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Pol M, Gao H, Fox JM, Jia X. TGFβ1 and RGD Cooperatively Regulate SMAD2/3-Mediated Oncogenic Effects in Prostate Cancer Cells in Bio-Orthogonally Constructed Hydrogels. ACS Biomater Sci Eng 2025; 11:3003-3018. [PMID: 40214406 DOI: 10.1021/acsbiomaterials.5c00007] [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] [Indexed: 05/13/2025]
Abstract
To recapitulate prostate cancer metastasis, DU145 cells were cultured in a hyaluronic acid-based, bio-orthogonally constructed, protease-degradable hydrogels. In the presence of a covalently conjugated integrin-binding peptide (GRGDSP), DU145 cells formed tumoroids and exhibited small protrusions. Upon addition of soluble transforming growth factor beta 1 (TGFβ1), cells underwent morphological changes to form extended interconnected cellular networks. Contrarily, in RGD-free hydrogels, cells maintained spherical structures even in the presence of TGFβ1. In RGD-conjugated hydrogels, TGFβ1 induced nuclear localization of SMAD2/3, upregulating a wide range of TGFβ1 target genes and proteins. Prolonged exposure to TGFβ1 led to matrix remodeling and induced epithelial-to-mesenchymal transition in DU145 cells, with loss of epithelial markers and gain of mesenchymal markers. A pharmacological inhibitor of TGFβRI/ALK5, SB-431542, attenuated TGFβ1-induced morphological changes, abrogated nuclear localization of SMAD2/3, and restored the expression of key epithelial markers. Our findings highlight the cooperative role of TGFβ1 signaling and integrin-binding peptide in the acquisition of an aggressive phenotype and the promotion of tumor progression.
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Affiliation(s)
- Mugdha Pol
- Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, United States
| | - Hanyuan Gao
- Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States
| | - Joseph M Fox
- Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
| | - Xinqiao Jia
- Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, United States
- Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States
- Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19716, United States
- Delaware Biotechnology Institute, Newark, Delaware 19713, United States
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2
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Durán AM, Whitley K, Santiago K, Yoo C, Valdez G, Cheng KW, Ochoa P, de Semir D, Xiu J, Chokkalingam P, Das S, Schaefer ES, Rowe SP, Das BC, Casiano CA, Almaguel F. Inhibition of Mitochondrial-Associated Protein MAGMAS Resensitizes Chemoresistant Prostate Cancer Cells to Docetaxel. Cancers (Basel) 2025; 17:1535. [PMID: 40361461 PMCID: PMC12072152 DOI: 10.3390/cancers17091535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/15/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Metastatic prostate cancer (PCa) is the leading cause of cancer-related deaths and a major contributor to cancer mortality in men. Most patients with metastatic PCa eventually develop metastatic castration-resistant prostate cancer (mCRPC), characterized by resistance to treatment with androgen-deprivation therapy, and often later the development of resistance to other types of agents. MAGMAS, a 13.8 kDa mitochondrial-associated protein, facilitates the import of nuclear-encoded proteins into the mitochondrial matrix. Overexpression of MAGMAS has been observed in several aggressive cancers, including breast, glioblastoma, and prostate cancer. When overexpressed, MAGMAS acts as a cytoprotective protein by scavenging reactive oxygen species (ROS), maintaining ROS levels that support cell proliferation while avoiding the induction of apoptosis. This study investigates the role of MAGMAS in therapy resistance in PCa cells. METHODS/RESULTS Quantitative immunoblotting revealed that MAGMAS is endogenously upregulated in docetaxel-resistant (DR) PCa cell lines compared to their docetaxel-sensitive parental counterparts. While MAGMAS depletion alone did not affect the survival of DR cells, it significantly sensitized them to docetaxel (DTX), as indicated by a marked reduction in clonogenic potential. Additionally, transient knockdown of MAGMAS in these resistant cells significantly decreased the levels of ABCB1 protein. Consistent with these findings, sub-therapeutic inhibition of MAGMAS using the novel BT#9 inhibitor, in combination with increasing concentrations of DTX, enhanced the sensitivity of DR cells to DTX, as demonstrated by proliferation and clonogenic assays. Lastly, RNA tumor expression predicts overall survival (OS). CONCLUSIONS These results implicate MAGMAS in PCa chemoresistance and suggest that targeting this protein could provide a novel therapeutic strategy for treating DR tumors.
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Affiliation(s)
- Alfonso M. Durán
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Cancer Center, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Kristen Whitley
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Krystal Santiago
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Christian Yoo
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
| | - Giancarlo Valdez
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
| | - Kai Wen Cheng
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
| | - Pedro Ochoa
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
| | - David de Semir
- Caris Life Sciences, Phoenix, AZ 85040, USA; (D.d.S.); (J.X.)
| | - Joanne Xiu
- Caris Life Sciences, Phoenix, AZ 85040, USA; (D.d.S.); (J.X.)
| | - Parthiban Chokkalingam
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14215, USA; (P.C.); (S.D.); (B.C.D.)
| | - Sasmita Das
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14215, USA; (P.C.); (S.D.); (B.C.D.)
| | | | - Steven P. Rowe
- Department of Radiology, University of North Carolina, Chapel Hill, NC 27514, USA;
| | - Bhaskar C. Das
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14215, USA; (P.C.); (S.D.); (B.C.D.)
| | - Carlos A. Casiano
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Cancer Center, Loma Linda University Health, Loma Linda, CA 92354, USA
- Department of Medicine, Rheumatology Division, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Frankis Almaguel
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (A.M.D.); (K.S.); (C.Y.); (K.W.C.); (P.O.); (C.A.C.)
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Cancer Center, Loma Linda University Health, Loma Linda, CA 92354, USA
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Ciaramicoli LM, Kwon HY, Im CY, Kim N, Oh Y, Chang YT, Kang NY. Label-Free Enrichment of Highly Metastatic Tumor-Initiating Cells up to a Monoclonal State. Biomater Res 2025; 29:0168. [PMID: 40177028 PMCID: PMC11964298 DOI: 10.34133/bmr.0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/30/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Affiliation(s)
- Larissa M. Ciaramicoli
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Haw-Young Kwon
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Chun Y. Im
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Namhui Kim
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Yoojin Oh
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Young-Tae Chang
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Nam-Young Kang
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
- Department of Convergence I.T. Engineering,
Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Trecarten S, Liss MA, Hamilton-Reeves J, DiGiovanni J. Obesity, dietary interventions and microbiome alterations in the development and progression of prostate cancer. Front Immunol 2025; 15:1448116. [PMID: 39840030 PMCID: PMC11747771 DOI: 10.3389/fimmu.2024.1448116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
Purpose of review The role of the microbiome in prostate cancer is an emerging subject of research interest. Certain lifestyle factors, such as obesity and diet, can also impact the microbiome, which has been implicated in many diseases, such as heart disease and diabetes. However, this link has yet to be explored in detail in the context of prostate cancer. The purpose of this review is to explore the cross-talk between obesity, dietary interventions, and microbiome alterations in the development and progression of prostate cancer. Recent findings Many possible mechanisms exist linking obesity and dietary interventions to microbiome alterations and prostate cancer. The gut microbiome produces metabolites that could play a role in prostate cancer oncogenesis, including short-chain fatty acids, cholesterol derivatives, and folic acid. The microbiome also plays a pivotal role in the prostate tumor microenvironment (TME), contributing to inflammation, local tissue hypoxia, and epithelial-mesenchymal transition. A bidirectional relationship exists between obesity and the microbiome, and certain diets can enact changes to the microbiome, its associated metabolites, and prostate cancer outcomes. Summary Cross-talk exists between obesity, dietary interventions, and the role of the microbiome in the development and progression of prostate cancer. To further our understanding, future human studies in prostate cancer should investigate microbiome changes and incorporate an assessment of microbiome-derived metabolites and cellular/immune changes in the TME.
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Affiliation(s)
- Shaun Trecarten
- Department of Urology, The University of Texas Health Sciences Center San Antonio, San Antonio, TX, United States
| | - Michael A. Liss
- Department of Urology, University of San Diego, San Diego, CA, United States
| | - Jill Hamilton-Reeves
- Department of Urology, University of Kansas Medical Center, Kansas City, KS, United States
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin and Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, United States
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6
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Alerasool P, Zhou S, Miller E, Anker J, Tsao B, Kyprianou N, Tsao CK. A Personalized Approach for Oligometastatic Prostate Cancer: Current Understanding and Future Directions. Cancers (Basel) 2025; 17:147. [PMID: 39796774 PMCID: PMC11720581 DOI: 10.3390/cancers17010147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/13/2025] Open
Abstract
Oligometastatic prostate cancer (OMPC) represents an intermediate state in the progression from localized disease to widespread metastasis when the radiographically significant sites are limited in number and location. With no clear consensus on a definition, its diagnostic significance and associated optimal therapeutic approach remain controversial, posing a significant challenge for clinicians. The current standard of care for metastatic disease is to start systemic therapy; however, active surveillance and targeted radiotherapy have become attractive options to mitigate the long-term effects of androgen deprivation therapy (ADT). Furthermore, evolving biomarker methodologies may further define optimal treatment selection. In this review, we summarize the current understanding that guides the treatment of OMPC, with a focus on how host response can be an important contributing factor. Evolving scientific understanding and clinical development will continue to shape the landscape of treatment strategies for this distinct disease state.
