new and useful candidate target for treating CC.
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Affiliation(s)
- Xiaoxia Zheng
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yanan Zhu
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Xiaoping Wang
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yanmei Hou
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yingji Fang
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
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Albacete-Albacete L, Sánchez-Álvarez M, Del Pozo MA. Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C. Front Immunol 2021; 12:671485. [PMID: 33981316 PMCID: PMC8107694 DOI: 10.3389/fimmu.2021.671485] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022] Open
Abstract
ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.
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Affiliation(s)
- Lucas Albacete-Albacete
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Angel Del Pozo
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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28
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Zhong C, Li ZX, Yang LJ, Wu G, Xiang B, Wang YL, Zhou Q. ITGB6 may promote proliferation and invasion in pancreatic cancer. Arch Med Sci 2021; 20:267-279. [PMID: 38414469 PMCID: PMC10895961 DOI: 10.5114/aoms/114039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/06/2019] [Indexed: 02/29/2024] Open
Abstract
Introduction The ITGB6 gene encoding a protein that can regulate the integrin αvβ6 heterodimer protein expression in different status was shown to play an important role in multiple human cancers, such as brain cancer, colon cancer and oral cancer, and is related to clinical progression. This study aims to explore the function and the mechanism of the ITGB6 gene or protein in pancreatic cancer. Material and methods We examined the expression of ITGB6 in pancreatic cancer using immunohistochemistry and analyzed the relationship between the expression of ITGB6 and the clinicopathologic features in pancreatic cancer patients. In addition, a bioinformatic method was used to analyze the ITGB6 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the correlation between high KIF23 expression and prognosis in pancreatic cancer patients. Moreover, colony formation assay, MTT assay, cell scratch, cell invasion and western blot assays in vitro and a xenograft mouse model in vivo were performed to analyze the effect of KIF23 on proliferation and invasion of pancreatic cancer cells. Results Increased expression of ITGB6 was significantly correlated with poor clinical outcome in both our clinical data and TCGA data of pancreatic cancer. Furthermore, functional assays revealed that ITGB6 knockdown in vivo and in vitro might inhibit cancer cell proliferation and the ability of invasion or migration. Conclusions Our data suggest that ITGB6 is associated with pancreatic cancer malignant progression. Hence, ITGB6 may serve as a potential target of pancreatic cancer for future research, and further study is needed.
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Affiliation(s)
- Chao Zhong
- Department of Traditional Chinese Medicine of Orthopedic and Traumatic, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Zhi-Xi Li
- Department of Respiratory Medicine, East Hospital, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Ling-Jing Yang
- Department of Respiratory Medicine, East Hospital, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Gang Wu
- Department of Hepatobiliary Surgery, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Bo Xiang
- Department of Cardiosurgery, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Yu-Lan Wang
- Department of Oncology, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Qing Zhou
- Department of Ultrasound, Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
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29
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Linders D, Deken M, van der Valk M, Tummers W, Bhairosingh S, Schaap D, van Lijnschoten G, Zonoobi E, Kuppen P, van de Velde C, Vahrmeijer A, Farina Sarasqueta A, Sier C, Hilling D. CEA, EpCAM, αvβ6 and uPAR Expression in Rectal Cancer Patients with a Pathological Complete Response after Neoadjuvant Therapy. Diagnostics (Basel) 2021; 11:diagnostics11030516. [PMID: 33799475 PMCID: PMC8002064 DOI: 10.3390/diagnostics11030516] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/07/2021] [Accepted: 03/11/2021] [Indexed: 01/19/2023] Open
Abstract
Rectal cancer patients with a complete response after neoadjuvant therapy can be monitored with a watch-and-wait strategy. However, regrowth rates indicate that identification of patients with a pathological complete response (pCR) remains challenging. Targeted near-infrared fluorescence endoscopy is a potential tool to improve response evaluation. Promising tumor targets include carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), integrin αvβ6, and urokinase-type plasminogen activator receptor (uPAR). To investigate the applicability of these targets, we analyzed protein expression by immunohistochemistry and quantified these by a total immunostaining score (TIS) in tissue of rectal cancer patients with a pCR. CEA, EpCAM, αvβ6, and uPAR expression in the diagnostic biopsy was high (TIS > 6) in, respectively, 100%, 100%, 33%, and 46% of cases. CEA and EpCAM expressions were significantly higher in the diagnostic biopsy compared with the corresponding tumor bed (p < 0.01). CEA, EpCAM, αvβ6, and uPAR expressions were low (TIS < 6) in the tumor bed in, respectively, 93%, 95%, 85%, and 62.5% of cases. Immunohistochemical evaluation shows that CEA and EpCAM could be suitable targets for response evaluation after neoadjuvant treatment, since expression of these targets in the primary tumor bed is low compared with the diagnostic biopsy and adjacent pre-existent rectal mucosa in more than 90% of patients with a pCR.
