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Li Q, Yang Y, Lin X, Chu LT, Chen H, Chen L, Tang J, Zeng T. Regulation of pancreatic cancer cells by suppressing KIN17 through the PI3K/AKT/mTOR signaling pathway. Oncol Rep 2025; 53:31. [PMID: 39791213 PMCID: PMC11736091 DOI: 10.3892/or.2025.8864] [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: 09/06/2024] [Accepted: 12/05/2024] [Indexed: 01/12/2025] Open
Abstract
Pancreatic cancer is an aggressive tumor, which is often associated with a poor clinical prognosis and resistance to conventional chemotherapy. Therefore, there is a need to identify new therapeutic markers for pancreatic cancer. Although KIN17 is a highly expressed DNA‑ and RNA‑binding protein in a number of types of human cancer, its role in pancreatic cancer development, especially in relation to progression, is currently unknown. The present study verified the upregulation of KIN17 in pancreatic cancer using The Cancer Genome Atlas and Gene Expression Omnibus databases (GSE15471, GSE71989 and GSE62165), and identified an association between the PI3K/Akt/mTOR pathway and patient prognosis using publicly available datasets (Gene Expression Profiling Interactive Analysis). Immunohistochemistry was performed to determine the association between KIN17 and the pathological features of clinical pancreatic cancer samples. Furthermore, knockdown of KIN17 was shown to inhibit the migration and invasion of pancreatic cancer cells, and to reverse epithelial‑mesenchymal transition in pancreatic cancer cells through downregulation of Vimentin and N‑cadherin, and upregulation of E‑cadherin. Through various cellular experiments, the role of KIIN17 was explored in PI3K/AKT/mTOR activity. KIN17 inhibition was shown to suppress the migration and invasion of pancreatic cancer cells through PI3K/AKT/mTOR‑mediated autophagy. Furthermore, combined with mTOR inhibition, dual inhibition could enhance autophagy, leading to anti‑migratory and anti‑invasion effects in pancreatic cancer. In conclusion, the present study indicated that KIN17 may have a role in carcinogenesis and could serve as a prognostic biomarker of pancreatic cancer, owing to its high expression. In addition, KIN17 may be considered a potential therapeutic target with its knockdown having an inhibitory effect on pancreatic cancer.
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Affiliation(s)
- Qiuyan Li
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Yuxia Yang
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Xiaocong Lin
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Lok Ting Chu
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Helian Chen
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Linsong Chen
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Jinjing Tang
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Tao Zeng
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
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Liu X, Shen L, Wang H. Decreased Expression of PLD2 Promotes EMT in Colorectal Cancer Invasion and Metastasis. J Cancer 2024; 15:2981-2993. [PMID: 38706911 PMCID: PMC11064252 DOI: 10.7150/jca.89970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 03/09/2024] [Indexed: 05/07/2024] Open
Abstract
Background and Objectives: PLD2 has been identified as playing a critical role in cancer cell motility and migration and other pathophysiological processes. We investigated the expression of PLD2 and its biological functions and clinical implications in human colorectal cancer. Materials and Methods: In this study, the expressions of PLD2 were analyzed in CRC cell lines and CRC samples by RT-PCR, western blot and immunohistochemistry. The PLD enzyme activity was studied using an PLD detection kit. We also performed matrigel invasion assay to evaluate the invasive capabilities in CRC cells. The expressions of EMT-related markers were quantified at mRNA and protein level using RT-PCR and western blot. We performed high-throughput RNA sequencing on PLD2 knockdown and overexpression CRC cell lines to explore the changes in gene expression associated with PLD2. Result: Herein, we showed that PLD2 expression was relatively low in CRC cell lines and CRC samples and PLD2 deficiency was significantly correlated with more advanced clinical phenotype regarding lymphatic and distant metastasis and poor patient survival. We also detected that PLD2 knockdown favored epithelial-mesenchymal transition (EMT) and thus promoted CRC invasion and metastasis. Further exploration uncovered that the expressions of several important genes closely related to metabolic pathways in CRC were noticeably altered due to PLD2 deficiency, including ID1, IFIT4, OASL, IFIT2 and CTAG2. Conclusion: Our results revealed that PLD2 deficiency promotes cell invasion and metastasis in CRC via EMT indicating PLD2 might have an important implication in carcinogenesis and progression and would be a new therapeutic target for cancer treatment.
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Affiliation(s)
- Xuan Liu
- Department of General Surgery, Central Hospital of Xuhui District, Shanghai, China
| | - Lei Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haiyu Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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3
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Sharma R, Malviya R. Cancer Stem Cells in Carcinogenesis and Potential Role in Pancreatic Cancer. Curr Stem Cell Res Ther 2024; 19:1185-1194. [PMID: 37711007 DOI: 10.2174/1574888x19666230914103420] [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: 04/11/2023] [Revised: 07/14/2023] [Accepted: 08/11/2023] [Indexed: 09/16/2023]
Abstract
A poor prognosis is associated with pancreatic cancer because of resistance during treatment and early distant metastases. The discovery of cancer stem cells has opened up novel avenues for research into the biology and treatment of cancer. Many investigations have pointed out the role of these types of stem cells in the oncogenesis and progression of hematologic and solid malignancies, specifically. Due to the existence of cancer stem cells in the proliferation and preservation of pancreatic tumors, such malignancies could be difficult to eradicate using conventional treatment techniques like chemotherapy and radiotherapy. It is hypothesized that pancreatic malignancies originate from a limited population of aberrant cancer stem cells to promote carcinogenesis, tumour metastasis, and therapeutic resistance. This review examines the role of pancreatic cancer stem cells in this disease and their significance in carcinogenesis, as well as the signals which modulate them, and also examines the ongoing clinical studies that are now being conducted with pancreatic stem cells.
