Loss of transforming growth factor-beta (TGF-β) type II receptor (TβRII, encoded by Tgfbr2) expression in the prostate stroma contributes to prostate cancer (PCa) initiation, progression, and invasion.
We evaluated whether TβRII loss also affected PCa bone metastatic growth. Immunohistological analysis revealed that TβRII expression was lost in cancer-associated fibroblasts in human PCa bone metastatic tissues. We recapitulated the human situation with a conditional stromal Tgfbr2 knockout (Tgfbr2-KO) mouse model. Conditioned media from primary cultured Tgfbr2-KO or control Tgfbr2-flox prostatic fibroblasts (koPFCM or wtPFCM, respectively) were applied to C4-2B PCa cells prior to grafting the cells tibially. We found that koPFCM promoted PCa cell growth in the bone and development of early mixed osteoblastic/osteolytic bone lesions. Further, the koPFCM promoted greater C4-2B adhesion to type-1 collagen, the major component of bone matrix, compared to wtPFCM treated C4-2B. Cytokine antibody array analysis revealed that koPFCM had more than 2-fold elevation in granulocyte colony-stimulating factor, CXCL1, CXCL16, and CXCL5 expression relative to wtPFCM. Interestingly, neutralizing antibodies of CXCL16 or CXCL1 was able to reduce koPFCM-associated C4-2B collagen I adhesion to that comparable to wtPFCM mediated adhesion. Collectively, our data indicate that loss of TGF-β responsiveness in prostatic fibroblasts results in upregulation of CXCL16 and CXCL1; and that these paracrine signals increase PCa cell adhesion in the bone matrix. These microenvironment changes at the primary tumor site can mediate early establishment of PCa cells in the bone and support subsequent tumor development at the metastatic site.
Written by:
Li X, Sterling JA, Fan KH, Vessella RL, Shyr Y, Hayward SW, Matrisian LM, Bhowmick NA. Are you the author?
Vanderbilt-Ingram Cancer Center.
Reference: Mol Cancer Res. 2012 Jan 30. [Epub ahead of print]
PubMed Abstract
PMID: 22290877
UroToday.com Investigational Urology Section