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Affiliation(s)
- Daan Linders
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Marion Deken
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Maxime van der Valk
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Willemieke Tummers
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Shadhvi Bhairosingh
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Dennis Schaap
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands;
| | - Gesina van Lijnschoten
- Laboratory of Pathology, Stichting Pathology and Medical Microbiology, 5623 EJ Eindhoven, The Netherlands;
| | - Elham Zonoobi
- Edinburgh Molecular Imaging Ltd., Edinburgh EH16 4UX, UK;
| | - Peter Kuppen
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Cornelis van de Velde
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | - Alexander Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
| | | | - Cornelis Sier
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
- Percuros BV, 2333 CL Leiden, The Netherlands
| | - Denise Hilling
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.L.); (M.D.); (M.v.d.V.); (W.T.); (S.B.); (P.K.); (C.v.d.V.); (A.V.); (C.S.)
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- Correspondence: ; Tel.: +31-71-526-2377
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30
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Desnoyers A, González C, Pérez-Segura P, Pandiella A, Amir E, Ocaña A. Integrin ανβ6 Protein Expression and Prognosis in Solid Tumors: A Meta-Analysis. Mol Diagn Ther 2021; 24:143-151. [PMID: 32100239 DOI: 10.1007/s40291-020-00450-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND OBJECTIVE Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ανβ6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ανβ6 integrin protein expression in solid tumors. METHODS A systematic search of electronic databases identified publications exploring the effect of ανβ6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ανβ6 integrins on OS. RESULTS Seventeen studies comprising 5795 patients met the inclusion criteria. High ανβ6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran's Q p < 0.001, I2 = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ανβ6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods. CONCLUSIONS High expression of ανβ6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ανβ6 integrin and its role as a therapeutic target are warranted.
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Affiliation(s)
- Alexandra Desnoyers
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada
| | - Carlos González
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada.,Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,CIC-Universidad de Salamanca, Salamanca, Spain.,Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (UCLM), Albacete, Spain
| | - Pedro Pérez-Segura
- Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Atanasio Pandiella
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,CIC-Universidad de Salamanca, Salamanca, Spain
| | - Eitan Amir
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada
| | - Alberto Ocaña
- Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain. .,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain. .,Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (UCLM), Albacete, Spain.
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31
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Cardle II, Jensen MC, Pun SH, Sellers DL. Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting. J Biol Chem 2021; 296:100657. [PMID: 33857478 PMCID: PMC8138772 DOI: 10.1016/j.jbc.2021.100657] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/03/2022] Open
Abstract
The integrin αvβ6 is an antigen expressed at low levels in healthy tissue but upregulated during tumorigenesis, which makes it a promising target for cancer imaging and therapy. A20FMDV2 is a 20-mer peptide derived from the foot-and-mouth disease virus that exhibits nanomolar and selective affinity for αvβ6 versus other integrins. Despite this selectivity, A20FMDV2 has had limited success in imaging and treating αvβ6+ tumors in vivo because of its poor serum stability. Here, we explore the cyclization and modification of the A20FMDV2 peptide to improve its serum stability without sacrificing its affinity and specificity for αvβ6. Using cysteine amino acid substitutions and cyclization by perfluoroarylation with decafluorobiphenyl, we synthesized six cyclized A20FMDV2 variants and discovered that two retained binding to αvβ6 with modestly improved serum stability. Further d-amino acid substitutions and C-terminal sequence optimization outside the cyclized region greatly prolonged peptide serum stability without reducing binding affinity. While the cyclized A20FMDV2 variants exhibited increased nonspecific integrin binding compared with the original peptide, additional modifications with the non-natural amino acids citrulline, hydroxyproline, and d-alanine were found to restore binding specificity, with some modifications leading to greater αvβ6 integrin selectivity than the original A20FMDV2 peptide. The peptide modifications detailed herein greatly improve the potential of utilizing A20FMDV2 to target αvβ6 in vivo, expanding opportunities for cancer targeting and therapy.
