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Sztankovics D, Moldvai D, Petővári G, Dankó T, Szalai F, Miyaura R, Varga V, Nagy N, Papp G, Pápay J, Krencz I, Sebestyén A. mTOR hyperactivity and RICTOR amplification as targets for personalized treatments in malignancies. Pathol Oncol Res 2024; 30:1611643. [PMID: 38515456 PMCID: PMC10954904 DOI: 10.3389/pore.2024.1611643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
The increasing knowledge of molecular alterations in malignancies, including mutations and regulatory failures in the mTOR (mechanistic target of rapamycin) signaling pathway, highlights the importance of mTOR hyperactivity as a validated target in common and rare malignancies. This review summarises recent findings on the characterization and prognostic role of mTOR kinase complexes (mTORC1 and mTORC2) activity regarding differences in their function, structure, regulatory mechanisms, and inhibitor sensitivity. We have recently identified new tumor types with RICTOR (rapamycin-insensitive companion of mTOR) amplification and associated mTORC2 hyperactivity as useful potential targets for developing targeted therapies in lung cancer and other newly described malignancies. The activity of mTOR complexes is recommended to be assessed and considered in cancers before mTOR inhibitor therapy, as current first-generation mTOR inhibitors (rapamycin and analogs) can be ineffective in the presence of mTORC2 hyperactivity. We have introduced and proposed a marker panel to determine tissue characteristics of mTOR activity in biopsy specimens, patient materials, and cell lines. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced-stage patients selected by genetic alterations, molecular markers, and/or protein expression changes in the mTOR signaling pathway. Hopefully, the summarized results, our findings, and the suggested characterization of mTOR activity will support therapeutic decisions.
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Canale M, Monti M, Rapposelli IG, Ulivi P, Sullo FG, Bartolini G, Tiberi E, Frassineti GL. Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer. Cancers (Basel) 2021; 13:5671. [PMID: 34830826 PMCID: PMC8616432 DOI: 10.3390/cancers13225671] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Elisa Tiberi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
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Zhang H, Yi JK, Huang H, Park S, Park S, Kwon W, Kim E, Jang S, Kim SY, Choi SK, Kim SH, Liu K, Dong Z, Ryoo ZY, Kim MO. Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13092176. [PMID: 33946531 PMCID: PMC8125196 DOI: 10.3390/cancers13092176] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/16/2021] [Accepted: 04/27/2021] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. Rhein has demonstrated therapeutic effects in various cancer models. However, its effects and underlying mechanisms of action in CRC remain poorly understood. We investigated the potential anticancer activity and underlying mechanisms of rhein in CRC in vitro and in vivo. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of rhein on CRC cells. Wound-healing and Transwell assays were conducted to assess cell migration and invasion capacity. Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. A tissue microarray was used to detect mTOR expression in CRC patient tissues. Gene overexpression and knockdown were done to analyze the function of mTOR in CRC. The anticancer effect of rhein in vivo was assessed in a CRC xenograft mouse model. The results show that rhein significantly inhibited CRC cell growth by inducing S-phase cell cycle arrest and apoptosis. Rhein inhibited CRC cell migration and invasion through the epithelial-mesenchymal transition (EMT) process. mTOR was highly expressed in CRC cancer tissues and cells. Overexpression of mTOR promoted cell growth, migration, and invasion, whereas mTOR knockdown diminished these phenomena in CRC cells in vitro. In addition, rhein directly targeted mTOR and inhibited the mTOR signaling pathway in CRC cells. Rhein promoted mTOR degradation through the ubiquitin-proteasome pathway. Intraperitoneal administration of rhein inhibited HCT116 xenograft tumor growth through the mTOR pathway. In conclusion, rhein exerts anticancer activity in vitro and in vivo by targeting mTOR and inhibiting the mTOR signaling pathway in CRC. Our results indicate that rhein is a potent anticancer agent that may be useful for the prevention and treatment of CRC.
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Affiliation(s)
- Haibo Zhang
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea; (H.Z.); (H.H.); (E.K.)
| | - Jun-Koo Yi
- Gyeongbuk Livestock Research Institute, Yeongju 36052, Korea;
| | - Hai Huang
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea; (H.Z.); (H.H.); (E.K.)
| | - Song Park
- Core Protein Resources Center, DGIST, Daegu 41566, Korea; (S.P.); (S.-K.C.)
- Department of Brain and Cognitive Science, DGIST, Daegu 41566, Korea
| | - Sijun Park
- School of Life Sciences, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu 41566, Korea; (S.P.); (S.J.); (S.-Y.K.)
| | - Wookbong Kwon
- Division of Biotechnology, DGIST, Daegu 41566, Korea;
| | - Eungyung Kim
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea; (H.Z.); (H.H.); (E.K.)
| | - Soyoung Jang
- School of Life Sciences, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu 41566, Korea; (S.P.); (S.J.); (S.-Y.K.)
| | - Si-Yong Kim
- School of Life Sciences, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu 41566, Korea; (S.P.); (S.J.); (S.-Y.K.)
| | - Seong-Kyoon Choi
- Core Protein Resources Center, DGIST, Daegu 41566, Korea; (S.P.); (S.-K.C.)