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Affiliation(s)
- Parissa Alerasool
- Department of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (C.-K.T.)
- Department of Medicine, Montefiore Medical Center Albert Einstein College of Medicine, Bronx, NY 10467, USA
| | - Susu Zhou
- Department of Medicine, Icahn School of Medicine at Mount Sinai (Morningside/West), New York, NY 10025, USA
| | - Eric Miller
- Department of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (C.-K.T.)
| | - Jonathan Anker
- Department of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (C.-K.T.)
| | - Brandon Tsao
- Department of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (C.-K.T.)
| | - Natasha Kyprianou
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Che-Kai Tsao
- Department of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (C.-K.T.)
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7
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Oguic R, Grskovic A, Spanjol J, Mikolasevic I, Djordjevic G. CD44 Immunohistochemical Expression in Central and Peripheral Parts of Prostatic Adenocarcinoma: An Institutional Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2032. [PMID: 39768912 PMCID: PMC11728140 DOI: 10.3390/medicina60122032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/18/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025]
Abstract
Background and Objectives: Prostate cancer is one of the most commonly diagnosed cancers in the male population and the fifth leading cause of cancer death worldwide in men as of 2022. One of the potential biomarkers that can predict the progression of the disease is the transmembrane adhesion molecule CD44s. The aims of this study were to determine the expression of CD44s in prostate cancer in the central tumor mass and in the tumor periphery of the disease and to compare it with the clinicopathological parameters (PSA, Gleason score, surgical margins, and biochemical recurrence of the disease) in patients treated with radical prostatectomy. Materials and Methods: The research was randomized retrospectively during the period from 2001 to 2006. Tissue microarrays of 121 archival acinar prostate carcinoma samples were immunohistochemically evaluated for CD44s expression. The immunoexpression was determined semiquantitatively, taking into account the percentage (0 (0-5%), 1 (6-24%), 2 (26-75%), and 3 (76-100%) and intensity of the membranous staining of the tumor cells (0 absent; 1 weak at 400×; 2 intermediates at 100×; 3 strong at 40×) and calculated to obtain a final score (0-3 were regarded as negative; 4-6 were regarded as positive). Results: For statistical purposes, we divided the tumors into two categories: Gleason grade group 1 makes up 80.7% and grade group 2, which includes all the remaining Gleason grade groups (out of 2-5), accounts for 19.3% of the tumors. Grade group 1 had the highest incidence of score 4 (positive expression). There were statistically significantly more positive expressions in those tumors with negative prostatectomy margins (chi square: p = 0.001; Cramer V: 0.319). There was no correlation between CD44s expression and biochemical recurrence (p = 0.218), nor with the preoperative PSA values (p = 0.165). In the grade group 1 tumors, the CD44s immunoexpression and status of prostatectomy margin were statistically significantly related with negative margins (p = 0.028). An analysis of the expression of CD44s according to the localization in the central part of the tumor mass and on the periphery of the cancer in the group of tumors with a positive margin did not show a significant correlation because the sample was too small. Descriptively, it can be noted that the expression on the periphery was higher, and the central/peripheral expression ratio was higher in favor of the periphery. Conclusions: Our results provide insight into the possible value of CD44s expression for predicting the behavior of prostate tumors and the justification of therapy after a prostatectomy. Also hypothetically, they indicate a protective role of CD44s in a group of well-differentiated tumors at the periphery of the tumor mass. Therefore, it is useful to study the CD44s molecule further in this sense.
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Affiliation(s)
- Romano Oguic
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Antun Grskovic
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Josip Spanjol
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Ivana Mikolasevic
- Clinical Institute of Oncology and Radiotherapy, University Hospital Centre Rijeka, 51000 Rijeka, Croatia;
| | - Gordana Djordjevic
- Department of Pathology and Cytology, University Hospital Center Rijeka, 51000 Rijeka, Croatia
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Habeshian TS, Cannavale KL, Slezak JM, Shu YH, Chien GW, Chen X, Shi F, Siegmund KD, Van Den Eeden SK, Huang J, Chao CR. DNA methylation markers for risk of metastasis in a cohort of men with localized prostate cancer. Epigenetics 2024; 19:2308920. [PMID: 38525786 DOI: 10.1080/15592294.2024.2308920] [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: 07/26/2023] [Accepted: 01/14/2024] [Indexed: 03/26/2024] Open
Abstract
Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.
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Affiliation(s)
- Talar S Habeshian
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kimberly L Cannavale
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Jeff M Slezak
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Yu-Hsiang Shu
- Biostatistics and Innovations, Biostatistics and Programming, Clinical Affairs, Inari Medical, CA, USA
| | - Gary W Chien
- Department of Urology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, CA, USA
| | - XuFeng Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Feng Shi
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Kimberly D Siegmund
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Chun R Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J Tyson School of Medicine, Pasadena, CA, USA
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9
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Alabi GO, Elekofehinti OO, Sanni DM, Ashaolu JO, Oluwatuyi AO. Polygenic anti-cancer activity of Indigofera macrophylla in prostate cancer induced animal model. Toxicol Rep 2024; 13:101774. [PMID: 39554609 PMCID: PMC11567122 DOI: 10.1016/j.toxrep.2024.101774] [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: 09/24/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Background Prostate cancer (Pca) is a deadly disease prevalent among men, and it accounts for about 7-8 % of mortality globally. Synthetic drugs have proved effective but have limitations and severe side effects. There is, therefore, a need to discover a less expensive, natural therapeutic agent with no side effects in treating the ailment. Aim The study aims to investigate the anti-prostate cancer activity of extracts of Indigofera macrophylla (I. macrophylla) at the physiological and molecular levels in experimental animals. Method Polyphenol-rich extract of I. macrophylla was subjected to HPLC analysis to identify the plant's phytochemical constituent. Adult Wistar rats were orally administered 2mls of 50, 100 and 200 PPM of the cacodylic acid solution for 28 days to induce prostate cancer, while treatment was carried out by orally administering extract of I. macrophylla at doses of 50, 100 and 200 mg/kg for up to 28 days. The anti-inflammatory and apoptotic properties of the extract in experimental animals were investigated by the expression levels of various genetic biomarkers such as Bax-2, TNF-α, IL-6, COX2, IL-1β, β-Catenin, APC, Bcl2, CEA, Caspase 3 and β-Catenin using reverse transcriptase polymerase chain reaction (RT-PCR). Result HPLC analysis shows that I. macrophylla has 21 bioactive components which are categorized into seven groups: flavonoid, terpenes, phenols, isoflavonoid, phytosterols, quinone and glycosides. Administration of the drug shows inconsistencies in the mean body weights of the experimental animals. Further investigation revealed that I. macrophylla increased TNF-α upregulation and expression, significantly downregulated IL-1β, significantly decreased IL-6 expression, ameliorated COX2 expression, downregulated β-catenin expression and significantly reduced the expression of the APC gene. These results show that the drug activity modulates the investigated inflammatory and apoptotic genes in the prostate gland of PCa-induced rats, thus demonstrating its anti-PCa potential. Conclusion The results of this study suggest the potential of a novel treatment protocol of I. macrophylla plant extract to improve therapeutic outcomes for patients with aggressive PCa, which reportedly claims hundreds of thousands of lives yearly.
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Affiliation(s)
- Gbenga Oluwaseyi Alabi
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Nigeria
| | - Olusola Olalekan Elekofehinti
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Nigeria
- Teady Bioscience Research Laboratory, 42, Adinlewa Street, Akure, Ondo State, Nigeria
| | - David Morakinyo Sanni
- Enzymology and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Nigeria
| | - Joseph Opeolu Ashaolu
- Department of Biochemistry, Faculty of Basic Medical Sciences, Redeemers University, PMB 230, Osun State, Nigeria
| | - Adedotun Olayemi Oluwatuyi
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Nigeria
- Teady Bioscience Research Laboratory, 42, Adinlewa Street, Akure, Ondo State, Nigeria
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10
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Sun X, Wu Y, Wang X, Gao X, Zhang S, Sun Z, Liu R, Hu K. Beyond Small Molecules: Antibodies and Peptides for Fibroblast Activation Protein Targeting Radiopharmaceuticals. Pharmaceutics 2024; 16:345. [PMID: 38543239 PMCID: PMC10974899 DOI: 10.3390/pharmaceutics16030345] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 04/05/2025] Open
Abstract
Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. The advent of FAP-based radiotheranostics is anticipated to revolutionize cancer management. Among various types of FAP ligands, peptides and antibodies have shown advantages over small molecules, exemplifying prolonged tumor retention in human volunteers. Within its scope, this review summarizes the recent research progress of the FAP radiopharmaceuticals based on antibodies and peptides in tumor imaging and therapy. Additionally, it incorporates insights from recent studies, providing valuable perspectives on the clinical utility of FAP-targeted radiopharmaceuticals.
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Affiliation(s)
- Xiaona Sun
- School of Printing and Packaging Engineer, Beijing Institute of Graphic Communication, Beijing 102600, China; (X.S.); (Y.W.); (Z.S.)
