Loss of TGF- Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions

Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
Molecular Cancer Research (Impact Factor: 4.38). 01/2012; 10(4):494-503. DOI: 10.1158/1541-7786.MCR-11-0506
Source: PubMed


Loss of TGF-β type II receptor (TβRII, encoded by Tgfbr2) expression in the prostate stroma contributes to prostate cancer initiation, progression, and invasion. We evaluated whether TβRII loss also affected prostate cancer bone metastatic growth. Immunohistologic analysis revealed that TβRII expression was lost in cancer-associated fibroblasts in human prostate cancer 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 prostate cancer cells before grafting the cells tibially. We found that koPFCM promoted prostate cancer cell growth in the bone and development of early mixed osteoblastic/osteolytic bone lesions. Furthermore, the koPFCM promoted greater C4-2B adhesion to type-I collagen, the major component of bone matrix, compared to wtPFCM-treated C4-2B. Cytokine antibody array analysis revealed that koPFCM had more than two-fold elevation in granulocyte colony-stimulating factor and CXCL1, CXCL16, and CXCL5 expression relative to wtPFCM. Interestingly, neutralizing antibodies of CXCL16 or CXCL1 were able to reduce koPFCM-associated C4-2B type-I collagen adhesion to that comparable with 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 prostate cancer cell adhesion in the bone matrix. These microenvironment changes at the primary tumor site can mediate early establishment of prostate cancer cells in the bone and support subsequent tumor development at the metastatic site.

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    • "In bone tissue associated with PCa, CAFs express the myofibroblast marker α-SMA, and the androgen receptor (AR). As observed in primary cancer, TGFβ receptor II (TGFβRII) expression was lost in CAFs in the majority of bone metastatic tissues examined [55]. The loss of TGFβ sensitivity in prostatic CAFs promoted PCa cell proliferation and invasion in a xenograft model [56]. "
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    ABSTRACT: The onset of metastases dramatically changes the prognosis of prostate cancer patients, determining increased morbidity and a drastic fall in survival expectancy. Bone is a common site of metastases in few types of cancer, and it represents the most frequent metastatic site in prostate cancer. Of note, the prevalence of tumor relapse to the bone appears to be increasing over the years, likely due to a longer overall survival of prostate cancer patients. Bone tropism represents an intriguing challenge for researchers also because the preference of prostate cancer cells for the bone is the result of a sequential series of targetable molecular events. Many factors have been associated with the peculiar ability of prostate cancer cells to migrate in bone marrow and to determine mixed osteoblastic/osteolytic lesions. As anticipated by the success of current targeted therapy aimed to block bone resorption, a better understanding of molecular affinity between prostate cancer and bone microenvironment will permit us to cure bone metastasis and to improve prognosis of prostate cancer patients.
    BioMed Research International 05/2014; 2014(2):167035. DOI:10.1155/2014/167035 · 2.71 Impact Factor
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    • "Very few studies appear to have compared the stroma in paired primary tumors and metastatic lesions in prostate cancer. TGFβRII expression in CAFs is absent in human cancer bone metastases [93] and prostate cancer cells in vitro are able to suppress TGFβRII, smooth muscle actin and ECM production, and increase vimentin, integrins, MMP9 and MMP14 in bone marrow stroma cells [94] resulting in the formation of a more fibroblast like than myofibroblast-like stroma. When we examined prostate cancer bone metastases in patients the cancer cells were growing in a fibroblast like stroma [84] with less smooth muscle actin and AR expression and more SDF-1 expression than in the corresponding primary tumor stroma [77]. "
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    ABSTRACT: Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or distant metastasis. Identification of new, improved prognostic and diagnostic biomarkers for prostate cancer and the finding of better treatment strategies for metastatic prostate cancer is therefore highly warranted. Interactions between epithelium and stroma are known to be important already during prostate development and this interplay is critical also in development, progression of primary tumors and growth of metastases. It is therefore reasonable to expect that future biomarkers and therapeutic targets can be identified in the prostate tumor and metastasis stroma and this possibility should be further explored.
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