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Affiliation(s)
- Rishav Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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4
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Zhang Z, Wang Y, Liang Z, Meng Z, Zhang X, Ma G, Chen Y, Zhang M, Su Y, Li Z, Liang Y, Niu H. Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience 2023; 26:108142. [PMID: 37867947 PMCID: PMC10585400 DOI: 10.1016/j.isci.2023.108142] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/11/2023] [Accepted: 10/02/2023] [Indexed: 10/24/2023] Open
Abstract
ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.
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Affiliation(s)
- Zhilei Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yonghua Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Zhijuan Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhaoyuan Meng
- School of Basic Medicine, Qingdao University, No.308 Ningxia Road, Qingdao 266071, China
| | - Xiangyan Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Guofeng Ma
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yuanbin Chen
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Mingxin Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Yinjie Su
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhiqiang Li
- The Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266071, China
| | - Ye Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Haitao Niu
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
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Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma. Front Oncol 2021; 11:760971. [PMID: 34976809 PMCID: PMC8714735 DOI: 10.3389/fonc.2021.760971] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.
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Affiliation(s)
- Junnv Xu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
| | - Haifeng Lin
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
| | - Gang Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
- Institution of Tumour, Hainan Medical College, Haikou, China
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6
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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7
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Safa AR. Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance. JOURNAL OF CANCER METASTASIS AND TREATMENT 2020; 6:36. [PMID: 34841087 PMCID: PMC8623975 DOI: 10.20517/2394-4722.2020.55] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Metastasis, tumor progression, and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor dissemination is associated with the activation of an epithelial-to-mesenchymal transition (EMT) process, a program by which epithelial cells lose their cell polarity and cell-to-cell adhesion, and acquire migratory and invasive abilities to become mesenchymal stem cells (MSC). These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state. Therefore, EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells. Furthermore, a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors. PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth. These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice. Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors. PCSCs express markers of cancer stem cells (CSCs) including CD24, CD133, CD44, and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium. A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize. Evidence highlights a linkage between CSC and EMT. In this review, The current understanding of the PCSCs, signaling pathways regulating these cells, PDAC heterogeneity, EMT mechanism, and links between EMT and metastasis in PCSCs are summarised. This information may provide potential therapeutic strategies to prevent EMT and trigger CSC growth inhibition and cell death.
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Affiliation(s)
- Ahmad R Safa
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
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8
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Monkman JH, Thompson EW, Nagaraj SH. Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease. Cancers (Basel) 2019; 11:E1745. [PMID: 31703358 PMCID: PMC6896204 DOI: 10.3390/cancers11111745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single 'master-key' remains elusive, making their collective interactions of greater importance in controlling the behaviours' of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality.
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Affiliation(s)
- James H. Monkman
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Erik W. Thompson
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Shivashankar H. Nagaraj
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
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Small-Molecule Ferroptotic Agents with Potential to Selectively Target Cancer Stem Cells. Sci Rep 2019; 9:5926. [PMID: 30976078 PMCID: PMC6459861 DOI: 10.1038/s41598-019-42251-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 03/22/2019] [Indexed: 02/07/2023] Open
Abstract
Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation. In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species to induce ferroptosis. Interestingly, we find that drug sensitivity is highest in tumor cells with a mesenchymal phenotype. Furthermore, these compounds showed enhanced toxicity towards mesenchymal breast cancer populations with cancer stem cell properties in vitro. In summary, we have identified a new class of small molecule ferroptotic agents that warrant further investigation.
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10
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Jagust P, de Luxán-Delgado B, Parejo-Alonso B, Sancho P. Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells. Front Pharmacol 2019; 10:203. [PMID: 30967773 PMCID: PMC6438930 DOI: 10.3389/fphar.2019.00203] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/18/2019] [Indexed: 02/02/2023] Open
Abstract
Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.