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
| | - Yuxuan Wu
- School of Printing and Packaging Engineer, Beijing Institute of Graphic Communication, Beijing 102600, China; (X.S.); (Y.W.); (Z.S.)
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
| | - Xingkai Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
| | - Xin Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
| | - Siqi Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
| | - Zhicheng Sun
- School of Printing and Packaging Engineer, Beijing Institute of Graphic Communication, Beijing 102600, China; (X.S.); (Y.W.); (Z.S.)
| | - Ruping Liu
- School of Printing and Packaging Engineer, Beijing Institute of Graphic Communication, Beijing 102600, China; (X.S.); (Y.W.); (Z.S.)
| | - Kuan Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (X.W.); (X.G.); (S.Z.)
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11
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Dakir EH, Gajate C, Mollinedo F. Antitumor activity of alkylphospholipid edelfosine in prostate cancer models and endoplasmic reticulum targeting. Biomed Pharmacother 2023; 167:115436. [PMID: 37683591 DOI: 10.1016/j.biopha.2023.115436] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic prostate cancer. The ether lipid edelfosine is considered the prototype of a family of promising antitumor drugs collectively named as alkylphospholipid analogs. Here, we found that edelfosine was the most potent alkylphospholipid analog in inducing apoptosis in three different human prostate cancer cell lines (LNCaP, PC3, and DU145) with distinct androgen dependency, and differing in tumor suppressor phosphatase and tensin homolog (PTEN) and p53 status. Edelfosine accumulated in the endoplasmic reticulum of prostate cancer cells, leading to endoplasmic reticulum stress and cell death in the three prostate cancer cells. Inhibition of autophagy potentiated the pro-apoptotic activity of edelfosine in LNCaP and PC3 cells, where autophagy was induced as a survival response. Edelfosine induced a slight and transient inhibition of AKT in PTEN-negative LNCaP and PC3 cells, but not in PTEN-positive DU145 cells. Daily oral administration of edelfosine in murine prostate restricted AKT kinase transgenic mice, expressing active AKT in a prostate-specific manner, and in a DU145 xenograft mouse model resulted in significant tumor regression and apoptosis in tumor cells. Taken together, these results show a significant in vitro and in vivo antitumor activity of edelfosine against prostate cancer, and highlight the endoplasmic reticulum as a novel and promising therapeutic target in prostate cancer.
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Affiliation(s)
- El-Habib Dakir
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Faculty of Biology, University of Latvia, Riga, Latvia.
| | - Consuelo Gajate
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas - Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain.
| | - Faustino Mollinedo
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas - Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain.
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12
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Gupta KR, Kyprianou N. Microbiota and the landscape of the prostate tumor microenvironment. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY 2023; 11:352-360. [PMID: 37941651 PMCID: PMC10628624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 08/07/2023] [Indexed: 11/10/2023]
Abstract
Prostate cancer remains one of the most common causes of cancer-related death in men globally. Progression of prostate cancer to lethal metastatic disease is mediated by multiple contributors. The role of prostate microbiota and their metabolites in metastasis, therapeutic resistance to castration resistant prostate cancer (CRPC), and tumor relapse has yet to be fully investigated. Characterization of microflora can provide new mechanistic insights into the functional significance in the emergence of therapeutic resistance, identification of novel effective targeted therapies, and development of biomarkers during prostate cancer progression. The tumor microenvironment (TME) and its components work concurrently with the prostate microbiota in promoting prostate cancer development and progression to metastasis. In this article, we discuss the growing evidence on the functional contribution of microbiota to the phenotypic landscape of the TME and its effect on prostate cancer therapeutic targeting and recurrent disease.
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Affiliation(s)
- Kasmira R Gupta
- Department of Urology, Icahn School of Medicine at Mount SinaiNew York, New York 10029, USA
| | - Natasha Kyprianou
- Department of Urology, Icahn School of Medicine at Mount SinaiNew York, New York 10029, USA
- Oncological Sciences and Pathology & Cell Based Medicine, Icahn School of Medicine at Mount SinaiNew York, New York 10029, USA
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13
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Pol M, Gao H, Zhang H, George OJ, Fox JM, Jia X. Dynamic modulation of matrix adhesiveness induces epithelial-to-mesenchymal transition in prostate cancer cells in 3D. Biomaterials 2023; 299:122180. [PMID: 37267701 PMCID: PMC10330660 DOI: 10.1016/j.biomaterials.2023.122180] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 04/27/2023] [Accepted: 05/25/2023] [Indexed: 06/04/2023]
Abstract
Synthetic matrices with dynamic presentation of cell guidance cues are needed for the development of physiologically relevant in vitro tumor models. Towards the goal of mimicking prostate cancer progression and metastasis, we engineered a tunable hyaluronic acid-based hydrogel platform with protease degradable and cell adhesive properties employing bioorthogonal tetrazine ligation with strained alkenes. The synthetic matrix was first fabricated via a slow tetrazine-norbornene reaction, then temporally modified via a diffusion-controlled method using trans-cyclooctene, a fierce dienophile that reacts with tetrazine with an unusually fast rate. The encapsulated DU145 prostate cancer single cells spontaneously formed multicellular tumoroids after 7 days of culture. In situ modification of the synthetic matrix via covalent tagging of cell adhesive RGD peptide induced tumoroid decompaction and the development of cellular protrusions. RGD tagging did not compromise the overall cell viability, nor did it induce cell apoptosis. In response to increased matrix adhesiveness, DU145 cells dynamically loosen cell-cell adhesion and strengthen cell-matrix interactions to promote an invasive phenotype. Characterization of the 3D cultures by immunocytochemistry and gene expression analyses demonstrated that cells invaded into the matrix via a mesenchymal like migration, with upregulation of major mesenchymal markers, and down regulation of epithelial markers. The tumoroids formed cortactin positive invadopodia like structures, indicating active matrix remodeling. Overall, the engineered tumor model can be utilized to identify potential molecular targets and test pharmacological inhibitors, thereby accelerating the design of innovative strategies for cancer therapeutics.
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Affiliation(s)
- Mugdha Pol
- Department of Biological Sciences, University of Delaware, Newark, DE, USA
| | - Hanyuan Gao
- Department of Materials Science and Engineering, University of Delaware, Newark, DE, USA
| | - He Zhang
- Department of Materials Science and Engineering, University of Delaware, Newark, DE, USA
| | - Olivia J George
- Department of Materials Science and Engineering, University of Delaware, Newark, DE, USA
| | - Joseph M Fox
- Department of Materials Science and Engineering, University of Delaware, Newark, DE, USA; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Xinqiao Jia
- Department of Biological Sciences, University of Delaware, Newark, DE, USA; Department of Materials Science and Engineering, University of Delaware, Newark, DE, USA; Department of Biomedical Engineering, University of Delaware, Newark, DE, USA; Delaware Biotechnology Institute, University of Delaware, Newark, DE, USA.
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14
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Vasilatis DM, Lucchesi CA, Ghosh PM. Molecular Similarities and Differences between Canine Prostate Cancer and Human Prostate Cancer Variants. Biomedicines 2023; 11:biomedicines11041100. [PMID: 37189720 DOI: 10.3390/biomedicines11041100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Dogs are one of few species that naturally develop prostate cancer (PCa), which clinically resembles aggressive, advanced PCa in humans. Moreover, PCa-tumor samples from dogs are often androgen receptor (AR)-negative and may enrich our understanding of AR-indifferent PCa in humans, a highly lethal subset of PCa for which few treatment modalities are available This narrative review discusses the molecular similarities between dog PCa and specific human-PCa variants, underscoring the possibilities of using the dog as a novel pre-clinical animal model for human PCa, resulting in new therapies and diagnostics that may benefit both species.
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Affiliation(s)
- Demitria M Vasilatis
- Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA 95718, USA
- Veterans Affairs (VA)-Northern California Healthcare System, Mather, CA 95655, USA
| | | | - Paramita M Ghosh
- Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA 95718, USA
- Veterans Affairs (VA)-Northern California Healthcare System, Mather, CA 95655, USA
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95718, USA
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15
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Martin J, Islam F. Detection and Isolation of Cancer Stem Cells. CANCER STEM CELLS: BASIC CONCEPT AND THERAPEUTIC IMPLICATIONS 2023:45-69. [DOI: 10.1007/978-981-99-3185-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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The Role of Tumor Microenvironment in Regulating the Plasticity of Osteosarcoma Cells. Int J Mol Sci 2022; 23:ijms232416155. [PMID: 36555795 PMCID: PMC9788144 DOI: 10.3390/ijms232416155] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Osteosarcoma (OS) is a malignancy that is becoming increasingly common in adolescents. OS stem cells (OSCs) form a dynamic subset of OS cells that are responsible for malignant progression and chemoradiotherapy resistance. The unique properties of OSCs, including self-renewal, multilineage differentiation and metastatic potential, 149 depend closely on their tumor microenvironment. In recent years, the likelihood of its dynamic plasticity has been extensively studied. Importantly, the tumor microenvironment appears to act as the main regulatory component of OS cell plasticity. For these reasons aforementioned, novel strategies for OS treatment focusing on modulating OS cell plasticity and the possibility of modulating the composition of the tumor microenvironment are currently being explored. In this paper, we review recent studies describing the phenomenon of OSCs and factors known to influence phenotypic plasticity. The microenvironment, which can regulate OSC plasticity, has great potential for clinical exploitation and provides different perspectives for drug and treatment design for OS.
