orphan receptor br Results br Discussion Prostate

Results
Discussion Prostate cancer dissemination and skeletal metastases represent major therapeutic challenges. Once the skeletal metastasis occurs, the incurable patient could just be symptomatically treated to alleviate the pain. Therefore it is of great necessity to disclose the molecular mechanisms underlying PCa metastasis and its propensity for bone, as well as uncovering the potential targets for future research. We found that the expression level of DDR2 was significantly higher in bone metastatic PCa orphan receptor and tissues, which prompted us to investigate the role of DDR2 in PCa dissemination and bone metastases. DDR2 has been implicated in playing essential roles in other cancer types but PCa. Our previous study suggested the function of DDR2 in the regulation of the transactivity and phosphorylation of Runx2, a key regulator of PCa bone metastasis. Based on these findings, we hypothesized that DDR2 promotes PCa metastasis and bone-homing via Runx2 regulation. In the present study, we initially observed that the expression level of DDR2 was notably elevated in the bone metastatic PCa cells and tissues, compared with normal and non-bone-metastatic controls. DDR2 positively regulated the migration and invasion abilities of PCa cells. DDR2 in PCa cells stimulated osteoblastogenesis and osteoclastogenesis in vitro, and DDR2 depletion alleviated osteolytic lesions in vivo. The underlying mechanism was that DDR2 in PCa cells regulated the expression, secretion, and promoter activity of PTHrP via regulating the transactivity and phosphorylation of Ruxn2, to affect the RANKL expression of osteoblasts, which in turn stimulated osteoclast activation and bone resorption. Moreover, DDR2 was responsive to TGF-β stimulation and participated in the TGF-β-induced bone resorption. DDR2 also mediated the adhesion of PCa cells to type I collagen, the main component of bone. DDR2 has been implicated in the progression of several types of cancer. DDR2 participates in the liver metastasis of melanoma, contributes to colorectal dissemination by increasing myofibroblasts, neoangiogenic vessels and proliferating cancer cells. DDR2 is closely associated with nasopharyngeal carcinoma (NPC) and aneuploid papillary thyroid carcinomas, and is involved in EMT of several types of cancer cells including breast and lung cancer cells using distinct mechanisms. Activated mutation of DDR2 was also found in lung squamous-cell carcinoma. However, there is another report regarding the negative regulatory role of DDR2 in tumor progression (DDR2 deficiency predisposes hepatic tissue to colon carcinoma) [44], suggesting that the role of DDR2 in tumors is complicated and cellular context dependent. Until now there is no literature reporting the roles of DDR2 in PCa and PCa bone colonization. Our original study implicates DDR2 in PCa bone metastasis for the first time and is of great significance for the future treatment of prostate cancer. Moreover, the target genes downstream of DDR2 are largely unknown, and the detailed signaling pathways mediating DDR2 regulation of target gene transcription are poorly understood. In the present study, we demonstrated that PTHrP is regulated by DDR2 in PCa cells. This finding expands the DDR2-Runx2 axis to TGFβ-DDR2-Runx2-PTHrP pathway. Prostate cancer bone metastases result in mixed, heterogeneous osteoblastic and osteolytic lesions. Osteoblastic lesions are characterized by excess deposition of new bone, whereas osteolytic lesions are characterized by the destruction of bone. These two types of PCa bone metastases all cause disturbance of bone microenvironment homeostasis. PCa cells secrete factors that stimulate the proliferation and differentiation of osteoprogenitor cells, or induce osteoclast precursors differentiate into mature osteoclasts in the tumor environment. Although clinically osteoblastic lesions account as a major component, there are still existing osteolytic lesions which are due to the activation of osteoclasts. It is unknown which kind of bone metastatic lesions, osteoblastic or osteolytic, occur initially. In our study, we demonstrated that the formation of osteolytic lesions required osteoblasts, suggesting the initiating role of osteoblastic lesions in PCa bone metastases. DDR2 acted as a stimulator for PCa bone metastases via regulating PTHrP, which has been implicated to function in an autocrine, paracrine or intracrine manner. Here we only discussed the paracrine manner of PTHrP to influence the bone microenvironment. Other aspects of PTHrP function, such as stimulating cell proliferation, adhesion and survival by directly acting on tumor cells, were not investigated in this study. Our results showed that PCa cell-derived PTHrP was responsible for the stimulated osteoblast proliferation and activation, as well as the promoted osteoclast differentiation and bone resorption, being consistent with previous reports [45].