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Affiliation(s)
- Petra Jagust
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz de Luxán-Delgado
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz Parejo-Alonso
- Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
| | - Patricia Sancho
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
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11
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Lowe ME, Goodman MT, Coté GA, Glesby MJ, Haupt M, Schork NJ, Singh VK, Andersen DK, Pandol SJ, Uc A, Whitcomb DC. Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Recurrent Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2019; 47:1193-1199. [PMID: 30325857 PMCID: PMC6195328 DOI: 10.1097/mpa.0000000000001164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recurrent acute pancreatitis (RAP) is a complex clinical syndrome with significant morbidity, unpredictable outcomes, and limited treatment options. The National Institute of Diabetes and Digestive and Kidney Disease sponsored a workshop on July 25, 2018, in Pittsburgh, Pennsylvania, to address research gaps impeding development of effective therapies for pancreatitis. The RAP working group identified challenges to clinical progress using existing definitions, risk assessment, diagnostic and severity criteria, disease trajectories, outcomes, and research methods. Recurrent acute pancreatitis includes all the risk of acute pancreatitis and often progresses to chronic pancreatitis with variable complications of chronic pain, exocrine insufficiency, diabetes, and pancreatic cancer. However, the great variability among individuals with RAP requires better precision in defining the risks, individual episodes, as well as their frequency, pathogenic pathways, and specific outcome measures for each of the systems affected by pancreatic inflammation. Because of disease complexity, few patients are similar enough for traditional studies and methods to conduct clinical trials with small sample sizes are required. The need for genetic testing, biomarker development, and better imaging methods was highlighted. Adaptive and N-of-one study designs, better endpoints, and outcome measures including patient-reported outcomes should considered early in developing future therapeutic trial design and include all stakeholders.
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Affiliation(s)
- Mark E. Lowe
- Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO
| | - Marc T. Goodman
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Gregory A. Coté
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | | | - Mark Haupt
- ARIEL Precision Medicine, Pittsburgh, PA
| | - Nicholas J. Schork
- Department of Quantitative Medicine, The Transcriptional Genomics Research Institute, Phoenix, AZ
| | - Vikesh K. Singh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Aliye Uc
- Division of Gastroenterology, Hepatology, Pancreatology and Nutrition, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA
| | - David C. Whitcomb
- Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
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12
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Yu Q, Qiu Y, Chen X, Wang X, Mei L, Wu H, Liu K, Liu Y, Li M, Zhang Z, He Q. Chemotherapy priming of the Pancreatic Tumor Microenvironment Promotes Delivery and Anti-Metastasis Efficacy of Intravenous Low-Molecular-Weight Heparin-Coated Lipid-siRNA Complex. Am J Cancer Res 2019; 9:355-368. [PMID: 30809279 PMCID: PMC6376180 DOI: 10.7150/thno.29137] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with high lethality. Its high tumor cell-density and large variety of extracellular matrix (ECM) components present major barriers for drug delivery. Methods: Paclitaxel-loaded PEGylated liposomes (PTX-Lip) were used as a tumor-priming agent to induce tumor cell apoptosis and decrease the abundance of ECM to promote cellular uptake and tumor delivery of nanodrugs. Paclitaxel exerts anti-cancer effects but, paradoxically, exacerbates cancer metastasis and drug resistance by increasing the expression of apoptotic B-cell lymphoma-2 protein (BCL-2). Thus, low-molecular-weight heparin-coated lipid-siRNA complex (LH-Lip/siBCL-2) was constructed to inhibit cancer metastasis and silence BCL-2 by BCL-2 siRNA (siBCL-2). Results: Significant tumor growth inhibition efficacy was observed, accompanied by obvious inhibition of cancer metastasis in vivo. Conclusion: These results suggested our sequential delivery of PTX-Lip and LH-Lip/siBCL-2 might provide a practical approach for PDAC or other ECM-rich tumors.
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13
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Yang Z, Qu CB, Zhang Y, Zhang WF, Wang DD, Gao CC, Ma L, Chen JS, Liu KL, Zheng B, Zhang XH, Zhang ML, Wang XL, Wen JK, Li W. Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway. Oncogene 2018; 38:2516-2532. [PMID: 30531834 PMCID: PMC6484770 DOI: 10.1038/s41388-018-0602-8] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/31/2018] [Accepted: 10/31/2018] [Indexed: 01/16/2023]
Abstract
p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.
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Affiliation(s)
- Zhan Yang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China.,Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China.,Department of Science and Technology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Chang-Bao Qu
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Yong Zhang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Wen-Feng Zhang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Dan-Dan Wang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Chun-Cheng Gao
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Long Ma
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Jin-Suo Chen
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Kai-Long Liu
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Bin Zheng
- Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China
| | - Xin-Hua Zhang
- Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China
| | - Man-Li Zhang
- Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China.,Department of Emergency Medicine, The second hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China
| | - Xiao-Lu Wang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China.
| | - Jin-Kun Wen
- Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China.
| | - Wei Li
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China.
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14
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Bao L, Lv L, Feng J, Chen Y, Wang X, Han S, Zhao H. MiR-876-5p suppresses epithelial-mesenchymal transition of lung cancer by directly down-regulating bone morphogenetic protein 4. J Biosci 2018; 42:671-681. [PMID: 29229885 DOI: 10.1007/s12038-017-9722-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Lung cancer is the leading cause of cancer-related death throughout the world. We aimed to investigate the role of a novel microRNA-876-5p and its potential molecular target bone morphogenetic protein 4 (BMP-4), in the epithelial-mesenchymal transition (EMT) of lung cancer. Expressions of microRNA-876-5p and its potential target BMP-4 were analysed in lung cancer cells and patient tissues. Luciferase activity assay was conducted to verify direct targeting of microRNA- 876-5p to the 3'-UTR of BMP-4 mRNA. Migration, invasion capacities of lung cancer cells expressing microRNA-876-5p were analysed, and characteristics of lung cancer EMT protein markers were also evaluated. A xenograft tumour mouse model was established to address the roles of microRNA-876-5p and BMP-4 in lung cancer EMT in vivo. MicroRNA-876- 5p was decreased while BMP-4 was increased in lung cancer cells and tissues. MicroRNA-876-5p directly targeted 3'-UTR of BMP-4 mRNA to inhibit its expression. MicroRNA-876-5p expression significantly inhibited the migration, invasion and EMT of lung cancer cells in vitro, as well as metastasis in vivo, which required BMP-4 expression. MicroRNA-876-5p suppresses EMT of lung cancer by directly down-regulating BMP-4, both of which could serve as potential therapeutic targets in the treatment of lung cancer.