- Division of Biotechnology, DGIST, Daegu 41566, Korea;
| | - Sung-Hyun Kim
- Department of Bio-Medical Analysis, Korea Polytechnic College, Chungnam 34134, Korea;
| | - Kangdong Liu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China; (K.L.); (Z.D.)
| | - Zigang Dong
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China; (K.L.); (Z.D.)
| | - Zae Young Ryoo
- School of Life Sciences, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu 41566, Korea; (S.P.); (S.J.); (S.-Y.K.)
- Correspondence: (Z.Y.R.); (M.O.K.); Tel.: +82-53-950-7361 (Z.Y.R.); +82-54-530-1234 (M.O.K.)
| | - Myoung Ok Kim
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea; (H.Z.); (H.H.); (E.K.)
- Correspondence: (Z.Y.R.); (M.O.K.); Tel.: +82-53-950-7361 (Z.Y.R.); +82-54-530-1234 (M.O.K.)
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García P, Lamarca A, Díaz J, Carrera E, Roa JC. Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients. Cancers (Basel) 2020; 12:E3670. [PMID: 33297469 PMCID: PMC7762341 DOI: 10.3390/cancers12123670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 01/17/2023] Open
Abstract
Gallbladder cancer (GBC) is an aggressive disease that shows evident geographic variation and is characterized by a poor prognosis, mainly due to the late diagnosis and ineffective treatment. Genetic variants associated with GBC susceptibility, including polymorphisms within the toll-like receptors TLR2 and TLR4, the cytochrome P450 1A1 (CYP1A1), and the ATP-binding cassette (ABC) transporter ABCG8 genes, represent promising biomarkers for the stratification of patients at higher risk of GBC; thus, showing potential to prioritize cholecystectomy, particularly considering that early diagnosis is difficult due to the absence of specific signs and symptoms. Similarly, our better understanding of the gallbladder carcinogenic processes has led to identify several cellular and molecular events that may influence patient management, including HER2 aberrations, high tumor mutational burden, microsatellite instability, among others. Despite these reports on interesting and promising markers for risk assessment, diagnosis, and prognosis; there is an unmet need for reliable and validated biomarkers that can improve the management of GBC patients and support clinical decision-making. This review article examines the most potentially significant biomarkers of susceptibility, diagnosis, prognosis, and therapy selection for GBC patients, highlighting the need to find and validate existing and new molecular biomarkers to improve patient outcomes.
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Affiliation(s)
- Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile;
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK;
| | - Javier Díaz
- Departamento del Aparato Digestivo, Hospital Nacional Edgardo Rebagliati Martins-Essalud, School of Medicine, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru;
| | - Enrique Carrera
- Department of Gastroenterology, Hospital Especialidades Eugenio Espejo, Universidad San Francisco de Quito, Quito 170136, Ecuador;
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile;
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Chan TG, O'Neill E, Habjan C, Cornelissen B. Combination Strategies to Improve Targeted Radionuclide Therapy. J Nucl Med 2020; 61:1544-1552. [PMID: 33037092 PMCID: PMC8679619 DOI: 10.2967/jnumed.120.248062] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 09/09/2020] [Indexed: 01/20/2023] Open
Abstract
In recent years, targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. In contrast to conventional radiotherapy, TRT delivers ionizing radiation to tumors in a targeted manner, reducing the dose that healthy tissues are exposed to. Existing TRT strategies include the use of 177Lu-DOTATATE, 131I-metaiodobenzylguanidine, Bexxar, and Zevalin, clinically approved agents for the treatment of neuroendocrine tumors, neuroblastoma, and non-Hodgkin lymphoma, respectively. Although promising results have been obtained with these agents, clinical evidence acquired to date suggests that only a small percentage of patients achieves complete response. Consequently, there have been attempts to improve TRT outcomes through combinations with other therapeutic agents; such strategies include administering concurrent TRT and chemotherapy, and the use of TRT with known or putative radiosensitizers such as poly(adenosine diphosphate ribose) polymerase and mammalian-target-of-rapamycin inhibitors. In addition to potentially achieving greater therapeutic effects than the respective monotherapies, these strategies may lead to lower dosages or numbers of cycles required and, in turn, reduce unwanted toxicities. As of now, several clinical trials have been conducted to assess the benefits of TRT-based combination therapies, sometimes despite limited preclinical evidence being available in the public domain to support their use. Although some clinical trials have yielded promising results, others have shown no clear survival benefit from particular combination treatments. Here, we present a comprehensive review of combination strategies with TRT reported in the literature to date and evaluate their therapeutic potential.