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Affiliation(s)
- Ian I Cardle
- Department of Bioengineering, University of Washington, Seattle, Washington, USA; Seattle Children's Therapeutics, Seattle, Washington, USA
| | - Michael C Jensen
- Department of Bioengineering, University of Washington, Seattle, Washington, USA; Seattle Children's Therapeutics, Seattle, Washington, USA; Department of Pediatrics, University of Washington, Seattle, Washington, USA; Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Suzie H Pun
- Department of Bioengineering, University of Washington, Seattle, Washington, USA
| | - Drew L Sellers
- Department of Bioengineering, University of Washington, Seattle, Washington, USA.
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32
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Meecham A, Marshall JF. The ITGB6 gene: its role in experimental and clinical biology. Gene 2020; 763S:100023. [PMID: 34493369 PMCID: PMC7285966 DOI: 10.1016/j.gene.2019.100023] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023]
Abstract
Integrin αvβ6 is a membrane-spanning heterodimeric glycoprotein involved in wound healing and the pathogenesis of diseases including fibrosis and cancer. Therefore, it is of great clinical interest for us to understand the molecular mechanisms of its biology. As the limiting binding partner in the heterodimer, the β6 subunit controls αvβ6 expression and availability. Here we describe our understanding of the ITGB6 gene encoding the β6 subunit, including its structure, transcriptional and post-transcriptional regulation, the biological effects observed in ITGB6 deficient mice and clinical cases of ITGB6 mutations.
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Affiliation(s)
- Amelia Meecham
- Centre for Tumour Biology, Barts Cancer Institute, Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
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33
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Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Cell Invasion through Integrin β6 Upregulation in Colorectal Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8032187. [PMID: 32855767 PMCID: PMC7443035 DOI: 10.1155/2020/8032187] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/05/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022]
Abstract
The metastatic potential of colorectal cancer (CRC) is intensively promoted by the tumor microenvironment (TME) in a paracrine manner. As a pleiotropic inflammatory cytokine, Interleukin-6 (IL-6) is produced and involved in CRC, the same scenario where integrin αvβ6 also becomes upregulated. However, the relationship between IL-6 and integrin αvβ6 as well as their involvement in the crosstalk between CRC and TME remains largely unclear. In the present study, we demonstrated a positive correlation between the expression of IL-6 and integrin β6 in CRC samples. The mutually promotive interaction between CRC and TME was further determined by an indirect coculture system. CRC cells could augment the secretion of IL-6 from fibroblasts, which in return induced invasion and integrin β6 expression of CRC cells. Through the classic IL-6 receptor/STAT-3 signaling pathway, IL-6 mediated the upregulation of integrin β6, which was involved in the invasion and epithelial-mesenchymal transition of CRC cells induced by IL-6. Taken together, our results reveal a paracrine crosstalk between IL-6 signals originating from the TME and increased the integrin β6 level of CRC. IL-6 induces CRC invasion via upregulation of integrin β6 through the IL-6 receptor/STAT-3 signaling pathway. Combined inhibition of IL-6 along with integrin β6-targeted strategy may indicate new directions for antitumor strategies for CRC.
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Krishn SR, Salem I, Quaglia F, Naranjo NM, Agarwal E, Liu Q, Sarker S, Kopenhaver J, McCue PA, Weinreb PH, Violette SM, Altieri DC, Languino LR. The αvβ6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis. J Extracell Vesicles 2020; 9:1763594. [PMID: 32595914 PMCID: PMC7301698 DOI: 10.1080/20013078.2020.1763594] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 03/26/2020] [Accepted: 04/18/2020] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer (PrCa) cells crosstalk with the tumour microenvironment by releasing small extracellular vesicles (sEVs). sEVs, as well as large extracellular vesicles (LEVs), isolated via iodixanol density gradients from PrCa cell culture media, express the epithelial-specific αvβ6 integrin, which is known to be induced in cancer. In this study, we show sEV-mediated protein transfer of αvβ6 integrin to microvascular endothelial cells (human microvascular endothelial cells 1 - HMEC1) and demonstrate that de novo αvβ6 integrin expression is not caused by increased mRNA levels. Incubation of HMEC1 with sEVs isolated from PrCa PC3 cells that express the αvβ6 integrin results in a highly significant increase in the number of nodes, junctions and tubules. In contrast, incubation of HMEC1 with sEVs isolated from β6 negative PC3 cells, generated by shRNA against β6, results in a reduction in the number of nodes, junctions and tubules, a decrease in survivin levels and an increase in a negative regulator of angiogenesis, pSTAT1. Furthermore, treatment of HMEC1 with sEVs generated by CRISPR/Cas9-mediated down-regulation of β6, causes up-regulation of pSTAT1. Overall, our findings suggest that αvβ6 integrin in cancer sEVs regulates angiogenesis during PrCa progression.