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Affiliation(s)
- Liang Bao
- Department of Respirology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi 214002, Jiangsu Province, China
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15
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Liu HY, Korc M, Lin CC. Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma. Biomaterials 2018; 160:24-36. [PMID: 29353105 PMCID: PMC5815383 DOI: 10.1016/j.biomaterials.2018.01.012] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 01/03/2018] [Accepted: 01/06/2018] [Indexed: 01/18/2023]
Abstract
The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT).
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Affiliation(s)
- Hung-Yi Liu
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Murray Korc
- Department of Medicine and Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Melvin and Bren Simon Cancer Center, and The Pancreatic Cancer Signature Center, Indianapolis, IN 46202, USA
| | - Chien-Chi Lin
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA; Indiana University Melvin and Bren Simon Cancer Center, and The Pancreatic Cancer Signature Center, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Purdue School of Engineering & Technology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
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16
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Can we better predict the biologic behavior of incidental IPMN? A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas. Langenbecks Arch Surg 2017; 403:151-194. [DOI: 10.1007/s00423-017-1644-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/24/2017] [Indexed: 02/07/2023]
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17
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Wu X, Tang W, Marquez RT, Li K, Highfill CA, He F, Lian J, Lin J, Fuchs JR, Ji M, Li L, Xu L. Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling. Oncotarget 2017; 7:11708-23. [PMID: 26887043 PMCID: PMC4905505 DOI: 10.18632/oncotarget.7336] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 01/23/2016] [Indexed: 12/17/2022] Open
Abstract
Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo. Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance.
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Affiliation(s)
- Xiaoqing Wu
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.,Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.,School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China
| | - Wenhua Tang
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.,Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Rebecca T Marquez
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA
| | - Ke Li
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA
| | - Chad A Highfill
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA
| | - Fengtian He
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.,Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China
| | - Jiqin Lian
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China
| | - Jiayuh Lin
- Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA
| | - James R Fuchs
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA
| | - Min Ji
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China
| | - Ling Li
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Cell Biology and Cell Engineering Research Centre, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shanxi, China
| | - Liang Xu
- Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.,Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA
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18
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miR-31 Functions as an Oncomir Which Promotes Epithelial-Mesenchymal Transition via Regulating BAP1 in Cervical Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6361420. [PMID: 29159179 PMCID: PMC5660773 DOI: 10.1155/2017/6361420] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/29/2017] [Indexed: 01/03/2023]
Abstract
MicroRNA-31 (miR-31) functions as tumor suppressors or oncogenes that are involved in tumor behavior. However, the function of miR-31 in cervical carcinogenesis remains unclear. The aim of this study was to validate the potential role of miR-31 and BRCA1-associated protein-1 (BAP1) on regulating epithelial-mesenchymal transition (EMT) in cervical cancer. In the present study, qRT-PCR assay revealed that the expression of miR-31 was upregulated in human cervical cancer cells and clinical tissues. Results of wound healing and cell migration assay revealed that knockdown of miR-31 inhibited cell metastasis and migration. Bioinformatic and dual-luciferase reporter gene assay showed that BAP1 was the direct target of miR-31. Furthermore, the results revealed that miR-31 promoted proliferation and EMT in cervical cancer cells and accelerated the development of tumor growth in vivo xenograft experiment by inhibiting BAP1 expression. Overall, these results highlight an important role of miR-31 functioning as an oncomir which could promote EMT in cervical cancer via downregulating BAP1 expression. Thus, downregulation of miR-31 could be a novel approach for the molecular treatment of cervical cancers and other malignancies.
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19
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Lin HJ, Lin J. Seed-in-Soil: Pancreatic Cancer Influenced by Tumor Microenvironment. Cancers (Basel) 2017; 9:cancers9070093. [PMID: 28753978 PMCID: PMC5532629 DOI: 10.3390/cancers9070093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 07/18/2017] [Accepted: 07/18/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is a fatal malignancy with a five-year survival rate lower than 7%, and most patients dying within six months of diagnosis. The factors that contribute to the aggressiveness of the disease include, but are not limited to: late diagnosis, prompt metastasis to adjacent vital organs, poor response, and resistance to anticancer treatments. This malignancy is uniquely associated with desmoplastic stroma that accounts for 80% of tumor mass. Understanding the biology of stroma can aid the discovery of innovative strategies for eradicating this lethal cancer in the future. This review highlights the critical components in the stroma and how they interact with the cancer cells to convey the devastating tumor progression.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical Laboratory Sciences, University of Delaware, Room 305, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA.
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, University of Maryland School of Medicine and Comprehensive Cancer Center, 108 N. Greene Street, Baltimore, MD 21201, USA.
