Abstract
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.
Highlights
From the Departments of ‡Translational Molecular Pathology, §Genitourinary Medical Oncology, University of Texas, M.D
The ectopic bone was detected as dense structures in x-ray images, as either a major focus or multifoci, with branches emanating from the central bony structure (Fig. 1A). These observations lead us to hypothesize that prostate cancer (PCa)-118b human tumor cells probably secreted factors that promoted tumor growth and modulated the mouse stromal cells in the microenvironment to promote bone formation, similar to those observed in human osteoblastic bone metastases
FGF2 is known to increase osteoblast proliferation accompanied with inhibition of osteoblast differentiation, as reflected in a decrease in alkaline phosphatase activity (Fig. 4H). Both FGF3 and FGF19 decrease alkaline phosphatase activity (Fig 4H), but with much weaker activity when compared with FGF2. These findings suggest that FGF3 and FGF19 secreted from PCa-118b cells exert both autocrine and paracrine effects on tumor cells and stromal cells (Fig. 4I)
Summary
From the Departments of ‡Translational Molecular Pathology, §Genitourinary Medical Oncology, University of Texas, M.D. A distinct feature of human prostate cancer (PCa) with lethal potential is the development of metastases in bone with a bone-forming phenotype [1]. This property of PCa bone metastasis suggests that PCa cells have unique interactions with cells in the bone microenvironment. The. Secreted Factors of an Osteogenic Prostate Cancer Xenograft capacity of PCa-118b cells to induce bone formation, in which human tumor cells interact with the murine stromal microenvironment, makes this PDX an ideal model system to study tumor-microenvironment signaling pathways that create a bone-like tumor microenvironment conducive to metastatic PCa growth
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