Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts
Journal Title
Molecular Oncology
Publication Type
Research article
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-beta 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.
Publisher
Wiley
Keywords
Male; Humans; Animals; Mice; *Prostate/pathology; Cell Communication; Fibroblasts/metabolism; Signal Transduction; Coculture Techniques; *Prostatic Neoplasms/pathology; Cell Line, Tumor; Epithelial Cells/metabolism; Tumor Microenvironment
Department(s)
Laboratory Research
PubMed ID
36608258
Open Access at Publisher's Site
https://doi.org/10.1002/1878-0261.13376
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2023-06-15 07:24:58
Last Modified: 2023-06-15 07:25:48

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