Abstract
Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
Highlights
Bone is the most common metastatic site for castration-resistant prostate cancer.[1]
To fraction of proliferating tumor cells was significantly decreased in address whether neuropilin 2 (NRP2) is present in human prostate cancer (PCa) bone metastasis, both the NRP2-depletion and the combination group compared we evaluated its expression by immunohistochemistry both in with the control (Fig. 1f–i)
The results presented here highlighted the potential of targeting the NRP2 axis as a novel therapy for PCa bone metastasis
Summary
Bone is the most common metastatic site for castration-resistant prostate cancer.[1]. A major consideration in this effort is that treatment strategies for PCa cells metastasized to bone are likely to influence the normal bone cells present at the site of metastatic lesions This is because the metastatic disease results from an interplay between cancer cells and the bone cells namely osteoblasts and osteoclasts, which contributes to a vicious cycle that provides a fertile soil for metastatic growth of cancer cells in the bone.[1,10,11] Radiographic studies of PCa patients with bone involvement characterized bone metastases as osteoblastic lesions as opposed to osteolytic lesions with decreased bone mineral density.[12] PCa bone metastases show a heterogeneous blend of osteoblastic and osteolytic functions with the balance shifted to favor osteoblastic metastasis. Almost all the metastatic lesions eludicated the overall effect of targeting NRP2 in both cancer cells became necrotic when combining NRP2 depletion with taxaneand osteoclasts in PCa bone metastasis, which can prove to be based chemotherapy (Fig. 1e) To validate these results, we beneficial in the development of an effective treatment strategy. In comparison to the control, apoptosis was increased in the groups receiving
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