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17
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Toledo B, Picon-Ruiz M, Marchal JA, Perán M. Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives. Int J Mol Sci 2022; 23:15576. [PMID: 36555218 PMCID: PMC9778751 DOI: 10.3390/ijms232415576] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/25/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME's cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal-cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs "re-education" and/or targeting tumour progression inhibition.
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Affiliation(s)
- Belén Toledo
- Department of Health Sciences, University of Jaén, E-23071 Jaén, Spain
| | - Manuel Picon-Ruiz
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, E-18100 Granada, Spain
- Instituto de Investigación Sanitaria ibs. GRANADA, Hospitales Universitarios de Granada-Universidad de Granada, E-18071 Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, E-18016 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), University of Granada, E-18016 Granada, Spain
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, E-18100 Granada, Spain
- Instituto de Investigación Sanitaria ibs. GRANADA, Hospitales Universitarios de Granada-Universidad de Granada, E-18071 Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, E-18016 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), University of Granada, E-18016 Granada, Spain
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, E-23071 Jaén, Spain
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, E-18100 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), University of Granada, E-18016 Granada, Spain
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18
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Castellón EA, Indo S, Contreras HR. Cancer Stemness/Epithelial-Mesenchymal Transition Axis Influences Metastasis and Castration Resistance in Prostate Cancer: Potential Therapeutic Target. Int J Mol Sci 2022; 23:ijms232314917. [PMID: 36499245 PMCID: PMC9736174 DOI: 10.3390/ijms232314917] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/18/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
Prostate cancer (PCa) is a leading cause of cancer death in men, worldwide. Mortality is highly related to metastasis and hormone resistance, but the molecular underlying mechanisms are poorly understood. We have studied the presence and role of cancer stem cells (CSCs) and the Epithelial-Mesenchymal transition (EMT) in PCa, using both in vitro and in vivo models, thereby providing evidence that the stemness-mesenchymal axis seems to be a critical process related to relapse, metastasis and resistance. These are complex and related processes that involve a cooperative action of different cancer cell subpopulations, in which CSCs and mesenchymal cancer cells (MCCs) would be responsible for invading, colonizing pre-metastatic niches, initiating metastasis and an evading treatments response. Manipulating the stemness-EMT axis genes on the androgen receptor (AR) may shed some light on the effect of this axis on metastasis and castration resistance in PCa. It is suggested that the EMT gene SNAI2/Slug up regulates the stemness gene Sox2, and vice versa, inducing AR expression, promoting metastasis and castration resistance. This approach will provide new sight about the role of the stemness-mesenchymal axis in the metastasis and resistance mechanisms in PCa and their potential control, contributing to develop new therapeutic strategies for patients with metastatic and castration-resistant PCa.
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Affiliation(s)
- Enrique A. Castellón
- Correspondence: (E.A.C.); (H.R.C.); Tel.: +56-229-786-863 (E.A.C.); +56-229-786-862 (H.R.C.)
| | | | - Héctor R. Contreras
- Correspondence: (E.A.C.); (H.R.C.); Tel.: +56-229-786-863 (E.A.C.); +56-229-786-862 (H.R.C.)
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19
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Cooke M, Zhang X, Zhang S, Eruslanov E, Lal P, Daniel RE, Feldman MD, Abba MC, Kazanietz MG. PROTEIN KINASE C ALPHA IS A CENTRAL NODE FOR TUMORIGENIC TRANSCRIPTIONAL NETWORKS IN HUMAN PROSTATE CANCER. CANCER RESEARCH COMMUNICATIONS 2022; 2:1372-1387. [PMID: 36818489 PMCID: PMC9933888 DOI: 10.1158/2767-9764.crc-22-0170] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/12/2022] [Accepted: 09/26/2022] [Indexed: 06/18/2023]
Abstract
Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKCα isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKCα expression. Immunohistochemical analysis showed abnormal up-regulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα expression from aggressive prostate cancer cells impairs cell cycle progression, proliferation and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of pro-inflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent down-regulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated in silico using human prostate cancer databases. Our studies established PKCα as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKCα as a pro-tumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches towards targeting PKCα or its effectors.
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Affiliation(s)
- Mariana Cooke
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, Pennsylvania
| | - Xuyao Zhang
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Suli Zhang
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Evgeniy Eruslanov
- Division of Thoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Priti Lal
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Reba E. Daniel
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael D. Feldman
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Martin C. Abba
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Marcelo G. Kazanietz
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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20
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Özdemir BC, Arnold N, Fleischmann A, Hensel J, Klima I, Kruithof-de Julio M, Burkhard F, Hayoz S, Kiss B, Thalmann GN. Prediction of Biochemical Recurrence Based on Molecular Detection of Lymph Node Metastasis After Radical Prostatectomy. EUR UROL SUPPL 2022; 44:1-10. [PMID: 36185585 PMCID: PMC9520506 DOI: 10.1016/j.euros.2022.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2022] [Indexed: 11/27/2022] Open
Abstract
Background Molecular detection of lymph node (LN) micrometastases by analyzing mRNA expression of epithelial markers in prostate cancer (PC) patients provides higher sensitivity than histopathological examination. Objective To investigate which type of marker to use and whether molecular detection of micrometastases in LNs was predictive of biochemical recurrence. Design, setting, and participants LN samples from PC patients undergoing radical prostatectomy with extended LN dissection between 2009 and 2011 were examined for the presence of micrometastases by both routine histopathology and molecular analyses. Outcome measurements and statistical analysis The mRNA expression of a panel of markers of prostate epithelial cells, prostate stem cell–like cells, epithelial-to-mesenchymal transition, and stromal activation, was performed by quantitative real-time polymerase chain reaction. The expression levels of these markers in LN metastases from three PC patients were compared with the expression levels in LN from five control patients without PC in order to identify the panel of markers best suited for the molecular detection of LN metastases. The predictive value of the molecular detection of micrometastases for biochemical recurrence was assessed after a follow-up of 10 yr. Results and limitations Prostate epithelial markers are better suited for the detection of occult LN metastases than molecular markers of stemness, epithelial-to-mesenchymal transition, or reactive stroma. An analysis of 1023 LNs from 60 PC patients for the expression of prostate epithelial cell markers has revealed different expression levels and patterns between patients and between LNs of the same patient. The positive predictive value of molecular detection of occult LN metastasis for biochemical recurrence is 66.7% and the negative predictive value is 62.5%. Limitations are sample size and the hypothesis-driven selection of markers. Conclusions Molecular detection of epithelial cell markers increases the number of positive LNs and predicts tumor recurrence already at surgery. Patient summary We show that a panel of epithelial prostate markers rather than single genes is preferred for the molecular detection of lymph node micrometastases not visible at histopathological examination.
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21
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Krause W. Resistance to prostate cancer treatments. IUBMB Life 2022; 75:390-410. [PMID: 35978491 DOI: 10.1002/iub.2665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/09/2022] [Indexed: 12/14/2022]
Abstract
A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross-resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter- and intra-individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review.
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22
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Jinna N, Rida P, Smart M, LaBarge M, Jovanovic-Talisman T, Natarajan R, Seewaldt V. Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer. Int J Mol Sci 2022; 23:ijms23168844. [PMID: 36012111 PMCID: PMC9408190 DOI: 10.3390/ijms23168844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 12/27/2022] Open
Abstract
Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Max Smart
- Rowland Hall, Salt Lake City, UT 84102, USA
| | - Mark LaBarge
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Victoria Seewaldt
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
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23
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High Expression of PDLIM2 Predicts a Poor Prognosis in Prostate Cancer and Is Correlated with Epithelial-Mesenchymal Transition and Immune Cell Infiltration. J Immunol Res 2022; 2022:2922832. [PMID: 35707002 PMCID: PMC9192325 DOI: 10.1155/2022/2922832] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/15/2022] [Accepted: 04/25/2022] [Indexed: 11/20/2022] Open
Abstract
Purpose To elucidate the clinical and prognostic role of PDZ and LIM domain protein (PDLIM) genes and the association to epithelial-mesenchymal transition (EMT) and immune cell infiltration in patients with prostate cancer (PRAD). Methods The data of RNA-seq, DNA methylation, and clinical features of PRAD patients were collected from The Cancer Genome Atlas (TCGA) database to define the prognostic value of PDLIM gene expression and the association with EMT and immune cell infiltration. A tissue microarray including 134 radical prostatectomy specimens was served as validation by immunohistochemistry (IHC) staining analysis. Results The mRNA levels of PDLIM1/2/3/4/6/7 were significantly downregulated, while PDLIM5 was upregulated in PRAD (P < 0.05). High expression of PDLIM2 mRNA suggests poor progression free interval in PRAD patients. DNA methylation of PDLIM2 was correlated with its mRNA expression level, and that the cg22973076 methylation site in PDLIM2 was associated with shorter PFI (P < 0.05) in PRAD. Single-sample gene-set enrichment and gene functional enrichment results showed that PDLIM2 was correlated with EMT and immune processes. Spearman's test showed a significant correlation with six reported EMT signatures and several EMT signature-related genes. Tumor microenvironment analysis revealed that the PDLIM2 mRNA expression was positively correlated with the immune score, stromal score, and various tumor infiltrating immune cells. Additionally, the results showed that patients in the high-PDLIM2 mRNA expression group may be more sensitive to immune checkpoint blockade therapy. Finally, IHC analysis further implicated the protein level of PDLIM2 was upregulated in PRAD and acts as a novel potential biomarker in predicting tumor progression. Conclusion Our study suggests that PDLIM family genes might be significantly correlated with oncogenesis and the progression of PRAD. PDLIM2 correlated with EMT and immune cell infiltration by acting as an oncogene in PRAD, which may serve as a potential prognostic biomarker for PRAD patients.