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Affiliation(s)
- Shiv Ram Krishn
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Israa Salem
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Fabio Quaglia
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Nicole M Naranjo
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Ekta Agarwal
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, USA.,Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, USA
| | - Qin Liu
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, USA
| | - Srawasti Sarker
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Jessica Kopenhaver
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Peter A McCue
- Department of Pathology, Thomas Jefferson University, Philadelphia, USA
| | | | | | - Dario C Altieri
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, USA.,Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, USA
| | - Lucia R Languino
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, USA.,Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
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Niu W, Bo QY, Niu J, Niu ZC, Peng C, Zou XQ, Zhang ZY. Identification of integrin β6 gene promoter and analysis of its transcription regulation in colon cancer cells. World J Gastrointest Oncol 2020; 12:526-534. [PMID: 32461784 PMCID: PMC7235184 DOI: 10.4251/wjgo.v12.i5.526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/29/2020] [Accepted: 04/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The integrin β6 gene, which is expressed in epithelial cancer, plays a pivotal role in various aspects of cancer progression. The present research for integrin β6 regulation mainly focuses on the post-transcription and translation related regulation mechanism and its role in tumorigenesis. The mechanisms of how the integrin β6 gene is regulated transcriptionally, and the promoter and transcription factors responsible for basic transcription of integrin β6 gene remain unknown.
AIM To clone and characterize the integrin β6 promoter.
METHODS Software analysis was used to predict the region of integrin β6 promoter. Luciferase reporter plasmids, which contained the integrin β6 promoter, were constructed. Element deletion analysis was performed to identify the location of core promoter and binding sites for transcription factors.
RESULTS The regulatory elements for the transcription of the integrin β6 gene were located between -286 and -85 and contained binding sites for transcription factors such as STAT3 and Ets-1.
CONCLUSION For the first time, we found the region of β6 core promoter and demonstrated the binding sites for transcription factors such as Ets-1 and STAT3, which are important for integrin β6 promoter transcription activity. These findings are important for investigating the mechanism of integrin β6 activation in cancer progression.
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Affiliation(s)
- Wei Niu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Qi-Yu Bo
- Department of Nursing, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Zheng-Chuan Niu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Cheng Peng
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Xue-Qing Zou
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Zhao-Yang Zhang
- Department of Emergency Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
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Azizi M, Dianat-Moghadam H, Salehi R, Farshbaf M, Iyengar D, Sau S, Iyer AK, Valizadeh H, Mehrmohammadi M, Hamblin MR. Interactions Between Tumor Biology and Targeted Nanoplatforms for Imaging Applications. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1910402. [PMID: 34093104 PMCID: PMC8174103 DOI: 10.1002/adfm.201910402] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Indexed: 05/04/2023]
Abstract
Although considerable efforts have been conducted to diagnose, improve, and treat cancer in the past few decades, existing therapeutic options are insufficient, as mortality and morbidity rates remain high. Perhaps the best hope for substantial improvement lies in early detection. Recent advances in nanotechnology are expected to increase the current understanding of tumor biology, and will allow nanomaterials to be used for targeting and imaging both in vitro and in vivo experimental models. Owing to their intrinsic physicochemical characteristics, nanostructures (NSs) are valuable tools that have received much attention in nanoimaging. Consequently, rationally designed NSs have been successfully employed in cancer imaging for targeting cancer-specific or cancer-associated molecules and pathways. This review categorizes imaging and targeting approaches according to cancer type, and also highlights some new safe approaches involving membrane-coated nanoparticles, tumor cell-derived extracellular vesicles, circulating tumor cells, cell-free DNAs, and cancer stem cells in the hope of developing more precise targeting and multifunctional nanotechnology-based imaging probes in the future.
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Affiliation(s)
- Mehdi Azizi
- Proteomics Research Centre, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Hassan Dianat-Moghadam
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz 5165665621, Iran
| | - Roya Salehi
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Street, Tabriz 516615731, Iran
| | - Masoud Farshbaf
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 6581151656, Iran
| | - Disha Iyengar
- U-BiND Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Samaresh Sau
- U-BiND Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Arun K Iyer
- U-BiND Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Hadi Valizadeh
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Street, Tabriz 516615731, Iran
| | | | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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Moore KM, Desai A, Delgado BDL, Trabulo SMD, Reader C, Brown NF, Murray ER, Brentnall A, Howard P, Masterson L, Zammarchi F, Hartley JA, van Berkel PH, Marshall JF. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics 2020; 10:2930-2942. [PMID: 32194845 PMCID: PMC7053198 DOI: 10.7150/thno.38702] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm3) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.
