Neoplastic Reprogramming of Patient-Derived Adipose Stem Cells by Prostate Cancer Cell-Associated Exosomes

Abstract

Emerging evidence suggests that mesenchymal stem cells (MSCs) are often recruited to tumor sites but their functional significance in tumor growth and disease progression remains elusive. Herein we report that prostate cancer (PC) cell microenvironment subverts PC patient adipose-derived stem cells (pASCs) to undergo neoplastic transformation. Unlike normal ASCs, the pASCs primed with PC cell conditioned media (CM) formed prostate-like neoplastic lesions in vivo and reproduced aggressive tumors in secondary recipients. The pASC tumors acquired cytogenetic aberrations and mesenchymal-to-epithelial transition (MET) and expressed epithelial, neoplastic, and vasculogenic markers reminiscent of molecular features of PC tumor xenografts. Our mechanistic studies revealed that PC cell-derived exosomes are sufficient to recapitulate formation of prostate tumorigenic mimicry generated by CM-primed pASCs in vivo. In addition to down-regulation of the large tumor suppressor homolog2 (Lats2) and the programmed cell death protein 4 (PDCD4), a neoplastic transformation inhibitor, the tumorigenic reprogramming of pASCs was associated with trafficking by PC cell-derived exosomes of oncogenic factors, including H-ras and K-ras transcripts, oncomiRNAs miR-125b, miR-130b, and miR-155 as well as the Ras superfamily of GTPases Rab1a, Rab1b, and Rab11a. Our findings implicate a new role for PC cell-derived exosomes in clonal expansion of tumors through neoplastic reprogramming of tumor tropic ASCs in cancer patients.

The biology and function of exosomes in cancer

“…Cancer cell-derived exosomes have been implicated in determining the tumorigenic potential of epithelial cells (14,21,84,85). Cancer exosome miR may also contribute to tumorigenesis, and cancer exosomes can mediate cell-independent miR biogenesis, a property not associated with normal exosomes.…”

Exosomes and tumor-mediated immune suppression

“…It has been suggested that stress, including hypoxia in the TME, accounts for this copious TEX secretion by tumor cells (36). TEX production and release by tumor cells was also reported to be regulated by p53 (37).…”

Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer

“…The qPCR and miRNA analyses were performed as previously described (20,21). Analysis details and primers used for gene expression (Supplementary Table S2) and miRNAs (Supplementary Table S3) are provided in the Supplementary Methods.…”

“…The assays were performed as previously described (21). Experimental details are furnished in Supplementary Information.…”