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24
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Lin Q, Cao J, Du X, Yang K, Shen Y, Wang W, Klocker H, Shi J, Zhang J. The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer. Front Oncol 2022; 11:787953. [PMID: 35096586 PMCID: PMC8789881 DOI: 10.3389/fonc.2021.787953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/13/2021] [Indexed: 01/14/2023] Open
Abstract
Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.
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Affiliation(s)
- Qimei Lin
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
| | - Jiasong Cao
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Nankai University, Tianjin, China
| | - Xiaoling Du
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
| | - Kuo Yang
- Department of Urology of the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yongmei Shen
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Nankai University, Tianjin, China
| | - Weishu Wang
- State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Helmut Klocker
- Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jiandang Shi
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Ju Zhang
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
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25
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Tian BR, Lin WF, Zhang Y. Effects of biomechanical forces on the biological behavior of cancer stem cells. J Cancer 2021; 12:5895-5902. [PMID: 34476003 PMCID: PMC8408108 DOI: 10.7150/jca.60893] [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: 03/26/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs), dynamic subsets of cancer cells, are responsible for malignant progression. The unique properties of CSCs, including self-renewal, differentiation, and malignancy, closely depend on the tumor microenvironment. Mechanical components in the microenvironment, including matrix stiffness, fluid shear stress, compression and tension stress, affect the fate of CSCs and further influence the cancer process. This paper reviews recent studies of mechanical components and CSCs, and further discusses the intrinsic correlation among them. Regulatory mechanisms of mechanical microenvironment, which act on CSCs, have great potential for clinical application and provide different perspectives to drugs and treatment design.
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Affiliation(s)
- Bo Ren Tian
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, People's Republic of China
| | - Wei Fan Lin
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, People's Republic of China
| | - Yan Zhang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, People's Republic of China
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26
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Marcellus KA, Crawford Parks TE, Almasi S, Jasmin BJ. Distinct roles for the RNA-binding protein Staufen1 in prostate cancer. BMC Cancer 2021; 21:120. [PMID: 33541283 PMCID: PMC7863451 DOI: 10.1186/s12885-021-07844-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Prostate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer. METHODS Using a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated. RESULTS We show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase. CONCLUSIONS Collectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.
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Affiliation(s)
- Kristen A Marcellus
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H8M5, Canada.,The Eric J. Poulin Centre for Neuromuscular Diseases, Ottawa, Ontario, Canada
| | - Tara E Crawford Parks
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H8M5, Canada.,The Eric J. Poulin Centre for Neuromuscular Diseases, Ottawa, Ontario, Canada
| | - Shekoufeh Almasi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H8M5, Canada.,The Eric J. Poulin Centre for Neuromuscular Diseases, Ottawa, Ontario, Canada
| | - Bernard J Jasmin
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H8M5, Canada. .,The Eric J. Poulin Centre for Neuromuscular Diseases, Ottawa, Ontario, Canada.
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27
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Sahiner N, Suner SS, Kurt SB, Can M, Ayyala RS. HA particles as resourceful cancer, steroidal and antibiotic drug delivery device with sustainable and multiple drug release capability. JOURNAL OF MACROMOLECULAR SCIENCE PART A-PURE AND APPLIED CHEMISTRY 2020. [DOI: 10.1080/10601325.2020.1832518] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Nurettin Sahiner
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida Eye Institute, Tampa, Florida, USA
- Chemistry Department, Faculty of Science & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Selin S. Suner
- Chemistry Department, Faculty of Science & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Saliha B. Kurt
- Chemistry Department, Faculty of Science & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Mehmet Can
- Chemistry Department, Faculty of Science & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Ramesh S. Ayyala
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida Eye Institute, Tampa, Florida, USA
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28
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Hintz HM, Gallant JP, Vander Griend DJ, Coleman IM, Nelson PS, LeBeau AM. Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography. Clin Cancer Res 2020; 26:4882-4891. [PMID: 32636317 PMCID: PMC7683011 DOI: 10.1158/1078-0432.ccr-20-1358] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/27/2020] [Accepted: 07/02/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, heterogeneous disease with few therapeutic strategies that significantly prolong survival. Innovative therapies for mCRPC are needed; however, the development of new therapies relies on accurate imaging to assess metastasis and monitor response. Standard imaging modalities for prostate cancer require improvement and there remains a need for selective and sensitive imaging probes that can be widely used in patients with mCRPC. EXPERIMENTAL DESIGN We evaluated the transmembrane protease fibroblast activation protein alpha (FAP) as a targetable cell surface antigen for mCRPC. Genomic and IHC analyses were performed to investigate FAP expression in prostate cancer. Our FAP-targeted antibody imaging probe, [89Zr]Zr-B12 IgG, was evaluated by PET/CT imaging in preclinical prostate cancer models. RESULTS Analysis of patient data documented FAP overexpression in metastatic disease across tumor subtypes. PET imaging with [89Zr]Zr-B12 IgG demonstrated high tumor uptake and long-term retention of the probe in the preclinical models examined. FAP-positive stroma tumor uptake of [89Zr]Zr-B12 IgG was 5-fold higher than the isotype control with mean %ID/cc of 34.13 ± 1.99 versus 6.12 ± 2.03 (n = 3/group; P = 0.0006) at 72 hours. Ex vivo biodistribution corroborated these results documenting rapid blood clearance by 24 hours and high tumor uptake of [89Zr]Zr-B12 IgG by 72 hours. CONCLUSIONS Our study reveals FAP as a target for imaging the tumor microenvironment of prostate cancer. Validation of [89Zr]Zr-B12 IgG as a selective imaging probe for FAP-expressing tumors presents a new approach for noninvasive PET/CT imaging of mCRPC.
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Affiliation(s)
- Hallie M Hintz
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Joseph P Gallant
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Donald J Vander Griend
- Department of Pathology and Surgery, University of Illinois at Chicago, Chicago, Illinois
| | - Ilsa M Coleman
- Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Peter S Nelson
- Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Aaron M LeBeau
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota.
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29
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Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells. Stem Cell Rev Rep 2020; 16:1185-1207. [DOI: 10.1007/s12015-020-10031-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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30
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Kamble PR, Rane S, Breed AA, Joseph S, Mahale SD, Pathak BR. Proteolytic cleavage of Trop2 at Arg87 is mediated by matriptase and regulated by Val194. FEBS Lett 2020; 594:3156-3169. [PMID: 32761920 DOI: 10.1002/1873-3468.13899] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/22/2020] [Accepted: 07/13/2020] [Indexed: 01/08/2023]
Abstract
Proteolytic processing is an important post-translational modification affecting protein activity and stability. In the current study, we investigate the N-terminal cleavage of Trop2, a protein which is overexpressed in many cancers. We demonstrate that Trop2 is cleaved at Arg87 by a transmembrane serine protease, matriptase. Homology modeling and site-directed mutagenesis of amino acids in close proximity to the matriptase cleavage site reveal the importance of Val194 in regulating Trop2 cleavage. Co-immunoprecipitation studies confirm that amino acid substitutions at Arg87, Thr88, Lys189, Val194, and His195 do not affect Trop2 dimerization. However, cleavage of wild-type Trop2 by matriptase is inhibited when it is allowed to dimerize with a V194 A mutant monomer, further confirming the role of Val194 in matriptase-mediated N-terminal cleavage.
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Affiliation(s)
- Pradnya R Kamble
- Division of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
| | - Sanjana Rane
- Division of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
| | - Ananya A Breed
- Division of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
| | - Shaini Joseph
- Genetic Research Center, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
| | - Smita D Mahale
- Division of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
| | - Bhakti R Pathak
- Division of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, India
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31
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Buhrmann C, Yazdi M, Bashiri Dezfouli A, Samani Sahraneshin F, Ebrahimi SM, Hamidollah Ghaffari S, Yaghmaie M, Barin A, Shakibaei M, Shayan P. Significant decrease in the viability and tumor stem cell marker expression in tumor cell lines treated with curcumin. J Herb Med 2020. [DOI: 10.1016/j.hermed.2020.100339] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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32
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Lin CJ, Lo UG, Hsieh JT. The regulatory pathways leading to stem-like cells underlie prostate cancer progression. Asian J Androl 2020; 21:233-240. [PMID: 30178777 PMCID: PMC6498735 DOI: 10.4103/aja.aja_72_18] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.