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Affiliation(s)
- Kate M. Moore
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Ami Desai
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Bea de Luxán Delgado
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Sara Maria David Trabulo
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Claire Reader
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Nicholas F. Brown
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Elizabeth R. Murray
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Adam Brentnall
- Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventative Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Philip Howard
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Luke Masterson
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Francesca Zammarchi
- ADC Therapeutics (UK) Ltd, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - John A. Hartley
- Cancer Research UK Drug-DNA Interactions Research Group, University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, U.K
| | | | - John F. Marshall
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Ong MS, Deng S, Halim CE, Cai W, Tan TZ, Huang RYJ, Sethi G, Hooi SC, Kumar AP, Yap CT. Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective. Cancers (Basel) 2020; 12:cancers12010238. [PMID: 31963677 PMCID: PMC7017214 DOI: 10.3390/cancers12010238] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 12/20/2022] Open
Abstract
Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression.
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Affiliation(s)
- Mei Shan Ong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (M.S.O.); (S.D.); (C.E.H.)
| | - Shuo Deng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (M.S.O.); (S.D.); (C.E.H.)
| | - Clarissa Esmeralda Halim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (M.S.O.); (S.D.); (C.E.H.)
| | - Wanpei Cai
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore (T.Z.T.); (R.Y.-J.H.)
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore (T.Z.T.); (R.Y.-J.H.)
| | - Ruby Yun-Ju Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore (T.Z.T.); (R.Y.-J.H.)
- School of Medicine, College of Medicine, National Taiwan University, No. 1 Ren Ai Road Sec. 1, Taipei City 10617, Taiwan
- Department of Obstetrics and Gynaecology, National University Hospital, National University Health System, Singapore 119074, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- Medical Science Cluster, Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
| | - Shing Chuan Hooi
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (M.S.O.); (S.D.); (C.E.H.)
- Medical Science Cluster, Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Correspondence: (S.C.H.); (A.P.K.); (C.T.Y.); Tel.: +65-6516-3294 (S.C.H. & C.T.Y.); +65-6873-5456 (A.P.K.); Fax: +65-6778-8161 (S.C.H. & C.T.Y.); +65-6873-9664 (A.P.K.)
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore (T.Z.T.); (R.Y.-J.H.)
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- Medical Science Cluster, Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
- Correspondence: (S.C.H.); (A.P.K.); (C.T.Y.); Tel.: +65-6516-3294 (S.C.H. & C.T.Y.); +65-6873-5456 (A.P.K.); Fax: +65-6778-8161 (S.C.H. & C.T.Y.); +65-6873-9664 (A.P.K.)
| | - Celestial T. Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (M.S.O.); (S.D.); (C.E.H.)
- Medical Science Cluster, Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
- Correspondence: (S.C.H.); (A.P.K.); (C.T.Y.); Tel.: +65-6516-3294 (S.C.H. & C.T.Y.); +65-6873-5456 (A.P.K.); Fax: +65-6778-8161 (S.C.H. & C.T.Y.); +65-6873-9664 (A.P.K.)
