Bone is the most common metastatic organ in men with androgen independent prostate cancer (AIPC). While localized prostate cancer may be cured, patients with bone metastasis and resulting complications often have a poor prognosis, with a median survival of 9 months or less. Over 70% of patients with metastases will die from their disease, rather than from unrelated complications. However, the mechanisms involved prostate cancer organ specific metastasis yet to be cleared. It has been demonstrated CXCL12-CXCR4 axis promote cancer cells, e.g., prostate and breast cancer cells, metastasis into bone, lung, and liver. We further demonstrated chemokines, such as BDNF, CCL5, CXCL5, CXCL16 and CXCL12 concomitantly over-express in tumor associated stromal cells after co-cultured in 3D-RWV systems. These can be confirmed in serum from AIPC patients with bone metastasis. In order to identify the receptors upregulation correlate with prostate cancer cells progression, we performed q PCR analyses and verified the increased of CXCR4 and CCRL2 in AIPC cell lines. FACS studies also showed increased of CCRL2 in AIPC cells and TrkB in DU145 whereas PC3 harvested from PCa patient with bone metastasis and DU145 from PCa patient with brain metastasis. This raises possibility of chemokine receptors, TrkB and CCRL2, concurrently promote prostate cancer organ specific metastasis through the interaction with chemokines released by stromal cells. Hence, we hypothesized the interaction of chemokine factors, CCL5 and BDNF, with novel receptors, CCRL2 and TrkB, enhance prostate cancer organ specific metastasis. The objective of this proposal is to determine the role of chemokine and receptor interaction and the potential therapeutic strategy. The proposal focuses on 3 aims. Aim 1, we will verify the interaction of chemokine and novel receptors to determine if the interaction is directory or not. Crosslinking studies will be performed to confirm their interaction. Aim 2, we will determine the downstream regulatory process. Promoter assay in prostate cancer will be performed to determine the possible regulatory signals. Aim 3, Determine if the interaction between chemokine and receptor is response to organ specific metastasis. We will assess the potential roles of CCL5-CCRL2 and BDNF-TrkB in inducing prostate cancer cell growth, survival and invasion in the in vitro and in vivo analyses. Finally, we will determine if combination of blocking chemokines and receptors interaction could decrease prostate cancer metastasis at higher degree. The goal of this proposal is to study the regulatory mechanisms of chemokine and receptor in prostate cancer organ specific metastasis. The results of these studies will help us understand: 1) chemokine-receptor intercellular regulatory network modulated by stromal cells in supporting cancer cell migration and metastasis. 2) The molecular mechanisms to induce novel chemokine receptor expression in malignant prostate cancer progression and bone metastasis; 3) and the understanding the mechanisms and developing of anti-stromal factors therapy to block the interaction of cancer organ specific metastasis in relevant animal models. With the studies we hope could significantly the understanding of the vicious cycle between tumor-stromal cells at different stage of cancer and provide a new direction for the therapeutic opportunity.
|Effective start/end date||8/1/12 → 9/30/13|