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Affiliation(s)
- Chun-Jung Lin
- Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - U-Ging Lo
- Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jer-Tsong Hsieh
- Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA
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33
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The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player? Prostate Cancer 2020; 2020:7938280. [PMID: 32292603 PMCID: PMC7149487 DOI: 10.1155/2020/7938280] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/19/2019] [Accepted: 02/14/2020] [Indexed: 12/18/2022] Open
Abstract
Prostate cancer (PCa) is initially driven by excessive androgen receptor (AR) signaling with androgen deprivation therapy (ADT) being a major therapeutic approach to its treatment. However, the development of drug resistance is a significant limitation on the effectiveness of both first-line and more recently developed second-line ADTs. There is a need then to study AR signaling within the context of other oncogenic signaling pathways that likely mediate this resistance. This review focuses on interactions between AR signaling, the well-known phosphatidylinositol-3-kinase/AKT pathway, and an emerging mediator of these pathways, the Hippo/YAP1 axis in metastatic castrate-resistant PCa, and their involvement in the regulation of epithelial-mesenchymal transition (EMT), a feature of disease progression and ADT resistance. Analysis of these pathways in circulating tumor cells (CTCs) may provide an opportunity to evaluate their utility as biomarkers and address their importance in the development of resistance to current ADT with potential to guide future therapies.
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34
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Zhu Z, Xu J, Li L, Ye W, Xu G, Chen B, Zeng J, Li J, Huang Z. Effect of gastric cancer stem cell on gastric cancer invasion, migration and angiogenesis. Int J Med Sci 2020; 17:2040-2051. [PMID: 32788883 PMCID: PMC7415381 DOI: 10.7150/ijms.46774] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/26/2020] [Indexed: 12/16/2022] Open
Abstract
Purpose: Using the gastric cancer cell line SGC7901 and gastric cancer stem cell (CSC-G), we conducted this study to investigate the role of cancer stem cells in invasion, metastasis and tumor angiogenesis. Methods: Stem cell markers (OCT4, SOX2, C-Myc and Klf4) expression was detected by RT-PCR and Western blotting. The proliferation, migration, invasion abilities, L-OHP and 5-FU resistance, angiogenesis were assessed using in vitro spherical clone formation assays, plate cloning experiments, transwell migration, transwell invasion, drug resistance, scratch-wound migration, ring formation assay, and their tumorigenic and ability were assessed using a tumor formation experiment in mice. Results: Compared with the SGC7901, the expression of Oct4, Sox2, Klf4 and CD44 mRNA was significantly higher in CSC-G, the mRNA relative expression of E-cadherin in CSC-G was lower than SGC7901, while the expression of c-Myc did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly higher in CSC-G, and the tumorigenic ability in mice was also significantly higher. Conclusion: The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of CSC-G significantly were higher than SGC7901. CSC-G plays important roles in proliferation, migration, invasion, and tumorigenicity.
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Affiliation(s)
- Zhipeng Zhu
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Jiuhua Xu
- Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
| | - Lulu Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Weipeng Ye
- Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
| | - Guoxing Xu
- Endoscopy center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Borong Chen
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Junjie Zeng
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Jiayi Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Zhengjie Huang
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China.,Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
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35
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O'Reilly D, Johnson P, Buchanan PJ. Hypoxia induced cancer stem cell enrichment promotes resistance to androgen deprivation therapy in prostate cancer. Steroids 2019; 152:108497. [PMID: 31521707 DOI: 10.1016/j.steroids.2019.108497] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 09/03/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023]
Abstract
Androgen deprivation therapy (ADT) is the main treatment to prolong survival in advance stage prostate cancer (PCa) but associated resistance leads to the development of terminal castrate resistant PCa (CRPC). Current research demonstrates that prostate cancer stem cells (PCSC) play a critical role in the development of treatment resistance and subsequent disease progression. Despite uncertainty surrounding the origin of these cells, studies clearly show they are associated with poorer outcomes and that ADT significantly enhances their numbers. Here in we highlight how activation of HIF signalling, in response to hypoxic conditions within the tumour microenvironment, results in the expression of genes associated with stemness and EMT promoting PCSC emergence which ultimately drives tumour relapse to CRPC. Hypoxic conditions are not only enhanced by ADT but the associated decrease in AR activation also promotes PI3K/AKT signalling which actively enhances HIF and its effects on PCSC's. Furthermore, emerging evidence now indicates that HIF-2α, rather than the commonly considered HIF-1α, is the main family member that drives PCSC emergence. Taken together this clearly identifies HIF and associated pathways as key targets for new therapeutic strategies that could potentially prevent or slow PCSC promoted resistance to ADT, thus holding potential to prolong patient survival.
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Affiliation(s)
- Debbie O'Reilly
- School of Nursing & Human Sciences, Dublin City University, Dublin, Ireland; National Institute of Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Patricia Johnson
- School of Nursing & Human Sciences, Dublin City University, Dublin, Ireland
| | - Paul J Buchanan
- School of Nursing & Human Sciences, Dublin City University, Dublin, Ireland; National Institute of Cellular Biotechnology, Dublin City University, Dublin, Ireland.
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36
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Lee CH, Decker AM, Cackowski FC, Taichman RS. Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer. Cell Biol Toxicol 2019; 36:115-130. [PMID: 31250347 DOI: 10.1007/s10565-019-09483-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 06/18/2019] [Indexed: 01/06/2023]
Abstract
Prostate cancer (PCa) is one of the most prevalent cancers and the second leading cause of cancer death among US males. When diagnosed in an early disease stage, primary tumors of PCa may be treated with surgical resection or radiation, sometimes combined with androgen deprivation therapy, with favorable outcomes. Unfortunately, the treatment efficacy of each approach decreases significantly in later stages of PCa that involve metastasis to soft tissues and bone. Metastatic PCa is a heterogeneous disease containing host cells, mature cancer cells, and subpopulation of cancer stem cells (CSC). CSCs are highly tumorigenic due to their self-renewing and differentiating potential, clinically resulting in recurrence and resistance to standard therapies. Therefore, there is a large unmet clinical need to develop therapies, which target CSC activity. In this review, we summarize the main signaling pathways that are implicated in the current pre-clinical and clinical studies of recurrent metastatic PCa within the bone microenvironment targeting CSCs and discuss the trajectory of therapeutics moving forward.
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Affiliation(s)
- Clara H Lee
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Ann M Decker
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Frank C Cackowski
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA.,Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
| | - Russell S Taichman
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA. .,Department of Periodontology, University of Alabama Birmingham School of Dentistry, Birmingham, Alabama, USA.
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37
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Chen B, Zhu Z, Li L, Ye W, Zeng J, Gao J, Wang S, Zhang L, Huang Z. Effect of overexpression of Oct4 and Sox2 genes on the biological and oncological characteristics of gastric cancer cells. Onco Targets Ther 2019; 12:4667-4682. [PMID: 31417271 PMCID: PMC6592062 DOI: 10.2147/ott.s209734] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 05/07/2019] [Indexed: 11/23/2022] Open
Abstract
Objective: Using the gastric cancer cell line SGC7901, we constructed a cell line that overexpressed octamer-binding protein 4 (Oct4) and SRY-box 2 (Sox2) to explore the stem cell oncological and biological characteristics of these cells and to elucidate the mechanisms of Oct4 and Sox2 in cancer. Methods: A lentiviral vector containing the Sox2 gene was constructed and transfected into a gastric cancer cell line overexpressing Oct4 (SGC7901-Oct4) to obtain a stably transfected cell line (SGC7901-Oct4-Sox2). Oct4 and Sox2 expression was detected by RT-PCR and Western blotting. The proliferation, drug resistance, migration, and invasion abilities of the cells were assessed using in vitro (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), drug resistance, scratch-wound migration, transwell migration, transwell invasion, and spherical clone formation assays, and their tumorigenic ability was assessed using a tumor formation experiment in mice. Results: Compared with the control group, the expression of Oct4, Sox2, CD44, and E-cadherin was significantly higher in the group that overexpressed Oct4 and Sox2, while the expression of c-Myc and Klf4 did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly enhanced in the overexpression group, and the tumorigenic ability in mice was also significantly enhanced, with significantly increased tumor size and weight. Conclusion: The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of SGC7901 cells overexpressing Oct4 and Sox2 were significantly improved. Oct4 and Sox2 play important roles in the proliferation, migration, invasion, and tumorigenicity of gastric cancer cells, and the two genes may be synergistic to a certain degree.
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Affiliation(s)
- Borong Chen
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Zhipeng Zhu
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Lulu Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Weipeng Ye
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
| | - Junjie Zeng
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Jin Gao
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Shengjie Wang
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Liang Zhang
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Zhengjie Huang
- Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China.,Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
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38
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Šimečková Š, Kahounová Z, Fedr R, Remšík J, Slabáková E, Suchánková T, Procházková J, Bouchal J, Kharaishvili G, Král M, Beneš P, Souček K. High Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of prostate cancer cells. Sci Rep 2019; 9:5695. [PMID: 30952903 PMCID: PMC6451010 DOI: 10.1038/s41598-019-42131-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 03/14/2019] [Indexed: 12/30/2022] Open
Abstract
Skp2 is a crucial component of SCFSkp2 E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44+CD24- cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.