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Onega M, Parker CA, Coello C, Rizzo G, Keat N, Ramada-Magalhaes J, Moz S, Tang SP, Plisson C, Wells L, Ashworth S, Slack RJ, Vitulli G, Wilson FJ, Gunn R, Lukey PT, Passchier J. Preclinical evaluation of [ 18F]FB-A20FMDV2 as a selective marker for measuring α Vβ 6 integrin occupancy using positron emission tomography in rodent lung. Eur J Nucl Med Mol Imaging 2020; 47:958-966. [PMID: 31897589 PMCID: PMC7075836 DOI: 10.1007/s00259-019-04653-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/09/2019] [Indexed: 11/18/2022]
Abstract
Purpose Integrin αvβ6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvβ6 in rodent lung to support human translational studies. Methods The synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvβ6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software. Results [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30–60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 μSv/MBq. Conclusion [18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvβ6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies. Electronic supplementary material The online version of this article (10.1007/s00259-019-04653-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mayca Onega
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Christine A Parker
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK
| | - Christopher Coello
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Gaia Rizzo
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Nicholas Keat
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Joaquim Ramada-Magalhaes
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Sara Moz
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Sac-Pham Tang
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Christophe Plisson
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Lisa Wells
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Sharon Ashworth
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Robert J Slack
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK
| | - Giovanni Vitulli
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK
| | - Frederick J Wilson
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK
| | - Roger Gunn
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Pauline T Lukey
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK
| | - Jan Passchier
- Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
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Ma X, Liang AL, Liu YJ. Research progress on the relationship between lung cancer drug-resistance and microRNAs. J Cancer 2019; 10:6865-6875. [PMID: 31839821 PMCID: PMC6909942 DOI: 10.7150/jca.31952] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 09/13/2019] [Indexed: 02/07/2023] Open
Abstract
Lung cancer, a malignant tumor with the highest death rate of cancer, seriously endangers human health. And its pathogenesis and mechanism of drug resistance has been partially clarified, especially for the signal pathway of epidermal growth factor receptor (EGFR). The targeting therapy of EGFR signaling pathway in non-small cell lung cancer (NSCLC) has achieved a certain effect, but the two mutation of EGFR and other mechanisms of lung cancer resistance still greatly reduce the therapeutic effect of chemotherapy on it. MicroRNA is an endogenous non coding RNA, which has a regulatory function after transcriptional level. Recent studies on the mechanism of lung cancer resistance have found that a variety of microRNAs are related to the mechanism of lung cancer drug-resistance. They can regulate lung cancer resistance by participating in signal pathways, drug resistance genes and cell apoptosis, thus affecting the sensitivity of cancer cells to drugs. Therefore, microRNAs can be used as a specific target for the treatment of lung cancer and plays a vital role in the early diagnosis, prognosis and treatment of lung cancer. This article reviews the mechanisms of lung cancer resistance and its relationship with microRNAs.
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Affiliation(s)
| | | | - Yong-Jun Liu
- Medical Molecular Diagnostics Key Laboratory of Guangdong & Departments of Biochemistry and Molecular Biology & Departments of Clinical Biochemistry, Guangdong Medical University, 523808, Dongguan, Guangdong, P.R. China
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Evaluation of integrin αvβ 6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. Nat Commun 2019; 10:4673. [PMID: 31611594 PMCID: PMC6791878 DOI: 10.1038/s41467-019-11863-w] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 08/06/2019] [Indexed: 12/13/2022] Open
Abstract
Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6. Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.
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Systemic delivery and SPECT/CT in vivo imaging of 125I-labelled oncolytic adenoviral mutants in models of pancreatic cancer. Sci Rep 2019; 9:12840. [PMID: 31492884 PMCID: PMC6731255 DOI: 10.1038/s41598-019-49150-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/19/2019] [Indexed: 12/20/2022] Open
Abstract
Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites. Here, we developed a protocol to directly radiolabel the virus for rapid and sensitive detection by single-photon emitted computed tomography (SPECT/CT) providing a convenient method for determining biodistribution following intravenous administration in murine models. Longitudinal whole-body scans, demonstrated efficient viral uptake in pancreatic Suit-2 and Panc04.03 xenografts with trace amounts of 125I-Ad-3∆-A20T up to 48 h after tail vein delivery. Hepatic and splenic radioactivity decreased over time. Analysis of tissues harvested at the end of the study, confirmed potency and selectivity of mutant viruses. Ad-3∆-A20T-treated animals showed higher viral genome copy numbers and E1A gene expression in tumors than in liver and spleen compared to Ad5wt. Our direct radiolabeling approach, allows for immediate screening of novel oncolytic adenoviruses and selection of optimal viral genome alterations to generate improved mutants.
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Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment. Cancers (Basel) 2019; 11:cancers11091221. [PMID: 31438626 PMCID: PMC6769837 DOI: 10.3390/cancers11091221] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/12/2019] [Accepted: 08/15/2019] [Indexed: 12/26/2022] Open
Abstract
TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.
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Whilding LM, Halim L, Draper B, Parente-Pereira AC, Zabinski T, Davies DM, Maher J. CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies. Cancers (Basel) 2019; 11:E674. [PMID: 31091832 PMCID: PMC6563120 DOI: 10.3390/cancers11050674] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/10/2019] [Indexed: 02/06/2023] Open
Abstract
Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors.
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Affiliation(s)
- Lynsey M Whilding
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Leena Halim
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Benjamin Draper
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Ana C Parente-Pereira
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Tomasz Zabinski
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - David Marc Davies
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - John Maher
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
- Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, London SE5 9RS, UK.
