| 摘要: | 前列腺癌末期最常發生的就是骨轉移，而前列腺癌骨轉移病患平均之生命期約為九個 月。但其轉移之機轉仍然混沌未明。科學研究指出趨化素與受器之交互作用是促使癌 細胞轉移之主因之ㄧ，先前研究發現CXCL12與CXCR4可促使癌細胞轉移，而近來更指 出基質細胞與癌細胞作用後會釋出CCL5，進而造成乳癌細胞之轉移。這與我們最近發 表之研究相符，我們發現基質細胞會釋放出多種趨化素，包括CCL5，BDNF，CCL26及 CXCL12。而與其作用之癌細胞則有增加CXCR4，TrkB 及CCRL3等受器之表現。初步研 究顯示降低CCRL2及TrkB之表現可抑制癌細胞移動。因此本計劃的理論假設在於CCL5 與CCRL2以及BDNF與TrkB之交互作用會促使前列腺癌之轉移至不同之器官，而本計劃 之宗旨是藉由研究趨化素與受器之作用所造成的癌細胞轉移之訊息傳導及其轉移機 制，以了解癌細胞與基質細胞之作用模式。此計劃共分為三項子計劃：計劃一、 確定 CCRL2是CCL5及TrkB是BDNF之活性受器。計劃二、研究其作用促使癌細胞轉移之下游 訊息傳導。計劃三、研究趨化因子與受器之間作用以造成癌細胞轉移之機轉。本計劃 新穎之處在於研究在前列腺癌細胞中趨化因子與受器之間作用所造成之癌細胞轉移機 制，以協助我們了解癌細胞是如何調控本身接受器之表現對於周邊環境改變之機轉及 臨床之應對方式。
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. |
