title: Androgen receptor in cancer-associated fibroblasts influences stemness in cancer cells.
abstract: Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten-/-L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells. A murine-specific AR antisense oligonucleotide (ASO) was used to suppress the expression of AR in the CAF cells. CAFs express low, but significant levels of AR relative to fibroblasts derived from non-malignant tissue. CAFs promoted growth and colony formation of hPCa cells, which was attenuated by the suppression of AR expression. Surprisingly, AR-depleted CAFs promoted increased stem cell marker expression in hPCa cells. Interferon gamma (IFN-γ) and macrophage colony-stimulating factor (M-CSF) were increased in AR-depleted CAF cells and exhibited similar effects on stem cell marker expression as seen in the CAF co-culture systems. Clinically, elevated IFN-γ expression was found to correlate with histologic grade in primary prostate cancer samples. In summary, AR and androgen-dependent signaling are active in CAFs and exert significant effects on prostate cancer cells. IFN-γ and M-CSF are AR-regulated factors secreted by CAF cells, which promote the expression of stem cell markers in prostate cancer epithelial cells. Understanding how CAFs and other constituents of stromal tissue react to anti-cancer therapies may provide insight into the development and progression of prostate cancer.
authors.affiliation: Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liao
authors.affiliation: Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Leng-Ying
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Luethy
authors.affiliation: Ionis Pharmaceuticals Inc.Carlsbad, California, USA.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Kian
authors.initials: K
authors.lastname: Kani
authors.affiliation: Ionis Pharmaceuticals Inc.Carlsbad, California, USA.
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.affiliation: Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA mitchell.gross@usc.edu.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Gross
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011944:Receptors, Androgen; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D017430:Prostate-Specific Antigen
keywords: androgen receptor; cancer-associated fibroblast; prostate cancer; stroma