- Department of Immunology, Eastbourne Hospital, East Sussex BN21 2UD, UK.
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High Mannose Binding Lectin (PFL) from Pseudomonas fluorescens Down-Regulates Cancer-Associated Integrins and Immune Checkpoint Ligand B7-H4. Cancers (Basel) 2019; 11:cancers11050604. [PMID: 31052260 PMCID: PMC6562446 DOI: 10.3390/cancers11050604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/17/2019] [Accepted: 04/28/2019] [Indexed: 11/26/2022] Open
Abstract
Pseudomonas fluorescens lectin (PFL), which belongs to the high mannose (HM)-binding OAAH (Oscillatoria agardhii agglutinin homologue) lectin family, induces cancer cell death. However, the detailed mechanisms underlying this process have not yet been elucidated. We found that PFL decreased various integrins as well as EGFR in cancer cells by promoting internalization and autophagic degradation of these molecules, subsequently inducing caspase-8 dependent cell apoptosis. As revealed by an ex vivo angiogenesis assay using the rat aortic model, PFL inhibited neovascularization in a dose-dependent manner, which was potentially mediated by down-regulation of endothelium integrins. Interestingly, PFL also down-regulated B7-H4 in cancer cells, which has been implicated as a negative regulator of T cell-mediated immunity. We found that B7-H4 co-localized with β3 integrin in MKN28 gastric cancer cells. siRNA silencing of B7-H4 in MKN28 cells decreased expression of β3 integrin, suggesting physical and functional association between these molecules. Direct interaction of PFL with integrin αvβ3 or B7-H4 was examined by surface plasmon resonance analysis, which detected high affinity glycan-dependent binding to PFL. These investigations suggest that PFL interaction with cell surface integrins is a key process for the anti-cancer activities of PFL.
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Liang B, Li L, Miao R, Wang J, Chen Y, Li Z, Zou X, Zhou M. Expression of Interleukin-6 and Integrin ανβ6 in Colon Cancer: Association with Clinical Outcomes and Prognostic Implications. Cancer Invest 2019; 37:174-184. [PMID: 30982362 DOI: 10.1080/07357907.2019.1597103] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανβ6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανβ6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανβ6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.
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Affiliation(s)
- Benjia Liang
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Leping Li
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Ruizheng Miao
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Jinshen Wang
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Yuezhi Chen
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Zequn Li
- b Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Public Health , Jinan , China
| | - Xueqing Zou
- c Department of Hepatobiliary Surgery , Qilu Hospital Shandong University , Jinan , China
| | - Mingliang Zhou
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
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Peng C, Li Z, Gao H, Zou X, Wang X, Zhou C, Niu J. Synchronous primary sigmoid colon cancer and primary thyroid cancer followed by a malignant tumor of the kidney: Case report of multiple primary cancer and review of the literature. Oncol Lett 2018; 17:2479-2484. [PMID: 30719116 DOI: 10.3892/ol.2018.9867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 11/13/2018] [Indexed: 12/12/2022] Open
Abstract
Multiple primary cancer (MPC) is relatively rare. With the development of diagnostic and anti-cancer therapeutic techniques, the incidence of MPC is rising annually. However, the incidence of triple or quadruple cancers in a single patient remains low. In this report, the case of a 58-year-old male with triple malignant cancer is outlined. Synchronous sigmoid colon cancer and thyroid cancer were diagnosed in May 2015; on subsequent re-examination, metastasis to the liver and a malignant kidney tumor were also identified. The diagnosis was established via computed tomography (CT), Positron emission tomography-CT (PET-CT) and other laboratory examination results, including analysis of tumor markers and liver function, and was confirmed by pathological diagnosis. The patient underwent radical surgery and standardized chemotherapy. Through literature review, the definition, characteristics, classification, incidence, possible causes of and treatment strategies for MPC were more clearly understood. In addition, immunohistochemical staining of integrin αvβ6 was performed on patient tissue specimens, where integrin αvβ6 expression was confirmed in cancer of the colon, thyroid and liver, as a result of colonic metastasis. Therefore, the involvement of integrin αvβ6 in the malignant progression of MPC was hypothesized, which may aid the investigation of MPC etiology in the future.