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Affiliation(s)
- Tiffany G Chan
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Edward O'Neill
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Christine Habjan
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Bart Cornelissen
- Department of Oncology, University of Oxford, Oxford, United Kingdom
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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Baichan P, Naicker P, Devar JWS, Smith M, Candy GP, Nweke E. Targeting gallbladder cancer: a pathway based perspective. Mol Biol Rep 2020; 47:2361-2369. [PMID: 32020429 DOI: 10.1007/s11033-020-05269-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/20/2020] [Indexed: 12/29/2022]
Abstract
Gallbladder cancer (GBC) has a poor prognosis with a 5-year survival rate suggesting the need for more effective treatment strategies. Studying the cross-talk of several pathways involved in crucial cellular and biological processes such as cell growth, proliferation, migration and apoptosis would prove beneficial in identifying key players of GBC progression and targeting them. This review highlights several pathways known to be dysregulated in GBC onset and progression and describes known and potential targets. Within these pathways, there are proteins involved in the signalling cascade, which may be targeted as potential biomarkers and drug targets. Furthermore, the cross-talk of these pathways is investigated in the context of GBC and the implications thereof. A better understanding of the pathways involved in GBC pathogenesis will aid clinicians in the prognosis, diagnosis and treatment of patients. There are significant clinical implications of GBC pathway-based studies as they permit the understanding of onset and progression of the disease.
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Affiliation(s)
- P Baichan
- Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Republic of South Africa.
| | - P Naicker
- Department of Biosciences, Council for Scientific and Industrial Research, Meiring Naude Rd, Brummeria, Pretoria, South Africa
| | - J W S Devar
- Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Republic of South Africa
| | - M Smith
- Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Republic of South Africa
| | - G P Candy
- Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Republic of South Africa
| | - E Nweke
- Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Republic of South Africa
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mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance. JOURNAL OF ONCOLOGY 2019; 2019:5956867. [PMID: 31929797 PMCID: PMC6942807 DOI: 10.1155/2019/5956867] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/20/2019] [Accepted: 11/30/2019] [Indexed: 12/27/2022]
Abstract
Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.
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Espinoza JA, Riquelme I, Sagredo EA, Rosa L, García P, Bizama C, Apud-Bell M, Leal P, Weber H, Benavente F, Vargas S, Romero D, Kalergis AM, Roa JC. Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma. Histopathology 2018; 74:597-607. [PMID: 30565710 DOI: 10.1111/his.13797] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023]
Abstract
AIMS Gallbladder cancer (GBC) is an aggressive tumour that is usually diagnosed at advanced stages and is characterised by a poor prognosis. Using public data of normal human tissues, we found that mRNA and protein levels of mucin 5B (MUC5B) and carbonic anhydrase 9 (CA9) were highly increased in gallbladder tissues. In addition, previous evidence has shown that claudin 18 (CLDN18) protein expression is higher in GBC. The aim of this study was to perform an analysis of these cell surface proteins during the histological progression of GBC in order to identify their theranostic potential. METHODS AND RESULTS MUC5B expression, CA9 expression and CLDN18 expression were examined by immunohistochemistry in a series of 179 chronic cholecystitis (including 16 metaplastic tissues), 15 dysplasia and 217 GBC samples by the use of tissue microarray analysis. A composite staining score was calculated from staining intensity and percentage of positive cells. Immunohistochemical analysis showed high expression of MUC5B and CA9 among normal epithelium, metaplastic tissues, and dysplastic tissues. However, expression of both proteins was observed in roughly 50% of GBC samples. In contrast, CLDN18 was absent in normal epithelium, but its expression was higher in metaplastic cells. Among GBC cases, approximately half showed high CLDN18 expression. No associations were found between MUC5B, CA9 and CLDN18 expression and any clinicopathological features. CONCLUSIONS CLDN18 is a new metaplasia marker in gallbladder tissues, and is conserved in approximately half of GBC cases. MUC5B and CA9 are highly conserved during GBC histological progression. The three markers are potential theranostic markers, in particular CA9 and CLDN18, for which there are already targeted therapies available.
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Affiliation(s)
- Jaime A Espinoza
- SciLifeLab, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco, Chile
| | - Eduardo A Sagredo
- Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lorena Rosa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María Apud-Bell
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pamela Leal
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile
| | - Helga Weber
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile
| | - Felipe Benavente
- Departamento de Procesos Diagnósticos y Evaluación, Facultad de Ciencias de la Salud, Universidad Católica de Temuco, Temuco, Chile
| | - Sergio Vargas
- Department of Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Diego Romero
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Department of Molecular Genetics and Microbiology, Millennium Institute of Immunology and Immunotherapy, Faculty of Biological Sciences, Santiago, Chile.,Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Molecular Genetics and Microbiology, Millennium Institute of Immunology and Immunotherapy, Faculty of Biological Sciences, Santiago, Chile
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Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives. Cancer Treat Rev 2018; 72:45-55. [PMID: 30476750 DOI: 10.1016/j.ctrv.2018.11.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches. The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes. Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy. This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.
