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Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells.

ABSTRACT: Signals originating from cancer-associated fibroblasts (CAF) may positively regulate proliferation and tumorigenicity in prostate cancer. In this study, we investigated whether CAFs may regulate the biology of prostate cancer stem cells (CSC) by using a conditional Pten deletion mouse model of prostate adenocarcinoma to isolate both CAF cultures and CSC-enriched cell fractions from the tumors. CSCs that were isolated possessed self-renewal, spheroid-forming, and multipotential differentiation activities in tissue culture, segregating with a cell fraction exhibiting a signature expression phenotype, including SCA-1 (high), CD49f (high), CK5 (high), p63 (high), Survivin (high), RUNX2 (high), CD44 (low), CD133 (low), CK18 (low), and Androgen Receptor (low). CSC spheroid-forming efficiency was differentially influenced by the nature of fibroblasts in a coculture system: Compared with mouse urogenital sinus mesenchyme or normal prostate fibroblasts, CAFs enhanced spheroid formation, with the spheroids displaying generally larger sizes and more complex histology. Graft experiments showed that CSCs admixed with CAFs produced prostatic glandular structures with more numerous lesions, high proliferative index, and tumor-like histopathologies, compared with those formed in the presence of normal prostate fibroblasts. Together, our findings underscore a significant role of CAFs in CSC biology.

SUBMITTER: Liao CP

PROVIDER: S-EPMC2940948 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells.

Liao Chun-Peng CP Adisetiyo Helty H Liang Mengmeng M Roy-Burman Pradip P

Cancer research 20100831 18

Signals originating from cancer-associated fibroblasts (CAF) may positively regulate proliferation and tumorigenicity in prostate cancer. In this study, we investigated whether CAFs may regulate the biology of prostate cancer stem cells (CSC) by using a conditional Pten deletion mouse model of prostate adenocarcinoma to isolate both CAF cultures and CSC-enriched cell fractions from the tumors. CSCs that were isolated possessed self-renewal, spheroid-forming, and multipotential differentiation ac ...[more]

PMID: 20807814

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Project description:Recently, several studies have demonstrated that cancer cell?derived exosomes can facilitate tumor development and metastasis formation. However, the detailed function of exosomes released by cancer stem cells (CSCs) requires further investigation. The aim of the present study was to investigate the role of CSC?derived exosomes in tumor development. For this purpose, Piwil2?induced cancer stem cells (Piwil2?iCSCs) were used as exosome?generating cells, while fibroblasts (FBs) served as recipient cells. Exosomes were isolated by the ultracentrifugation of Piwil2?iCSC?conditioned medium and identified by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. To evaluate the effects of the exosomes on cell proliferation, migration and invasion, cell counting assay (CCK?8), a wound healing assay and a Transwell assay were performed. Protein expression [matrix metalloproteinase (MMP)2, MMP9, ??smooth muscle actin (??SMA) and vimentin and fibroblast?activating protein (FAP)] was examined in FBs by western blot analysis. It was found that the Piwil2?iCSC?derived exosomes (Piwil2?iCSC?Exo) were oval or spherical, membrane?coated vesicles with a uniform size (30?100 nm in diameter). They are characterized by the surface expression of CD9, CD63, Hsp70 and Piwil2 proteins. Additional results from functional analyses revealed that Piwil2?iCSC?Exo enhanced the proliferative, migratory and invasive abilities of FBs, accompanied by the upregulated expression of MMP2 and MMP9. In addition, the increased expression of ??SMA (P<0.05), vimentin (P<0.01 vs. control group, P<0.05 vs. PBS group) and FAP (P<0.001 vs. control group, P<0.01 vs. PBS group) following exposure to Piwil2?iCSC?Exo suggested that the exosomes induced FB transformation into cancer?associated fibroblasts (CAFs). On the whole, the findings of this study demonstrate that Piwil2?iCSC?Exo induce the cancer?associated phenotype in fibroblasts in vitro, suggesting that CSCs can promote tumor development through the modulation of the tumor microenvironment.

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Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells.

Publications

Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells.

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