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20
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Wang J, Nikhil K, Viccaro K, Chang L, Jacobsen M, Sandusky G, Shah K. The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma. J Cell Sci 2017; 130:1078-1093. [PMID: 28167680 PMCID: PMC5358340 DOI: 10.1242/jcs.196790] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 01/27/2017] [Indexed: 12/21/2022] Open
Abstract
We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors in vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.
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Affiliation(s)
- Jing Wang
- Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA
| | - Kumar Nikhil
- Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA
| | - Keith Viccaro
- Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA
| | - Lei Chang
- Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA
| | - Max Jacobsen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, room A-128, Indianapolis, IN 46202, USA
| | - George Sandusky
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, room A-128, Indianapolis, IN 46202, USA
| | - Kavita Shah
- Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA
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21
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Wang J, Nikhil K, Viccaro K, Chang L, White J, Shah K. Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer. BMC Biol 2017; 15:10. [PMID: 28193222 PMCID: PMC5307883 DOI: 10.1186/s12915-016-0335-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 11/24/2016] [Indexed: 12/20/2022] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are key underlying causes that promote extensive metastasis, drug resistance, and tumor recurrence in highly lethal pancreatic cancer. The mechanisms leading to EMT and CSC phenotypes are not fully understood, which has hindered the development of effective targeted therapies capable of improving treatment outcomes in patients with pancreatic cancer. Results We show a central role of Aurora kinase A (AURKA) in promoting EMT and CSC phenotypes via ALDH1A1, which was discovered as its direct substrate using an innovative chemical genetic screen. AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. ALDH1A1 also reciprocates and prevents AURKA degradation, thereby triggering a positive feedback activation loop which drives highly aggressive phenotypes in cancer. Phospho-resistant ALDH1A1 fully reverses EMT and CSC phenotypes, thus serving as dominant negative, which underscores the clinical significance of the AURKA-ALDH1A1 signaling axis in pancreatic cancer. Conclusions While increased levels and activity of ALDH1A1 are hallmarks of CSCs, the underlying molecular mechanism remains unclear. We show the first phosphorylation-dependent regulation of ALDH1A1, which increases its levels and activity via AURKA. Recent global phospho-proteomic screens have revealed increased phosphorylation of ALDH1A1 at the T267 site in human cancers and healthy liver tissues where ALDH1A1 is highly expressed and active, indicating that this regulation is likely crucial both in normal and diseased states. This is also the first study to demonstrate oligomer-dependent activity of ALDH1A1, signifying that targeting its oligomerization state may be an effective therapeutic approach for counteracting its protective functions in cancer. Finally, while AURKA inhibition provides a potent tool to reduce ALDH1A1 levels and activity, the reciprocal loop between them ensures that their concurrent inhibition will be highly synergistic when inhibiting tumorigenesis, chemoresistance, and metastasis in highly aggressive pancreatic cancer and beyond. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0335-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jing Wang
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Kumar Nikhil
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Keith Viccaro
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Lei Chang
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Jacoba White
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Kavita Shah
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
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22
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Song J, Li Y. miR-25-3p reverses epithelial-mesenchymal transition via targeting Sema4C in cisplatin-resistance cervical cancer cells. Cancer Sci 2016; 108:23-31. [PMID: 27743413 PMCID: PMC5276840 DOI: 10.1111/cas.13104] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/01/2016] [Accepted: 10/09/2016] [Indexed: 12/19/2022] Open
Abstract
Acquisition of epithelial-mesenchymal transition (EMT) has recently been proposed as an important contributor of drug resistance in cervical cancer cells. However, the underlying mechanisms are still unclear. MicroRNAs play a crucial role in regulating EMT. The aim of this study was to explore the potential role of miR-25-3p in regulating EMT in cisplatin-resistant (CR) cervical cancer cells. To this end, we established stable CR cervical cancer cells, HeLa-CR and CaSki-CR, and investigated the function of miR-25-3p in regulating EMT. It is found that CR cervical cancer cells possessed more EMT characteristics and demonstrated higher migratory abilities and invasiveness. miR-25-3p downregulation was also seen in HeLa-CR and CaSki-CR cells. Of note, ectopic expression of miR-25-3p reversed the EMT phenotype and sensitized CR cells to cisplatin via targeting Sema4C. Furthermore, stable overexpression of miR-25-3p in HeLa-CR cells suppressed tumor growth in mice, downregulated Sema4C and Snail, and upregulated E-cadherin compared with the control group. These results suggest that miR-25-3p is an important regulator of cervical cancer EMT and chemoresistance. Thus, upregulation of miR-25-3p could be a novel approach to treat cervical cancers that are resistant to chemotherapy.