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Nemunaitis JM, Brown-Glabeman U, Soares H, Belmonte J, Liem B, Nir I, Phuoc V, Gullapalli RR. Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico. BMC Cancer 2018; 18:665. [PMID: 29914418 PMCID: PMC6006713 DOI: 10.1186/s12885-018-4575-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/01/2018] [Indexed: 12/18/2022] Open
Abstract
Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.
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Affiliation(s)
- Jacklyn M Nemunaitis
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Ursa Brown-Glabeman
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Heloisa Soares
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Jessica Belmonte
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Ben Liem
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Itzhak Nir
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Surgery, Division of Surgical Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Victor Phuoc
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Surgery, Division of Surgical Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Rama R Gullapalli
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA. .,Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. .,Department of Chemical and Biological Engineering, University of New Mexico, Room 333A, MSC08-4640, Albuquerque, NM, 87131, USA.
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12
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Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer. Oncotarget 2018; 8:26169-26184. [PMID: 28412732 PMCID: PMC5432248 DOI: 10.18632/oncotarget.15410] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/01/2017] [Indexed: 12/22/2022] Open
Abstract
Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
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13
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Targeting AMPK, mTOR and β-Catenin by Combined Metformin and Aspirin Therapy in HCC: An Appraisal in Egyptian HCC Patients. Mol Diagn Ther 2017; 22:115-127. [PMID: 29094287 DOI: 10.1007/s40291-017-0307-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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14
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 250] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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15
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Zhou L, Yuan D, Zhang ZG, Liang ZY, Zhou WX, Yang JY, Jiang SH, Lu J, Zhang TP, You L, Guo JC, Zhao YP. Expression of key mTOR pathway components in pancreatic ductal adenocarcinoma: A multicenter study for clinicopathologic and prognostic significance. Cancer Lett 2017; 395:45-52. [DOI: 10.1016/j.canlet.2017.02.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 02/07/2023]
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16
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Mayr C, Ocker M, Ritter M, Pichler M, Neureiter D, Kiesslich T. Biliary tract cancer stem cells - translational options and challenges. World J Gastroenterol 2017; 23:2470-2482. [PMID: 28465631 PMCID: PMC5394510 DOI: 10.3748/wjg.v23.i14.2470] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 02/27/2017] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells - the cancer stem cells - possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.
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17
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Ding XF, Li LF, Zhou XL, Guo LN, Dou MM, Chi YY, Wu SX, Zhang YN, Shan ZZ, Zhang YJ, Wang F, Fan QX, Zhao J, Sun TW. P-mTOR Expression and Implication in Breast Carcinoma: A Systematic Review and Meta-Analysis. PLoS One 2017; 12:e0170302. [PMID: 28114374 PMCID: PMC5256929 DOI: 10.1371/journal.pone.0170302] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/03/2017] [Indexed: 11/24/2022] Open
Abstract
Objective Phosphorylated mammalian target of rapamycin (p-mTOR) is a promising prognostic marker in many types of cancer. However, its survival benefit in patients with breast carcinoma remains unknown. The aim of the present study was to assess the relationship between p-mTOR expression and prognosis in breast carcinoma based on a systematic review and meta-analysis. Materials and Methods Electronic databases (including Pubmed, Embase, ISI web of science, and Cochrane Library) were searched up to November 24, 2015. The outcome measures were hazard ratios (HRs) with 95% confidence interval (CI) for the association between the prognosis of breast carcinoma patients and p-mTOR expression. Primary end points were disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS). Statistical analysis was performed with STATA 12.0. Results Nine cohort studies including 3051 patients met full eligibility criteria. The pooled HRs (95% CI) for OS, DFS, and RFS were 0.84 (0.27–2.63), 0.71 (0.40–1.23), and 0.48 (0.20–1.18), respectively. Conclusions Our findings suggested that p-mTOR overexpression was not significantly related to prognosis in breast carcinoma regarding OS and disease recurrence. Prospective studies are warranted to examine the association between p-mTOR expression and survival outcomes in breast carcinoma.
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Affiliation(s)
- Xian-Fei Ding
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Feng Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xue-Liang Zhou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Na Guo
- Department of Gerontology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Meng-Meng Dou
- Department of Integrated Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yan-Yan Chi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shao-Xuan Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ya-Na Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zheng-Zheng Shan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yi-Jie Zhang
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Feng Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qing-Xia Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tong-Wen Sun
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- * E-mail:
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18
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Weber H, Leal P, Stein S, Kunkel H, García P, Bizama C, Espinoza JA, Riquelme I, Nervi B, Araya JC, Grez M, Roa JC. Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice. Oncotarget 2016; 6:31877-88. [PMID: 26397134 PMCID: PMC4741647 DOI: 10.18632/oncotarget.5047] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 09/01/2015] [Indexed: 01/17/2023] Open
Abstract
Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.
