探討細胞吸附分子L1在前列腺癌轉移的生物機制與治療之可行性

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题名:	探討細胞吸附分子L1在前列腺癌轉移的生物機制與治療之可行性
作者:	謝嘉玲
贡献者:	醫學院癌症生物學研究所;中國附醫分子醫學中心腫瘤基因
关键词:	前列腺癌;細胞吸附分子;骨轉移;prostate cancer;cell adhesion molecule;bone metastasis
日期:	2010-07-31
上传时间:	2009-09-01 15:56:50 (UTC+8)
摘要:	前列腺癌病人的骨轉移是造成患者病痛及死亡的主因。高於90%的前列腺癌死者皆有骨轉移的病症，然而造成此高骨轉移率的機制仍未明。去雄激素內分泌療法雖對骨轉移的初期有療效，但癌細胞終究會發展為對雄激素不依賴性而無任何傳統醫療措施得以有效控制病情。病人在此階段的平均中值存活期只有九個月或更低。因此本計劃的宗旨即在解讀前列腺癌骨轉移之生物及分子機制，進而研發出一套有效的治療方針足以預防和終止此惡質化病程的發生。前列腺癌細胞已被證實偏好吸附在骨髓血管內皮層。此器官特異性的吸附作用可能是促成高骨轉移率的關鍵步驟。本計劃的內容因此著重於探討癌細胞與骨髓血管內皮層間藉由L1細胞吸附分子所調節的交錯反應在前列腺癌症骨轉移過程中所扮演的角色及臨床醫療之應用。計劃一將研究藉由L1誘導出之血管內皮因子的表現及其對前列腺癌細胞之生長和漫延的調節作用。計畫二將研究L1和受器間的訊息傳導在腫瘤-血管內皮交錯反應中扮演的生物角色其分子機制。計畫三即將評估以L1為標的物的基因療法去阻斷腫瘤-血管內皮的交錯反應能否達到降低前列腺骨轉移的成效。釐清前列腺癌親骨髓內皮層的生物及分子機制將有助於發展以機理為基礎的骨轉移治療方針。 The most common site of prostate cancer metastasis is the bone with skeletal metastases identified at autopsy in up to 90% of patients dying from prostate cancer. The bone metastasis is initially sensitive to hormonal therapy, but with time the cancer eventually progresses to an androgen-independent state for which there is no effective treatment and has a medium survival of 9 months or less. It is critical that a solid understanding of the biology of prostate cancer skeletal metastatic process is developed to provide the basis for creating strategies to prevent or diminish their occurrence and associated complications. The intricate intercellular communication within the tumor microenvironment involves cell-cell, cell-insoluble extracellular matrices (ECMs), and cell-soluble factor mediated signaling processes, which support cancer cells growth and dissemination, therefore present an attractive target for therapeutic intervention. One critical step governing the process of bone metastasis is through selective attachment to organ’s lining endothelium and subsequently the organ’s ECM components though specific cell adhesion molecules (CAMs) utilized by prostate cancer cells. The goal of this project is to understand the molecular pathway of CAM-mediated tumor-stromal interaction in prostate cancer bone metastasis and design a reasonable therapeutic approach targeting the most vulnerable sites required for cell proliferation, survival, and intercellular communication. The hypothesis of this proposal is that a L1 cell adhesion molecule (L1CAM) expressed by both prostate cancer and bone marrow endothelial cells is responsible for site-specific tumor-endothelial interaction and tumor colonization in bone microenvironment. Interrupting L1CAM-mediated signaling can combat the lethal prostate cancer bone metastases. The proposal focuses on three themes. First, L1CAM-mediated reciprocal interaction confers tumor-stromal co-evolution in tumor microenvironment. Specific Aim 1 will address this theme by characterizing the possible L1CAM-responsive endothelial factors involved in prostate cancer cells homing to bone. Second, L1CAM functions not only as an adhesive molecule but also as a signal-transducing receptor regulating prostate cancer cell growth, migration, survival and its predilection for bone. Specific Aim 2 will assess this theme by defining the molecular pathway underlying L1CAM-mediated tumor-endothelial interaction in prostate cancer progression. Third, therapy for prostate bone metastasis can target not only the tumor cells but also the crosstalk between metastatic cells and organ-specific endothelium that enables tumor metastasis to organs. Specific Aim 3 will validate a L1CAM-based gene therapy approach based on the concept of targeting tumor-endothelium interaction on prostate cancer bone metastasis. Elucidation of the cellular and molecular mechanisms by which prostate cancer preferentially interacts with bone marrow endothelium is essential for the development of effective mechanism-based therapeutic intervention in prostate cancer metastasis.
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