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Affiliation(s)
- Jing Song
- Department of Gynecology and Obstetrics, The Fourth Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yue Li
- Department of Gynecology, The Hospital of Heilongjiang Province, Nangang Branch, Harbin, Heilongjiang, China
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23
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Kanamoto A, Ninomiya I, Harada S, Tsukada T, Okamoto K, Nakanuma S, Sakai S, Makino I, Kinoshita J, Hayashi H, Oyama K, Miyashita T, Tajima H, Takamura H, Fushida S, Ohta T. Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma. Int J Oncol 2016; 49:1859-1869. [PMID: 27826618 PMCID: PMC5063503 DOI: 10.3892/ijo.2016.3712] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 08/10/2016] [Indexed: 12/14/2022] Open
Abstract
Esophageal carcinoma is one of the most aggressive malignancies, and is characterized by poor response to current therapy and a dismal survival rate. In this study we investigated whether irradiation induces epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) TE9 cells and whether the classic histone deacetylase (HDAC) inhibitor valproic acid (VPA) suppresses these changes. First, we showed that 2 Gy irradiation induced spindle cell-like morphologic changes, decreased expression of membranous E-cadherin, upregulated vimentin expression, and altered the localization of β-catenin from its usual membrane-bound location to cytoplasm in TE9 cells. Irradiation induced upregulation of transcription factors including Slug, Snail, and Twist, which regulate EMT. Stimulation by irradiation resulted in increased TGF-β1 and HIF-1α expression and induced Smad2 and Smad3 phosphorylation. Furthermore, irradiation enhanced CD44 expression, indicating acquisition of cancer stem-like cell properties. In addition, irradiation enhanced invasion and migration ability with upregulation of matrix metalloproteinases. These findings indicate that single-dose irradiation can induce EMT in ESCC cells. Second, we found that treatment with 1 mM VPA induced reversal of EMT caused by irradiation in TE9 cells, resulting in attenuated cell invasion and migration abilities. These results suggest that VPA might have clinical value to suppress irradiation-induced EMT. The reversal of EMT by HDAC inhibitors may be a new therapeutic strategy to improve the effectiveness of radiotherapy in ESCC by inhibiting the enhancement of invasion and metastasis.
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Affiliation(s)
- Ayako Kanamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Itasu Ninomiya
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Shinichi Harada
- Center for Biomedical Research and Education, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomoya Tsukada
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Koichi Okamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Shinichi Nakanuma
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Seisho Sakai
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Isamu Makino
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hironori Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Katsunobu Oyama
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomoharu Miyashita
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hiroyuki Takamura
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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Ma J, Zeng F, Ma C, Pang H, Fang B, Lian C, Yin B, Zhang X, Wang Z, Xia J. Synergistic reversal effect of epithelial-to-mesenchymal transition by miR-223 inhibitor and genistein in gemcitabine-resistant pancreatic cancer cells. Am J Cancer Res 2016; 6:1384-95. [PMID: 27429851 PMCID: PMC4937740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/02/2016] [Indexed: 06/06/2023] Open
Abstract
Emerging studies have demonstrated that EMT phenotype is closely related with tumor progression and drug resistance in a variety of human cancers. Recently, it has been extensively demonstrated that microRNAs (miRNAs) play a pivotal role in regulating EMT. In our previously reports, we have reported that inhibition of miR-223 could reverse EMT phenotype and improve chemotherapeutic drug sensitivity. We also reported that genistein down-regulated miR-223 expression in gemcitabine-resistant (GR) pancreatic cancer cells. Here, we explored whether there was the synergistic effect between miR-223 inhibitor and genistein on cell growth, migration, invasion and reversal of EMT in GR pancreatic cancer. We found that the combination of miR-223 inhibitor and genistein synergistically reduced cell motility and invasion and enhanced gemcitabine sensitivity in GR cells. In addition, we further observed that miR-223 inhibitor and genistein reversed EMT features in GR cells. This study suggests that the combination of miR-223 inhibitor and genistein may be a potential therapeutic strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Jia Ma
- The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China
- Department of Biochemistry and Molecular Biology, Bengbu Medical CollegeAnhui 233030, China
| | - Fanpeng Zeng
- Research Center of Clinical Laboratory Science, Bengbu Medical CollegeAnhui 233030, China
| | - Cong Ma
- Research Center of Clinical Laboratory Science, Bengbu Medical CollegeAnhui 233030, China
| | - Haijie Pang
- Research Center of Clinical Laboratory Science, Bengbu Medical CollegeAnhui 233030, China
| | - Binbin Fang
- Research Center of Clinical Laboratory Science, Bengbu Medical CollegeAnhui 233030, China
| | - Chaoqun Lian
- Department of Biochemistry and Molecular Biology, Bengbu Medical CollegeAnhui 233030, China
| | - Bin Yin
- The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China
| | - Xueping Zhang
- Department of Anesthesiology, Shenzhen People’s Hospital, 2nd Clinical Medical College of Jinan UniversityShenzhen 518020, China
| | - Zhiwei Wang
- The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolBoston, MA 02215, USA
| | - Jun Xia
- Department of Biochemistry and Molecular Biology, Bengbu Medical CollegeAnhui 233030, China
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25
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The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells. Stem Cells Int 2016; 2016:8352684. [PMID: 27006664 PMCID: PMC4783541 DOI: 10.1155/2016/8352684] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/24/2015] [Accepted: 01/27/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.
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26
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Borah A, Raveendran S, Rochani A, Maekawa T, Kumar DS. Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy. Oncogenesis 2015; 4:e177. [PMID: 26619402 PMCID: PMC4670961 DOI: 10.1038/oncsis.2015.35] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/10/2015] [Accepted: 09/22/2015] [Indexed: 12/21/2022] Open
Abstract
Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction for future cancer therapy.
