A distinct feature of human
prostate cancer (PCa) is the development of osteoblastic (bone-forming) bone
metastases. Metastatic growth in the bone is supported by factors secreted by PCa cells that activate signaling networks in the tumor microenvironment that augment
tumor growth. To better understand these signaling networks and identify potential targets for
therapy of bone
metastases, we characterized the secretome of a patient-derived xenograft, MDA-PCa-118b (PCa-118b), generated from osteoblastic bone lesion. PCa-118b induces osteoblastic
tumors when implanted either in mouse femurs or subcutaneously. To study signaling molecules critical to these unique tumor/microenvironment-mediated events, we performed mass spectrometry on
conditioned media of isolated PCa-118b
tumor cells, and identified 26 secretory
proteins, such as TGF-β2, GDF15, FGF3, FGF19, CXCL1,
galectins, and β2-microglobulin, which represent both novel and previously published secreted
proteins. RT-PCR using human versus mouse-specific primers showed that TGFβ2, GDF15, FGF3, FGF19, and CXCL1 were secreted from PCa-118b cells. TGFβ2, GDF15, FGF3, and FGF19 function as both autocrine and paracrine factors on
tumor cells and stromal cells, that is, endothelial cells and osteoblasts. In contrast, CXCL1 functions as a paracrine factor through the
CXCR2 receptor expressed on endothelial cells and osteoblasts. Thus, our study reveals a complex PCa bone
metastasis secretome with paracrine and autocrine signaling functions that mediate cross-talk among multiple cell types within the tumor microenvironment.