Abstract
Reciprocal interactions between prostate cancer cells and carcinoma-associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co-culture of prostate epithelial or cancer cells with fibroblasts that mimic bi-directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono- and co-cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co-culture compared to mono-culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL-17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co-cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF-β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co-culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell–fibroblast communication, demonstrates that co-culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour-microenvironment-derived secreted factor that represents a candidate therapeutic target.
Original language | English |
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Pages (from-to) | 469-486 |
Number of pages | 18 |
Journal | Molecular Oncology |
Volume | 17 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2023 |
Keywords
- cell signalling
- chemokine
- co-culture
- cytokine
- follistatin
- tumour microenvironment