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Affiliation(s)
- A Borah
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - S Raveendran
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - A Rochani
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - T Maekawa
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - D S Kumar
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
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27
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Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Oncotarget 2015; 6:1740-9. [PMID: 25638153 PMCID: PMC4359328 DOI: 10.18632/oncotarget.2714] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/08/2014] [Indexed: 12/13/2022] Open
Abstract
Recent studies have demonstrated that acquisition of epithelial-to-mesenchymal transition (EMT) is associated with drug resistance in pancreatic cancer cells; however, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aims of this study were to explore the potential role of miR-223 in governing EMT in gemcitabine-resistant (GR) pancreatic cancer cells. To achieve this goal, real-time reverse transcription-PCR and western blot analysis were used to validate whether GR cells acquired EMT in AsPC-1 and PANC-1 cells. Invasion, migration, and detachment assays were performed to further identify the EMT characteristics in GR cells. The miR-223 inhibitor was used to determine its role in GR-induced EMT. We found that GR cells acquired EMT features, which obtained elongated fibroblastoid morphology, decreased expression of epithelial marker E-cadherin, and up-regulation of mesenchymal markers. Furthermore, we observed that GR cells are associated with high expression of miR-223. Notably, inhibition of miR-223 led to the reversal of EMT phenotype. More importantly, miR-223 governs GR-induced EMT in part due to down-regulation of its target Fbw7 and subsequent upregulation of Notch-1 in pancreatic cancer. Our study implied that down-regulation of miR-223 could be a novel therapy for pancreatic cancer.
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28
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Xu C, Xia C, Zhang SJ, Qin H, Li DM, Zhao Q. Effect of salinomycin on growth and migration of pancreatic cancer cells in vitro. Shijie Huaren Xiaohua Zazhi 2015; 23:3831-3837. [DOI: 10.11569/wcjd.v23.i24.3831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of salinomycin on proliferation and migration of pancreatic cancer cell lines Capan-2 and PANC-1 and the possible mechanisms of inhibition of cell migration.
METHODS: Canpan-2 and PANC-1 cells were treated with different concentrations of salinomycin for 24 h, while the cells treated with dimethyl sulphoxide (DMSO) were used as controls. Cell proliferation and the half maximal inhibitory concentration (IC50) of salinomycin were measured by CCK8 assay. Transwell assay was used to measure the migration of these cells which were pretreated with salinomycin at a concentration of IC50. The protein and mRNA expression of biomarkers for epithelial-mesenchymal transition (EMT) was detected by Western blot and Real-time PCR, respectively.
RESULTS: Salinomycin inhibited the proliferation of Capan-2 and PANC-1 cells in a dose-dependent manner. The IC50 values for Capan-2 and PANC-1 cells were 20 μmol/L and 10 μmol/L, respectively. Salinomycin significantly decreased the migration ability of pancreatic cancer cells as revealed by Transwell migration assay (P < 0.05). The protein expression of E-cadherin was increased while that of Vimentin was decreased after salinomycin treatment. The expression of E-cadherin mRNA was increased in both Capan-2 and PANC-1 cells (P < 0.05), while the expression of Vimentin mRNA was decreased in both Capan-2 and PANC-1 cells (P < 0.05).
CONCLUSION: Salinomycin can inhibit the proliferation and migration of Capan-2 and PANC-1 cells possibly by inhibiting the process of EMT.
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29
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Jiao F, Hu H, Han T, Yuan C, Wang L, Jin Z, Guo Z, Wang L. Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. Int J Mol Sci 2015; 16:6677-93. [PMID: 25811929 PMCID: PMC4424983 DOI: 10.3390/ijms16046677] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/20/2015] [Accepted: 02/20/2015] [Indexed: 12/31/2022] Open
Abstract
Cancer stem cells (CSCs) play a vital role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. The mechanisms that maintain the stemness of these cells remain largely unknown. Our previous study indicated that MALAT-1 may serve as an oncogenic long noncoding RNA in pancreatic cancer by promoting epithelial-mesenchymal transition (EMT) and regulating CSCs markers expression. More significantly, there is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. Therefore, we hypothesized that MALAT-1 might enhance stem cell-like phenotypes in pancreatic cancer cells. In this study, our data showed that MALAT-1 could increase the proportion of pancreatic CSCs, maintain self-renewing capacity, decrease the chemosensitivity to anticancer drugs, and accelerate tumor angiogenesis in vitro. In addition, subcutaneous nude mouse xenografts revealed that MALAT-1 could promote tumorigenicity of pancreatic cancer cells in vivo. The underlying mechanisms may involve in increased expression of self-renewal related factors Sox2. Collectively, we for the first time found the potential effects of MALAT-1 on the stem cell-like phenotypes in pancreatic cancer cells, suggesting a novel role of MALAT-1 in tumor stemness, which remains to be fully elucidated.
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Affiliation(s)
- Feng Jiao
- Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Hai Hu
- Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Ting Han
- Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Cuncun Yuan
- Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
| | - Lei Wang
- Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Ziliang Jin
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Zhen Guo
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
| | - Liwei Wang
- Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 201620, China.
