Abstract
Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.
Highlights
Prostate cancer (PCa), the most common malignant tumor in men, is the second leading cause of cancer deaths in males worldwide[1].Patients with advanced PCa frequently exhibit distant metastasis, with bone being the preferential site in nearly 90% of metastatic PCa patients[2]
Together, assessed the mRNA expression of C-C chemokines (CCL2, CCL3, these findings strongly suggest that growth differentiation factor-15 (GDF15) overexpression in PCa CCL7, and CCL12) in osteoblasts following treatment with either cells promotes skeletal metastasis
PCa-secreted GDF15 induces osteoclastogenesis Since GDF15 deficiency in PCa cells dramatically reduced the recruitment of bone macrophages phosphatase (TRAP) staining in the bone microand CD68-positive macrophages in C4-2B (GDF15 KO)-injected environment, we examined whether GDF15 released by PCa cells tibiae was lower than that in tibiae implanted with parental cells might control osteoclast (OC) formation
Summary
Prostate cancer (PCa), the most common malignant tumor in men, is the second leading cause of cancer deaths in males worldwide[1]. The bone microenvironment comprises osteoclasts and osteoblasts that function to resorb and mineralize (form new) bone, respectively. The activities of these two cell populations are tightly coupled to balance bone turnover. The bone microenvironment regularly secretes factors for bone maintenance that inadvertently provide a fertile environment for the establishment and growth of tumors within the bone, leading to a vicious cycle[7]. Bone metastases in PCa are osteoblastic in nature, characterized by the net formation of new bone of poor mechanical quality but featuring high levels of markers of bone resorption/osteoclast activity[8]. We provide preclinical and clinical evidence to establish the role of PCa-secreted GDF15 in bone metastasis and reveal the mechanism underlying GDF15-mediated osteomac recruitment and alteration of the bone microenvironment. Role of GDF15 in prostate cancer bone metastasis JA Siddiqui et al
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