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Affiliation(s)
- Helga Weber
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Pamela Leal
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Stefan Stein
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Hana Kunkel
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Patricia García
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jaime A Espinoza
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ismael Riquelme
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, UC-Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan C Araya
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Manuel Grez
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Juan C Roa
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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19
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Mohri D, Ijichi H, Miyabayashi K, Takahashi R, Kudo Y, Sasaki T, Asaoka Y, Tanaka Y, Ikenoue T, Tateishi K, Tada M, Isayama H, Koike K. A potent therapeutics for gallbladder cancer by combinatorial inhibition of the MAPK and mTOR signaling networks. J Gastroenterol 2016; 51:711-21. [PMID: 26614007 DOI: 10.1007/s00535-015-1145-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 11/06/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallbladder cancer (GBC) is the most common type of cancer with the worst prognosis among the bile duct cancers. There still remains a clear need for effective mechanism-based novel therapeutic approaches. A crosstalk between mitogen-activated protein kinase (MAPK) and the mammalian target of Rapamycin (mTOR) signaling pathways has been reported in several cancers. We hypothesized that targeting both pathways in combination will be a potent therapeutic for GBC. METHODS Expression of phospho-ERK and phospho-S6rp protein were evaluated by immunostaining in surgically resected GBC specimens (n = 30). GBC cell lines and a xenograft model were treated with CI-1040, an inhibitor of MEK (mitogen-activated protein kinase kinase) and RAD001, an inhibitor of mTOR, alone or in combination, and then, we examined the cell proliferation and tumor growth, cell cycle status, and apoptosis. RESULTS Analysis of human GBC tissues demonstrated that MAPK and mTOR signaling pathways were frequently coordinately dysregulated in one third of them. The combination therapy inhibited both signaling pathways and subsequently inhibited human GBC cell proliferation in vitro and xenograft tumor growth in vivo. Compared to the single treatment, the combination therapy significantly induced cell cycle arrest and apoptosis with decreased cyclin D1 expression. CONCLUSIONS The double blockade of MAPK and mTOR signaling pathways inhibits the signal crosstalk and shows anti-tumor activity, which can be a potent therapeutic for GBC, especially for the patients with hyperactivated signaling of both pathways.
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Affiliation(s)
- Dai Mohri
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Hideaki Ijichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Ryota Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Yotaro Kudo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Takashi Sasaki
- Division of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koutou-Ku, Tokyo, 135-8550, Japan
| | - Yoshinari Asaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Yasuo Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, Institute of Medical Sciences, University of Tokyo, 4-6-1 Shiroganedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Keisuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Minoru Tada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
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20
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Hu J, Yin B. Advances in biomarkers of biliary tract cancers. Biomed Pharmacother 2016; 81:128-135. [PMID: 27261586 DOI: 10.1016/j.biopha.2016.02.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 02/16/2016] [Accepted: 02/16/2016] [Indexed: 12/14/2022] Open
Abstract
Tumor biomarkers can be applied for early diagnosis or precise treatment, thereby leading to personalized treatment and better outcomes. Biliary tract cancers (BTCs) are a group of cancers that occurs in different locations and have different clinical or genetic properties. Though the incidence of BTCs is rare, BTCs are among the most lethal cancers in the world and all have very low 5-year survivals. Lack of efficient early diagnostic approaches or adjuvant therapies for BTCs are main reasons. These urge us to broaden the researches into BTC biomarkers. Although few progresses of diagnostic biomarkers for BTCs have been achieved, there are still some advances in prognostic, predictive and therapeutic areas. In this review, we will focus on these achievements.
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Affiliation(s)
- Jun Hu
- Department of General Surgery, Huashan Hosptial, Fudan University, Shanghai 200040, PR China.
| | - Baobing Yin
- Department of General Surgery, Huashan Hosptial, Fudan University, Shanghai 200040, PR China; Department of General Surgery, Jing'an Branch of Huashan Hospital, Fudan University (Jing'an District Centre Hospital of Shanghai), Shanghai 200040, PR China.
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21
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Marks EI, Yee NS. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 2016; 22:1335-47. [PMID: 26819503 PMCID: PMC4721969 DOI: 10.3748/wjg.v22.i4.1335] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.
