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

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

Cancers ◽

10.3390/cancers12010053 ◽

2019 ◽

Vol 12 (1) ◽

pp. 53 ◽

Cited By ~ 7

Author(s):

Sarmistha Talukdar ◽

Swadesh K. Das ◽

Anjan K. Pradhan ◽

Luni Emdad ◽

Jolene J. Windle ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Stem Cell ◽

Cancer Stem Cells ◽

Multiple Drug Resistance ◽

Trichostatin A ◽

Tumor Formation ◽

Multiple Drug ◽

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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Expression profiling of stem cell signaling alters with spheroid formation in CD133high/CD44high prostate cancer stem cells

Oncology Letters ◽

10.3892/ol.2014.1992 ◽

2014 ◽

Vol 7 (6) ◽

pp. 2103-2109 ◽

Cited By ~ 32

Author(s):

GULPERI OKTEM ◽

AYHAN BILIR ◽

RUCHAN USLU ◽

SEVINC V. INAN ◽

SIRIN B. DEMIRAY ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cell Signaling ◽

Expression Profiling ◽

Spheroid Formation ◽

Prostate Cancer Stem Cells

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The Isolation and Characterization of Human Prostate Cancer Stem Cells

10.21236/ada518099 ◽

2009 ◽

Author(s):

Ganesh S. Palapattu

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Prostate ◽

Human Prostate Cancer ◽

Isolation And Characterization ◽

Prostate Cancer Stem Cells

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The Isolation and Characterization of Human Prostate Cancer Stem Cells

10.21236/ada542728 ◽

2011 ◽

Author(s):

Ganesh Palappattu

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Prostate ◽

Human Prostate Cancer ◽

Isolation And Characterization ◽

Prostate Cancer Stem Cells

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The Isolation and Characterization of Human Prostate Cancer Stem Cells

10.21236/ada560654 ◽

2012 ◽

Author(s):

Ganesh Palapattu

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Prostate ◽

Human Prostate Cancer ◽

Isolation And Characterization ◽

Prostate Cancer Stem Cells

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Induction of Stem Cell Like Cells from Mouse Embryonic Fibroblast by Short-Term Shear Stress and Vitamin C

Applied Sciences ◽

10.3390/app11041941 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1941

Author(s):

Seungmin Yeom ◽

Myung Chul Lee ◽

Shambhavi Pandey ◽

Jaewoon Lim ◽

Sangbae Park ◽

...

Keyword(s):

Stem Cells ◽

Shear Stress ◽

Stem Cell ◽

Vitamin C ◽

Suspension Culture ◽

Small Molecules ◽

Tumor Development ◽

Embryonic Stem ◽

Short Term ◽

External Stimuli

Induced pluripotent stem cells (iPSCs) are a good medicine source because of their potential to differentiate into various tissues or cells. However, traditionally, iPSCs made by specific transgenes and virus vectors are not appropriate for clinical use because of safety concerns and risk of tumor development. The goal of this research was to develop an alternative method for reprogramming, using small molecules and external stimuli. Two groups were established: short-term shear stress (STSS) under suspension culture and a combination of short-term shear stress and vitamin C (SSVC) under suspension culture. For STSS, the pipetting was carried out for cells twice per day for 2 min for 14 days in the embryonic stem cell (ES) medium. In the case of SSVC, the procedure was the same as for STSS however, its ES medium included 10 µM of vitamin C. After 14 days, all spheroids were picked and checked for pluripotency by ALP (alkaline phosphatase) assay and immunocytochemistry. Both groups partially showed the characteristics of stem cells but data demonstrated that the spheroids under shear stress and vitamin C had improved stem cell-like properties. This research showed the possibility of external stimuli and small molecules to reprogram the somatic cells without the use of transgenes.

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