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Affiliation(s)
- Šárka Šimečková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Zuzana Kahounová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic
| | - Radek Fedr
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic
| | - Ján Remšík
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA
| | - Eva Slabáková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
| | - Tereza Suchánková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
| | - Jiřina Procházková
- Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech Republic
| | - Jan Bouchal
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Gvantsa Kharaishvili
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Milan Král
- Department of Urology, University Hospital, Olomouc, Czech Republic
| | - Petr Beneš
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Karel Souček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
- Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne´s University Hospital Brno, Brno, Czech Republic.
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39
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Costa CD, Justo AA, Kobayashi PE, Story MM, Palmieri C, Laufer Amorim R, Fonseca-Alves CE. Characterization of OCT3/4, Nestin, NANOG, CD44 and CD24 as stem cell markers in canine prostate cancer. Int J Biochem Cell Biol 2019; 108:21-28. [PMID: 30633985 DOI: 10.1016/j.biocel.2019.01.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/02/2019] [Accepted: 01/05/2019] [Indexed: 12/14/2022]
Abstract
The cancer cell population is heterogeneous, and cancer stem cells (CSCs) are important for tumor growth and maintenance. The CSC population is associated with different neoplastic characteristics, such as cell migration, resistance to apoptosis, radiation therapy and chemotherapy. To increase the knowledge of CSCs in canine prostate cancer (PC), we characterized CSC markers in canine PC tissues and tumorspheres. We performed immunohistochemistry of OCT3/4, Nestin, NANOG, CD44 and CD24 in 10 normal canine prostatic tissue samples, 10 prostatic hyperplastic (PH) tissue samples and 28 PC tissue samples. Then, we established two canine prostate cancer cell cultures and characterized the CSC profile of tumorspheres grown from these cultures. Normal and PH tissues were positive for Nestin, NANOG, CD44 and CD24 only in the basal cell layer. OCT3/4 was expressed in the luminal cells of normal and PH tissues. There was no significant difference in Nestin expression among the prostatic tissues. However, we found higher expression of NANOG and CD44 in canine PC tissues than that in normal and PH tissues. Tumorspheres from canine prostate cancer cells express OCT3/4, Nestin, NANOG and CD44, indicating that these markers may be potential cancer stem cell markers in canine PC. The results obtained can be useful to better characterize the stem cell population in canine prostatic cancer and to guide future studies in comparative oncology.
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Affiliation(s)
- Camila Dorotea Costa
- São Paulo State University - UNESP, Department of Veterinary Surgery and Anaesthesiology, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil
| | - Andre Augusto Justo
- São Paulo State University - UNESP, Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil
| | - Priscila Emiko Kobayashi
- São Paulo State University - UNESP, Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil
| | - Michelle M Story
- School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton, Queensland, Australia
| | - Chiara Palmieri
- School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton, Queensland, Australia
| | - Renée Laufer Amorim
- São Paulo State University - UNESP, Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil
| | - Carlos Eduardo Fonseca-Alves
- São Paulo State University - UNESP, Department of Veterinary Surgery and Anaesthesiology, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil.
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40
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Srinivasan D, Senbanjo L, Majumdar S, Franklin RB, Chellaiah MA. Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2. J Cell Biochem 2019; 120:2413-2428. [PMID: 30206982 PMCID: PMC6411465 DOI: 10.1002/jcb.27573] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/02/2018] [Indexed: 01/24/2023]
Abstract
Studies have shown that a subgroup of tumor cells possess stemness characteristics having self-renewal capacity and the ability to form new tumors. We sought to identify the plausible stemness factor that determines the "molecular signature" of prostate cancer (PCa) cells derived from different metastases (PC3, PCa2b, LNCaP, and DU145) and whether androgen receptor (AR) influences the maintenance of stemness features. Here we show sex-determining region Y (SRY)-box 2 (SOX2) as a putative stem cell marker in PC3 PCa cells and not in DU145, PCa2b, or LNCaP cells. PCa2b and PC3 cells were derived from bone metastases. PCa2b cells which are positive for the AR failed to demonstrate the expression of either cluster of differentiation 44 (CD44) or SOX2. Knockdown (KD) of AR in these cells did not affect the expression of either CD44 or SOX2. Conversely, PC3 cells, which are negative for AR, expressed both CD44 and SOX2. However, the expression of AR downregulated the expression of both CD44 and SOX2 in PC3 cells. CD44 regulates SOX2 expression as KD of CD44 and reduces SOX2 levels considerably. SOX2 KD attenuated not only the expression of SNAIL and SLUG but also the migration and tumorsphere formation in PC3 cells. Collectively, our findings underscore a novel role of CD44 signaling in the maintenance of stemness and progression of cancer through SOX2 in AR-independent PC3 cells. SOX2 has a role in the regulation of expression of SNAIL and SLUG. SOX2 could be a potential therapeutic target to thwart the progression of SOX2-positive cancer cells or recurrence of androgen-independent PCa.
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Affiliation(s)
- Deepa Srinivasan
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Linda Senbanjo
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Sunipa Majumdar
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Renty B. Franklin
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Meenakshi A. Chellaiah
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
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41
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Fort RS, Trinidad Barnech JM, Dourron J, Colazzo M, Aguirre-Crespo FJ, Duhagon MA, Álvarez G. Isolation and Structural Characterization of Bioactive Molecules on Prostate Cancer from Mayan Traditional Medicinal Plants. Pharmaceuticals (Basel) 2018; 11:E78. [PMID: 30110911 PMCID: PMC6160984 DOI: 10.3390/ph11030078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/09/2018] [Accepted: 08/11/2018] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer is the most common cancer in men around the world. It is a complex and heterogeneous disease in which androgens and their receptors play a crucial role in the progression and development. The current treatment for prostate cancer is a combination of surgery, hormone therapy, radiation and chemotherapy. Therapeutic agents commonly used in the clinic include steroidal and non-steroidal anti-androgens, such as cyproterone acetate, bicalutamide and enzalutamide. These few agents have multiple adverse effects and are not 100% effective. Several plant compounds and mixtures, including grape seed polyphenol extracts, lycopene and tomato preparations, soy isoflavones, and green tea extracts, have been shown to be effective against prostate cancer cell growth. In vivo activity of some isolated compounds like capsaicin and curcumin was reported in prostate cancer murine models. We prepared a library of plant extracts from traditional Mayan medicine. These plants were selected for their use in the contemporaneous Mayan communities for the treatment of different diseases. The extracts were assessed in a phenotypic screening using LNCaP prostate cancer androgen sensitive cell line, with a fixed dose of 25 μg/mL. MTT assay identified seven out of ten plants with interesting anti-neoplastic activity. Extracts from these plants were subjected to a bioguided fractionation to study their major components. We identified three compounds with anti-neoplastic effects against LNCaP cells, one of which shows selectivity for neoplastic compared to benign cells.
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Affiliation(s)
- Rafael Sebastián Fort
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Montevideo, C.P. 11400, Uruguay.
| | - Juan M Trinidad Barnech
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Montevideo, C.P. 11400, Uruguay.
- Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Ruta 3 (km 363), Paysandú, C.P. 60000, Uruguay.
| | - Juliette Dourron
- Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Ruta 3 (km 363), Paysandú, C.P. 60000, Uruguay.
| | - Marcos Colazzo
- Departamento de Química del Litoral, CENUR Litoral Norte, Universidad de la República, Paysandú, C.P. 60000, Uruguay.
| | - Francisco J Aguirre-Crespo
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Campeche, Campeche, C.P. 24039, Mexico.
| | - María Ana Duhagon
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Montevideo, C.P. 11400, Uruguay.
- Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, C.P. 11800, Uruguay.
| | - Guzmán Álvarez
- Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Ruta 3 (km 363), Paysandú, C.P. 60000, Uruguay.
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42
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Profiling Prostate Cancer Therapeutic Resistance. Int J Mol Sci 2018; 19:ijms19030904. [PMID: 29562686 PMCID: PMC5877765 DOI: 10.3390/ijms19030904] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/16/2018] [Accepted: 03/16/2018] [Indexed: 02/06/2023] Open
Abstract
The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.
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43
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Sun Y, Schaar A, Sukumaran P, Dhasarathy A, Singh BB. TGFβ-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression. Mol Carcinog 2018; 57:752-761. [PMID: 29500887 PMCID: PMC5947546 DOI: 10.1002/mc.22797] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/22/2018] [Accepted: 02/28/2018] [Indexed: 12/13/2022]
Abstract
Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for treatment of advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non‐malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial‐to‐mesenchymal transition (EMT). Importantly, addition of Mg2+, but not Ca2+, increased cell migration. Furthermore, TRPM7 expression, which functions as an Mg2+ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2‐APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFβ showed a further increase in cell migration, which was again blocked by the addition of 2‐APB. Importantly, TGFβ addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFβ‐induced cell migration along with a decrease in EMT markers showing loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFβ‐induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg2+ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis.