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22
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Espinoza JA, García P, Bizama C, Leal JL, Riquelme I, Weber H, Macanas P, Aguayo G, Viñuela E, Roa JC, Nervi B. Low expression of equilibrative nucleoside transporter 1 is associated with poor prognosis in chemotherapy-naïve pT2 gallbladder adenocarcinoma patients. Histopathology 2015; 68:722-8. [PMID: 26266900 DOI: 10.1111/his.12805] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 08/08/2015] [Indexed: 12/28/2022]
Abstract
AIMS Equilibrative nucleoside transporter 1 (ENT1) is the major transporter of the chemotherapeutic drug gemcitabine, the current therapy for advanced gallbladder cancer (GBC). ENT1 expression has been proposed as a predictive marker for gemcitabine-treated pancreatic cancer patients. The aim of study was to explore the value of ENT1 measurement in chemotherapy-naïve patients with advanced GBC. MATERIALS AND RESULTS Immunohistochemistry for ENT1 was performed on 214 GBC samples from patients who had never undergone co-adjuvant or neo-adjuvant chemotherapy. Advanced GBC cases were divided into groups with low or high ENT1 expression. Kaplan-Meier tests were used for survival analyses. The Cox regression method was used to assess the association of ENT1 expression with overall survival (OS). Low ENT1 expression was associated with younger patient age (P = 0.03) and moderate-to-poor histological differentiation (P = 0.01). pT2 patients with low ENT1 expression had shorter median survival (17.3 versus 28.7 months) and lower OS (17.3% versus 33.3%, P < 0.05) than patients with high ENT1 expression. Low ENT1 expression was an independent prognostic factor for OS (P = 0.036). CONCLUSIONS ENT1 is a prognostic marker for pT2 GBC patients. Additional studies are needed to determine whether ENT1 has predictive value for gemcitabine response in GBC.
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Affiliation(s)
- Jaime A Espinoza
- Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia García
- Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - José L Leal
- Department of Haematology and Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ismael Riquelme
- Department of Pathology, School of Medicine, CEGIN-BIOREN, Molecular Pathology Laboratory, Universidad de La Frontera, Temuco, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, CEGIN-BIOREN, Molecular Pathology Laboratory, Universidad de La Frontera, Temuco, Chile
| | - Patricia Macanas
- UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Haematology and Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gloria Aguayo
- Department of Pathology, Hospital Dr Sótero del Río, Santiago, Chile
| | - Eduardo Viñuela
- Department of Digestive Surgery, Hospital Dr Sótero del Río, Santiago, Chile
| | - Juan C Roa
- Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Haematology and Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
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23
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Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer. Br J Cancer 2015; 112:1042-51. [PMID: 25742482 PMCID: PMC4366884 DOI: 10.1038/bjc.2014.625] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/08/2014] [Accepted: 11/25/2014] [Indexed: 12/20/2022] Open
Abstract
Background: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). Methods: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. Results: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. Conclusions: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.
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24
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Suzuki H, Roa JC, Kawamoto T, Ishige K, Wistuba II, Li D, Thomas MB, Shoda J. Expression of insulin-like growth factor I receptor as a biomarker for predicting prognosis in biliary tract cancer patients. Mol Clin Oncol 2015; 3:464-470. [PMID: 26137252 DOI: 10.3892/mco.2015.515] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 01/09/2015] [Indexed: 11/06/2022] Open
Abstract
Carcinomas of the gallbladder (GBCa) and bile ducts are aggressive tumors with poor survival and it is, therefore, essential to elucidate the molecular mechanisms of the various signaling pathways in order to develop effective therapies. In this study, tumor specimens from 40 GBCa patients, 12 extrahepatic bile duct carcinoma patients and 26 intrahepatic bile duct carcinoma patients from the USA and Japan were investigated for insulin-like growth factor I receptor (IGF-IR), mammalian target of rapamycin (mTOR) and rapidly accelerated fibrosarcoma-1 (Raf-1) expression by immunohistochemistry; in addition, the correlations with histological type, pathological stage and patient outcome were analyzed. Positive expression of IGF-IR, mTOR and Raf-1 were identified in 68, 73 and 85% of the specimens, respectively. There was no association with histological type and pathological stage, although the positive expression rate of Raf-1 was higher in advanced-stage GBCa. Moreover, patients with positive expression of IGF-IR exhibited significantly reduced survival compared to those with negative IGF-IR expression. In conclusion, IGF-IR, mTOR and Raf-1 were highly expressed in biliary tract cancer and targeted therapy against IGF-IR may be an effective strategy. Among these molecules, IGF-IR expression was found to be a useful biomarker for identifying patients who may benefit from additional treatment.
