MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells

Despite some progress, treating advanced prostate cancer remains a major clinical challenge. Recent studies have shown that prostate cancer can originate from undifferentiated, rare, stem cell-like populations within the heterogeneous tumor mass, which play seminal roles in tumor formation, maintenance of tumor homeostasis and initiation of metastases. These cells possess enhanced propensity toward chemoresistance and may serve as a prognostic factor for prostate cancer recurrence. Despite extensive studies, selective targeted therapies against these stem cell-like populations are limited and more detailed experiments are required to develop novel targeted therapeutics. We now show that MDA-9/Syntenin/SDCBP (MDA-9) is a critical regulator of survival, stemness and chemoresistance in prostate cancer stem cells (PCSCs). MDA-9 regulates the expression of multiple stem-regulatory genes and loss of MDA-9 causes a complete collapse of the stem-regulatory network in PCSCs. Loss of MDA-9 also sensitizes PCSCs to multiple chemotherapeutics with different modes of action, such as docetaxel and trichostatin-A, suggesting that MDA-9 may regulate multiple drug resistance. Mechanistically, MDA-9-mediated multiple drug resistance, stemness and survival are regulated in PCSCs through activation of STAT3. Activated STAT3 regulates chemoresistance in PCSCs through protective autophagy as well as regulation of MDR1 on the surface of the PCSCs. We now demonstrate that MDA-9 is a critical regulator of PCSC survival and stemness via exploiting the inter-connected STAT3 and c-myc pathways.

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Multiple drug resistance due to resistance to stem cells and stem cell treatment progress in cancer (Review)

Experimental and Therapeutic Medicine ◽

10.3892/etm.2014.2141 ◽

2014 ◽

Vol 9 (2) ◽

pp. 289-293 ◽

Cited By ~ 48

Author(s):

CHONG DI ◽

YAODONG ZHAO

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Stem Cell ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Treatment Progress ◽

Cancer Review ◽

Stem Cell Treatment

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Prostate Cancer Stem Cells: A New Target for Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.1472 ◽

2008 ◽

Vol 26 (17) ◽

pp. 2862-2870 ◽

Cited By ~ 210

Author(s):

Norman J. Maitland ◽

Anne T. Collins

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Gene Expression Signature ◽

Theoretical Explanation ◽

Gleason Grade ◽

Prostate Cancer Stem Cells ◽

Pure Cell ◽

Hormone Refractory

The existence of prostate cancer stem cells offers a theoretical explanation for many of the enduring uncertainties surrounding the etiology and treatment of the most commonly diagnosed tumor in US males. The study of cancer stem cells in prostate, as in other complex tissues, is critically dependent on the availability of pure cell populations, a situation complicated by the heterogeneity of prostate tumors. However, selection of cells with a CD133+/α2β1 integrin/ CD44+ phenotype enriches for a tumor-initiating population from human prostate cancers. Among the most pressing needs is for enduring therapy in patients who have experienced failure of hormonal treatments. Because the putative cancer stem cell does not express androgen receptor, it is likely to be immune from most androgen-based therapies, and an inherent genetic instability would enable the tumor to develop the new variants present in hormone-refractory disease. Prostate cancer stem cells have a unique gene expression signature that can also be related to Gleason grade and patient outcome. The scarcity of cancer stem cells in a prostate tumor will probably limit their usefulness in cancer diagnosis and prognosis. However, the emergence of new stem-cell therapeutic targets not only will require new assays for efficacy (because of their relatively quiescent nature), but also holds real promise of more lasting treatments to augment those currently directed against the remaining tumor cells, which comprise 99.9% of tumor mass, but paradoxically have a poor tumor-initiating capacity.

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Elimination of SOX2/OCT4-Associated Prostate Cancer Stem Cells Blocks Tumor Development and Enhances Therapeutic Response

Cancers ◽

10.3390/cancers11091331 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1331 ◽

Cited By ~ 6

Author(s):

Prasanna Kumar Vaddi ◽

Mark A. Stamnes ◽

Huojun Cao ◽

Songhai Chen

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Tumor Development ◽

Embryonic Stem ◽

Therapeutic Resistance ◽

Reporter System ◽

Fluorescent Reporter ◽

Prostate Cancer Stem Cells

SOX2 and OCT4 are key regulators of embryonic stem cell pluripotency. They are overexpressed in prostate cancers and have been associated with cancer stem cell (CSC) properties. However, reliable tools for detecting and targeting SOX2/OCT4-overexpressing cells are lacking, limiting our understanding of their roles in prostate cancer initiation, progression, and therapeutic resistance. Here, we show that a fluorescent reporter called SORE6 can identify SOX2/OCT4-overexpressing prostate cancer cells. Among tumor cells, the SORE6 reporter identified a small fraction with CSC hallmarks: rapid self-renewal, the capability to form tumors and metastasize, and resistance to chemotherapies. Transcriptome and biochemical analyses identified PI3K/AKT signaling as critical for maintaining the SORE6+ population. Moreover, a SORE6-driven herpes simplex virus thymidine kinase (TK) expression construct could selectively ablate SORE6+ cells in tumors, blocking tumor initiation and progression, and sensitizing tumors to chemotherapy. This study demonstrates a key role of SOX2/OCT4-associated prostate cancer stem cells in tumor development and therapeutic resistance, and identifies the SORE6 reporter system as a useful tool for characterizing CSCs functions in a native tumor microenvironment.

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