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Affiliation(s)
- Yuyang Sun
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota
| | - Anne Schaar
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota
| | - Pramod Sukumaran
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota
| | - Archana Dhasarathy
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota
| | - Brij B Singh
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota
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44
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Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol 2018; 15:271-286. [PMID: 29460922 DOI: 10.1038/nrurol.2018.22] [Citation(s) in RCA: 298] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The success of next-generation androgen receptor (AR) pathway inhibitors, such as abiraterone acetate and enzalutamide, in treating prostate cancer has been hampered by the emergence of drug resistance. This acquired drug resistance is driven, in part, by the ability of prostate cancer cells to change their phenotype to adopt AR-independent pathways for growth and survival. Around one-quarter of resistant prostate tumours comprise cells that have undergone cellular reprogramming to become AR-independent and to acquire a continuum of neuroendocrine characteristics. These highly aggressive and lethal tumours, termed neuroendocrine prostate cancer (NEPC), exhibit reactivation of developmental programmes that are associated with epithelial-mesenchymal plasticity and acquisition of stem-like cell properties. In the past few years, our understanding of the link between lineage plasticity and an emergent NEPC phenotype has considerably increased. This new knowledge can contribute to novel therapeutic modalities that are likely to improve the treatment and clinical management of aggressive prostate cancer.
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Affiliation(s)
- Alastair H Davies
- Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC, Canada.,Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, Canada
| | - Himisha Beltran
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, 413 East 69th Street, New York, NY, USA
| | - Amina Zoubeidi
- Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC, Canada.,Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, Canada
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45
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Zhou Y, Wang Y, Wen J, Zhao H, Dong X, Zhang Z, Wang S, Shen L. Aquaporin 3 promotes the stem-like properties of gastric cancer cells via Wnt/GSK-3β/β-catenin pathway. Oncotarget 2017; 7:16529-41. [PMID: 26918728 PMCID: PMC4941333 DOI: 10.18632/oncotarget.7664] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/11/2016] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are believed to contribute to the tumor growth in gastric carcinoma (GC), a common lethal malignancy. This study investigated the effect of aquaporin 3 (AQP3) on stem-like properties of human GC cells. Elevated AQP3 expression was associated with CD44 expression in human GC specimens. Expression of AQP3 and that of CD44 positively correlated with Lauren classification, lymph node metastasis, and lymphovascular invasion. Altering the AQP3 expression had pronounced effects on the tumorigenic potential and self-renewal capacity of the gastric cancer cell lines SGC7901, MGC803, and AGS, both in vitro and in vivo. Overexpression of AQP3 induced CD44 expression and activation of the β-catenin signaling pathway, whereas silencing AQP3 expression using short hairpin RNA had the opposite effect. Furthermore, pharmacological inhibition of GSK-3β using LiCl impaired the effect of AQP3 knockdown in CSCs, whereas the inhibition of the Wnt/β-catenin pathway by XAV939 blocked the effect of AQP3 overexpression. These results demonstrate that AQP3 promotes stem-like properties of human GC cells by activating the Wnt/GSK-3β/β-catenin signaling pathway.
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Affiliation(s)
- Yangchun Zhou
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of General Surgery, Sir Run Run Shaw Hospital, Third Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yao Wang
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianfei Wen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haijian Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.,Division of Gastrointestinal Surgery, Department of General Surgery, Affiliated Huai'an Hospital, Xuzhou Medical College, Huai'an, Jiangsu, China
| | - Xuqiang Dong
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhihong Zhang
- Department of Pathology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shoulin Wang
- School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lizong Shen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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Jaworska D, Szliszka E. Targeting Apoptotic Activity Against Prostate Cancer Stem Cells. Int J Mol Sci 2017; 18:ijms18081648. [PMID: 28758908 PMCID: PMC5578038 DOI: 10.3390/ijms18081648] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 07/21/2017] [Accepted: 07/26/2017] [Indexed: 12/17/2022] Open
Abstract
Numerous data suggest that an increase of cancer stem cells (CSCs) in tumor mass can be the reason for failure of conventional therapies because of their resistance. CD44+/CD24- cells are a putative cancer stem cells subpopulation in prostate cancer. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an activator of apoptosis in tumor cells. However, some tumors are TRAIL-resistant. Cancer cells can be re-sensitized to TRAIL induced apoptosis by a combination of TRAIL and taxanes. The aim of this work was to analyze the enhancement of the anticancer effect of TRAIL by paclitaxel, cabazitaxel and docetaxel in the whole population of PC3 and DU145 prostate cancer cells, but also in CD44+/CD24- prostate cancer stem cells. We examined the apoptotic effect of TRAIL and taxanes using flow cytometry and Annexin-V-PE staining. The co-treatment with taxanes and TRAIL enhanced significantly the apoptosis in CD44+/CD24- cells only in PC3 cell line but not in DU145 cells. We discovered also that taxanes can increase the expression of death receptor TRAIL-R2 in PC3 prostate cancer cells. The results of our study show that treatment with paclitaxel, cabazitaxel and docetaxel is able to enhance the apoptosis induced by TRAIL even in prostate cancer stem cells.
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Affiliation(s)
- Dagmara Jaworska
- Department of Microbiology and Immunology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland.
| | - Ewelina Szliszka
- Department of Microbiology and Immunology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland.
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Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis. Stem Cells Int 2017; 2017:8629234. [PMID: 28690641 PMCID: PMC5485361 DOI: 10.1155/2017/8629234] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 03/29/2017] [Accepted: 05/03/2017] [Indexed: 02/07/2023] Open
Abstract
Metastatic or recurrent tumors are the primary cause of cancer-related death. For prostate cancer, patients diagnosed with local disease have a 99% 5-year survival rate; however, this 5-year survival rate drops to 28% in patients with metastatic disease. This dramatic decline in survival has driven interest in discovering new markers able to identify tumors likely to recur and in developing new methods to prevent metastases from occurring. Biomarker discovery for aggressive tumor cells includes attempts to identify cancer stem cells (CSCs). CSCs are defined as tumor cells capable of self-renewal and regenerating the entire tumor heterogeneity. Thus, it is hypothesized that CSCs may drive primary tumor aggressiveness, metastatic colonization, and therapeutic relapse. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after therapy allowing for prostate cancer to finally be cured. Here, we will review potential CSC markers and highlight evidence that describes how cells expressing each marker may drive prostate cancer progression, metastatic colonization and growth, tumor recurrence, and resistance to treatment.
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Chen J, Kumar S. Biophysical Regulation of Cancer Stem/Initiating Cells: Implications for Disease Mechanisms and Translation. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2017; 1:87-95. [PMID: 29082354 DOI: 10.1016/j.cobme.2017.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cancer stem/initiating cells (CSCs) are a subset of tumor cells proposed to play privileged roles in seeding tumors and driving metastasis. CSCs have emerged as an increasingly important target of interest in cancer biology and therapy. Recent work has suggested that CSC maintenance and metastatic potential may be modulated by physical inputs within the tissue microenvironment, including interstitial pressure and extracellular matrix stiffness. Here we review recent progress in our understanding of CSC regulation by biophysical signals within the tumor microenvironment. While the mechanistic basis of this signaling remains incompletely understood, we discuss emerging evidence that mechanical inputs can epigenetically regulate CSC behavior and that some CSCs can evade mechanotransductive signals to more efficiently infiltrate tissue. We also describe efforts to leverage these findings to engineer culture platforms for the characterization of CSC mechanics for discovery and screening.
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Affiliation(s)
- Joseph Chen
- Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720
| | - Sanjay Kumar
- Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720
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Miao L, Yang L, Li R, Rodrigues DN, Crespo M, Hsieh JT, Tilley WD, de Bono J, Selth LA, Raj GV. Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial–Mesenchymal Plasticity in Prostate Cancer. Cancer Res 2017; 77:3101-3112. [DOI: 10.1158/0008-5472.can-16-2169] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 10/04/2016] [Accepted: 03/07/2017] [Indexed: 11/16/2022]
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Jafri MA, Al-Qahtani MH, Shay JW. Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention. Semin Cancer Biol 2017; 44:117-131. [PMID: 28188828 DOI: 10.1016/j.semcancer.2017.02.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/23/2022]
Abstract
Metastasis is the spread and growth of localized cancer to new locations in the body and is considered the main cause of cancer-related deaths. Metastatic cancer cells display distinct genomic and epigenomic profiles and almost universally an aggressive pathophysiology. A better understanding of the molecular mechanisms and regulation of metastasis, including how metastatic tumors grow and survive in the nascent niche and the interactions of the emergent metastatic cancer cells within the local microenvironment may provide tools to design strategies to restrict metastatic dissemination. Aberrant microRNAs (miRNA) expression has been reported in metastatic cancer cells. MicroRNAs are known to regulate divergent and/or convergent metastatic gene pathways including activation of reprogramming switches during metastasis. An in-depth understanding of role of miRNAs in the metastatic cascade may lead to the identification of novel targets for anti-metastatic therapeutics as well as potential candidate miRNAs for cancer treatment. This review primarily focuses on the role of miRNAs in the mechanisms of cancer metastasis as well as implications for metastatic cancer treatment.
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Affiliation(s)
- Mohammad Alam Jafri
- Center of Excellence for Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | | | - Jerry William Shay
- Center of Excellence for Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Cell Biology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
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