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Affiliation(s)
- Cheng Peng
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zequn Li
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Huijie Gao
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xueqing Zou
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiao Wang
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Changkuo Zhou
- Department of Urology Surgery, Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
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Peng C, Zou X, Xia W, Gao H, Li Z, Liu N, Xu Z, Gao C, He Z, Niu W, Fang R, Biswas S, Agrez M, Zhi X, Niu J. Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts. Biosci Rep 2018; 38:BSR20180243. [PMID: 30355650 PMCID: PMC6435516 DOI: 10.1042/bsr20180243] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 09/20/2018] [Accepted: 10/09/2018] [Indexed: 12/11/2022] Open
Abstract
Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C-X-C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.
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Affiliation(s)
- Cheng Peng
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Xueqing Zou
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Wanying Xia
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
| | - Huijie Gao
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Zequn Li
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Naiqing Liu
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
- Department of General Surgery, Linyi Central Hospital, Linyi, Shandong, China
| | - Zongquan Xu
- Department of General Surgery, Jiangxi Provincial Tumor Hospital, Nanchang, Jiangxi, China
| | - Chao Gao
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Zhaobin He
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Weibo Niu
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Ruliang Fang
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China
| | - Siddhartha Biswas
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
| | - Michael Agrez
- Newcastle Bowel Cancer Research Collaborative, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Xuting Zhi
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
| | - Jun Niu
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
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Xu R, Xu M, Fu Y, Deng X, Han H, Chen X, He W, Chen G. Transforming growth factor-β1 and lysophosphatidic acid activate integrin β6 gene promoter in Hep-3B cells. Oncol Lett 2018; 16:439-446. [PMID: 29930716 PMCID: PMC6006494 DOI: 10.3892/ol.2018.8672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 11/16/2017] [Indexed: 02/05/2023] Open
Abstract
Although it is difficult to detect αvβ6 integrin (αvβ6) in normal epithelia cells, its expression is upregulated during wound healing and carcinogenesis. Overexpression of αvβ6 has been demonstrated in epithelial cell carcinomas, such as adenocarcinoma of the colon and ovary. However, the expression of αvβ6 has not been reported in hepatocellular carcinoma (HCC). We previously indicated that LPA may induce αvβ6-mediated TGF-β1 signaling mechanisms during the pathogenesis of lung injury and fibrosis. In addition, transforming growth factor-β1 (TGF-β1) and lysophosphatidic acid (LPA) have been demonstrated to participate in the progression of HCC. In the present study, we hypothesized that TGF-β1 and LPA would serve a key role in the subunit integrin β6 (Itgβ6) transcriptional regulatory mechanism in HCC. It was identified that human HCC tissues and Hep-3B cells expressed Itgβ6. Treatment of Hep-3B with TGF-β1 or LPA increased the expression of Itgβ6. Furthermore, truncation experiments indicated a positive regulatory region at -326 to -157 bp of the Itgβ6 promoter. TGF-β1 and LPA increased transcriptional activation at this regulatory region. To the best of our knowledge, the present study was the first to demonstrate Itgβ6 expression in HCC, and the data indicate that TGF-β1 and LPA regulate Itgβ6 expression through the Itgβ6 gene promoter, which is an important factor in the development of HCC.
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Affiliation(s)
- Ruirui Xu
- Minimally Invasive Medical Center, The Second Affiliated Hospital of Shantou Medical College, Shantou, Guangdong 515041, P.R. China
| | - Mingyan Xu
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yucai Fu
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Xiaoling Deng
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Hui Han
- Minimally Invasive Medical Center, The Second Affiliated Hospital of Shantou Medical College, Shantou, Guangdong 515041, P.R. China
| | - Xihe Chen
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Wenjing He
- Minimally Invasive Medical Center, The Second Affiliated Hospital of Shantou Medical College, Shantou, Guangdong 515041, P.R. China
| | - Gengzhen Chen
- Minimally Invasive Medical Center, The Second Affiliated Hospital of Shantou Medical College, Shantou, Guangdong 515041, P.R. China
- Correspondence to: Professor Gengzhen Chen, Minimally Invasive Medical Center, The Second Affiliated Hospital of Shantou Medical College, 69 Dongxia North Road, Shantou, Guangdong 515041, P.R. China, E-mail:
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Baker AT, Aguirre-Hernández C, Halldén G, Parker AL. Designer Oncolytic Adenovirus: Coming of Age. Cancers (Basel) 2018; 10:E201. [PMID: 29904022 PMCID: PMC6025169 DOI: 10.3390/cancers10060201] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 06/06/2018] [Accepted: 06/11/2018] [Indexed: 12/26/2022] Open
Abstract
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.
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Affiliation(s)
- Alexander T Baker
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
| | - Carmen Aguirre-Hernández
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Gunnel Halldén
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Alan L Parker
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
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