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30
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Satoh K, Hamada S, Shimosegawa T. Involvement of epithelial to mesenchymal transition in the development of pancreatic ductal adenocarcinoma. J Gastroenterol 2015; 50:140-6. [PMID: 25216997 DOI: 10.1007/s00535-014-0997-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 08/29/2014] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease as a result of its rapid dissemination and resistance to conventional chemotherapy and radiotherapy. Surgical resection is the only curative therapy, but most of the tumors are unresectable at the time of diagnosis. The molecular mechanisms underlying the biological aggressiveness of this tumor type remain to be clarified. Epithelial to mesenchymal transition (EMT) is a developmental process that leads the phenotype shift from an epithelial morphology to a motile, fibroblast-like morphology. Recent studies showed that EMT is involved in the invasion and metastasis of many types of carcinomas including PDAC. In addition, PDAC cells with the EMT phenotype also exhibit chemoresistance and the cancer stem cell property. Various factors such as cytokines, growth factors, or transcriptional factors were found to promote the EMT program in PDAC cells. In this review, we summarize the current knowledge about the EMT in PDAC cells, focusing on the involvement of this process and its regulatory molecules including microRNA during the development of PDAC cells.
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Affiliation(s)
- Kennichi Satoh
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiote, Natori, Miyagi, Japan,
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31
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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32
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Kaliberov SA, Kaliberova LN, Buchsbaum DJ, Curiel DT. Experimental virotherapy of chemoresistant pancreatic carcinoma using infectivity-enhanced fiber-mosaic oncolytic adenovirus. Cancer Gene Ther 2014; 21:264-74. [PMID: 24903014 PMCID: PMC4157623 DOI: 10.1038/cgt.2014.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 05/02/2014] [Accepted: 05/02/2014] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer is a significant clinical problem and novel therapeutic approaches are desperately needed. Recent advances in conditionally replicative adenovirus-based (CRAd) oncolytic virus design allow the application of CRAd vectors as a therapeutic strategy to efficiently target and eradicate chemoresistant pancreatic cancer cells, thereby improving the efficacy of pancreatic cancer treatment. The goal of this study was to construct and validate the efficacy of an infectivity-enhanced, liver-untargeted, tumor-specific CRAd vector. A panel of CRAds has been derived that embodies the C-X-C chemokine receptor type 4 promoter for conditional replication, two-fiber complex mosaicism for targeting expansion and hexon hypervariable region 7 (HVR7) modification for liver untargeting. We evaluated CRAds for cancer virotherapy using a human pancreatic tumor xenograft model. Employment of the fiber mosaic approach improved CRAd replication in pancreatic tumor xenografts. Substitution of the HVR7 of the Ad5 hexon for Ad serotype 3 hexon resulted in decreased liver tropism of systemically administrated CRAd. Obtained data demonstrated that employment of complex mosaicism increased efficacy of the combination of oncolytic virotherapy with chemotherapy in a human pancreatic tumor xenograft model.
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Affiliation(s)
- S A Kaliberov
- Department of Radiation Oncology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - L N Kaliberova
- Department of Radiation Oncology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - D J Buchsbaum
- Division of Radiation Biology, Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - D T Curiel
- Department of Radiation Oncology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
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33
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McCarroll JA, Naim S, Sharbeen G, Russia N, Lee J, Kavallaris M, Goldstein D, Phillips PA. Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Front Physiol 2014; 5:141. [PMID: 24782785 PMCID: PMC3988387 DOI: 10.3389/fphys.2014.00141] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 03/24/2014] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer.
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Affiliation(s)
- Joshua A McCarroll
- Tumour Biology and Targeting Program, Lowy Cancer Research Centre, Children's Cancer Institute Australia, University of New South Wales Sydney, NSW, Australia ; Australian Centre for Nanomedicine, University of New South Wales Sydney, NSW, Australia
| | - Stephanie Naim
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
| | - George Sharbeen
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
| | - Nelson Russia
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
| | - Julia Lee
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
| | - Maria Kavallaris
- Tumour Biology and Targeting Program, Lowy Cancer Research Centre, Children's Cancer Institute Australia, University of New South Wales Sydney, NSW, Australia ; Australian Centre for Nanomedicine, University of New South Wales Sydney, NSW, Australia
| | - David Goldstein
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
| | - Phoebe A Phillips
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales Sydney, NSW, Australia
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34
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Rucki AA, Zheng L. Pancreatic cancer stroma: Understanding biology leads to new therapeutic strategies. World J Gastroenterol 2014; 20:2237-2246. [PMID: 24605023 PMCID: PMC3942829 DOI: 10.3748/wjg.v20.i9.2237] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/14/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is among the deadliest cancers in the United States and in the world. Late diagnosis, early metastasis and lack of effective therapy are among the reasons why only 6% of patients diagnosed with PDA survive past 5 years. Despite development of targeted therapy against other cancers, little progression has been made in the treatment of PDA. Therefore, there is an urgent need for the development of new treatments. However, in order to proceed with treatments, the complicated biology of PDA needs to be understood first. Interestingly, majority of the tumor volume is not made of malignant epithelial cells but of stroma. In recent years, it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells, leading to cancer progression. The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery. Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery. In this review, we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.
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