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Affiliation(s)
- Hideo Suzuki
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Juan C Roa
- Molecular Pathology Laboratory, Department of Pathology, Pontifical Catholic University of Chile, Santiago 8320000, Chile
| | | | - Kazunori Ishige
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Ignacio I Wistuba
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Melanie B Thomas
- Medical University of South Carolina, Hollings Cancer Center, Charleston, SC 29425, USA
| | - Junichi Shoda
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
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25
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Cao Y, Liu X, Lu W, Chen Y, Wu X, Li M, Wang XA, Zhang F, Jiang L, Zhang Y, Hu Y, Xiang S, Shu Y, Bao R, Li H, Wu W, Weng H, Yen Y, Liu Y. Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer. Cancer Lett 2015; 360:141-50. [PMID: 25657110 DOI: 10.1016/j.canlet.2015.01.041] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 01/27/2015] [Accepted: 01/29/2015] [Indexed: 12/20/2022]
Abstract
Fibronectin (FN), a heterodimeric glycoprotein overexpressed in several types of tumors, has been implicated in cancer progression via the activation of integrin-mediated pro-oncogenic pathways. The FN level in human bile fluid is dramatically increased in malignant biliary diseases; however, FN expression and its biological functions in gallbladder cancer (GBC) remain unknown. In this study, we found that FN was overexpressed in GBC tissues and was associated with a worse prognosis in GBC patients. In vitro experimental studies indicated that exogenous FN significantly enhanced cell proliferation, invasion and active MMP-9 secretion in human GBC cell lines (GBC-SD and NOZ). Moreover, the key kinases of the mTOR signaling pathway, including FAK, Akt, mTOR and 4E-BP1, were markedly activated in a time-dependent manner in FN-treated GBC-SD and NOZ cells. The IHC statistical analyses validated that FN expression was positively correlated with the phosphorylation levels of the 4E-BP1 protein in GBC tissues. Furthermore, rapamycin, a specific inhibitor of mTOR, almost completely blocked FN-induced phosphorylation of 4E-BP1 and also partially abrogated the stimulatory effects of FN on GBC cell proliferation and invasion. In vivo, FN treatment significantly promoted the proliferation and metastasis of GBC cells and markedly activated Akt/mTOR/4E-BP1 signaling cascade. These findings demonstrate that FN may play a critical role in the modulation of cell proliferation and invasion via mTOR signaling pathway activation during GBC progression.
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Affiliation(s)
- Yang Cao
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiyong Liu
- Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Wei Lu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanyuan Chen
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangsong Wu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Maolan Li
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xu-An Wang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fei Zhang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Jiang
- Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yijian Zhang
- Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yunping Hu
- Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shanshan Xiang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yijun Shu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Runfa Bao
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huaifeng Li
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenguang Wu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Weng
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Yen
- Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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26
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Bizama C, García P, Espinoza JA, Weber H, Leal P, Nervi B, Roa JC. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev 2015; 41:222-34. [PMID: 25639632 DOI: 10.1016/j.ctrv.2015.01.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/12/2015] [Accepted: 01/13/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways-Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis-which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.
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Affiliation(s)
- Carolina Bizama
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jaime A Espinoza
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Pamela Leal
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 26767000, Chile
| | - Juan Carlos Roa
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
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27
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Afonso J, Longatto-Filho A, DA Silva VM, Amaro T, Santos LL. Phospho-mTOR in non-tumour and tumour bladder urothelium: Pattern of expression and impact on urothelial bladder cancer patients. Oncol Lett 2014; 8:1447-1454. [PMID: 25202348 PMCID: PMC4156165 DOI: 10.3892/ol.2014.2392] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 06/24/2014] [Indexed: 12/28/2022] Open
Abstract
Urothelial bladder carcinoma (UBC) is heterogeneous in its pathology and clinical behaviour. Evaluation of prognostic and predictive biomarkers is necessary, in order to produce personalised treatment options. The present study used immunohistochemistry to evaluate UBC sections containing tumour and non-tumour areas from 76 patients, for the detection of p-mTOR, CD31 and D2-40 (blood and lymphatic vessels identification, respectively). Of the non-tumour and tumour sections, 36 and 20% were scored positive for p-mTOR expression, respectively. Immunoexpression was observed in umbrella cells from non-tumour urothelium, in all cell layers from non-muscle-invasive (NMI) tumours (including expression in superficial cells), and in spots of cells from muscle-invasive (MI) tumours. Positive expression decreased from non-tumour to tumour urothelium, and from pT1/pTis to pT3/pT4 tumours; however, the few pT3/pT4 positive cases had worse survival rates, with 5-year disease-free survival being significantly lower. Angiogenesis occurrence was impaired in pT3/pT4 tumours that did not express p-mTOR. In conclusion, p-mTOR expression in non-tumour umbrella cells is likely a reflection of their metabolic plasticity, and extension to the inner layers of the urothelium in NMI tumours is consistent with an enhanced malignant potential. The expression in cell spots in a few MI tumours and absence of expression in the remaining tumours is intriguing and requires further research. Additional studies regarding the up- and downstream effectors of the mTOR pathway should be conducted.
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Affiliation(s)
- Julieta Afonso
- Life and Health Sciences Research Institute (ICVS), School of Healh Sciences (ECS) University of Minho, Braga 4710-057, Portugal ; ICVS/3B's, PT Government Associate Laboratory, Braga 4710-057/Guimarães 4806-909, Portugal
| | - Adhemar Longatto-Filho
- Life and Health Sciences Research Institute (ICVS), School of Healh Sciences (ECS) University of Minho, Braga 4710-057, Portugal ; ICVS/3B's, PT Government Associate Laboratory, Braga 4710-057/Guimarães 4806-909, Portugal ; Laboratory of Medical Investigation (LIM 14), Faculty of Medicine, São Paulo State University, São Paulo 01246-000, Brazil ; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo 14784-400, Brazil
| | | | - Teresina Amaro
- Experimental Pathology and Therapeutics Research Center, Portuguese Institute of Oncology (IPO), Porto 4200-072, Portugal
| | - Lúcio L Santos
- Department of Surgical Oncology, Portuguese Institute of Oncology (IPO), Porto 4200-072, Portugal ; Faculty of Health Sciences, University Fernando Pessoa, Porto 4200-150, Portugal
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28
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Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep 2014; 41:4507-12. [PMID: 24623408 DOI: 10.1007/s11033-014-3321-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Accepted: 02/24/2014] [Indexed: 10/25/2022]
Abstract
Gallbladder cancer (GBC) is an aggressive disease in which epithelial-mesenchymal transition (EMT) plays a critical role. Whether inhibition of mTOR effects via EMT reversal in GBC remains unclear. Using genetic and pharmacologic inhibitions of mTOR, we investigated the changes of EMT levels in GBC cells. Expressions of EMT related genes were also studied. Migration and invasion assays were carried out and in vivo tumour metastasis mouse models were established. Circulating tumour DNA was quantified. We used EMT index (ratio of Vimentin/Ecadherin expression) to profile EMT levels. We found that inhibition of mTOR using shRNAs and rapamycin inhibited EMT in GBC-SD gallbladder cancer cells. Inhibition of mTOR inhibited EMT in GBC-SD cells in TGF-β-dependent manner, which was contributed majorly by mTORC2 inhibition. Rapamycin decreased invasiveness and migration of GBC-SD cells in vitro and in vivo. We have in the current study shown that rapamycin diminishes the ability of invasion and migration of GBC via inhibition of TGF-β-dependent EMT. Our findings contribute to the understanding of the carcinogenesis of GBC.
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29
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Leal P, Garcia P, Sandoval A, Buchegger K, Weber H, Tapia O, Roa JC. AKT/mTOR substrate P70S6K is frequently phosphorylated in gallbladder cancer tissue and cell lines. Onco Targets Ther 2013; 6:1373-84. [PMID: 24124380 PMCID: PMC3794848 DOI: 10.2147/ott.s46897] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Gallbladder carcinoma is a highly malignant tumor and a public health problem in some parts of the world. It is characterized by a poor prognosis and its resistance to radio and chemotherapy. There is an urgent need to develop novel therapeutic alternatives for the treatment of gallbladder carcinoma. The mammalian target of the rapamycin (mTOR) signaling pathway is activated in about 50% of human malignancies, and its role in gallbladder carcinoma has previously been suggested. In the present study, we investigated the phosphorylation status of the mTOR substrate p70S6K in preneoplastic and neoplastic gallbladder tissues and evaluated the effect of three mTOR inhibitors on cell growth and migration in gallbladder carcinoma cell lines. Methods Immunohistochemical staining of phospho-p70S6K was analyzed in 181 gallbladder carcinoma cases, classified according to lesion type as dysplasia, early carcinoma, or advanced carcinoma. Protein expression of AKT/mTOR members was also evaluated in eight gallbladder carcinoma cell lines by Western blot analysis. We selected two gallbladder carcinoma cell lines (G415 and TGBC-2TKB) to evaluate the effect of rapamycin, RAD001, and AZD8055 on cell viability, cell migration, and protein expression. Results Our results showed that phospho-p70S6K is highly expressed in dysplasia (66.7%, 12/18), early cancer (84.6%, 22/26), and advanced cancer (88.3%, 121/137). No statistical correlation was observed between phospho-p70S6K status and any clinical or pathological features, including age, gender, ethnicity, wall infiltration level, or histological differentiation (P < 0.05). In vitro treatment with rapamycin, RAD001, and AZD8055 reduced cell growth, cell migration, and phospho-p70S6K expression significantly in G-415 and TGBC-2TKB cancer cells (P < 0.001). Conclusion Our findings confirm the upregulation of this signaling pathway in gallbladder carcinoma and provide a rationale for the potential use of mTOR inhibitors as a therapeutic strategy for human gallbladder carcinoma.
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Affiliation(s)
- Pamela Leal
- Department of Pathology, Universidad de La Frontera, Center of Genetical and Immunological Studies-Scientific and Technological Bioresource Nucleus, Temuco, Santiago, Chile
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