Modeling MIC Shedding in Prostate Cancer Progression

描述(申请人提供)：本申请中提出的研究旨在通过动物模型了解前列腺癌中的一种特定的抗肿瘤免疫。转化诱导的主要组织相容性(MHC)I链相关分子(MIC)在包括前列腺癌在内的大多数上皮性肿瘤中都有表达。MIC被认为是NKG2D的配体，NKG2D是一种由所有人类自然杀伤(NK)和细胞毒性T细胞表达的刺激性免疫受体。MIC与NKG2D结合可激活NK细胞，增强T细胞抗肿瘤免疫。转化细胞表面MIC的表达被建议用来标记新生肿瘤以用于免疫监测。研究表明，晚期癌细胞产生两种形式的MIC，即表面膜结合的MIC和可溶性MIC(SMIC)。研究表明，SIMIC介导了MIC-NKG2D介导的抗肿瘤免疫缺陷。前列腺癌的临床研究表明，晚期前列腺癌患者血清SMIC水平升高。目前尚不清楚是中芯国际允许较低级别的肿瘤变得更具侵袭性，还是向更具侵袭性的表型进展导致了中芯国际的产生。这项拟议研究的长期目标是勾勒出中芯国际水平与前列腺癌进展之间的关系，并确定和验证对抗中芯国际产生肿瘤的策略。为了实现这一长期目标，这项拟议的研究特别旨在建立一种动物模型，以进一步研究前列腺癌的这些临床观察。这项拟议研究的结果可能对前列腺癌的治疗具有直接的临床意义。此外，由于研究表明SMIC也在其他上皮性肿瘤中产生，如乳腺癌、肺癌和结肠癌，这项拟议的研究结果也将对其他上皮性肿瘤具有广泛的临床意义。

DESCRIPTION (provided by applicant): The proposed research in this application is aimed at understanding a specific anti-tumor immunity in prostate cancer using animal models. The transformation-induced major histocompatibility (MHC) I chain-related molecule (MIC) is shown to be expressed on most epithelial tumors, including prostate carcinoma. MIC is identified as a ligand for NKG2D, a stimulatory immune receptor expressed by all human natural killer (NK) and cytotoxic T cells. Engagement of MIC to NKG2D triggers NK cell and augments T cell anti-tumor immunity. Surface expression of MIC on transformed cells is proposed to mark nascent tumors for immune surveillance. Studies have shown that advanced cancer cells produce two forms of MIC, the surface membrane-bound MIC and the soluble form of MIC (sMIC). It has been shown that siMIC mediates deficiency in MIC-NKG2D mediated anti-tumor immunity. Compelling clinical studies in prostate cancer have demonstrated that levels of serum sMIC increase in advanced cancers. It is unknown whether sMIC allows a lower grade tumor to become more aggressive or whether the progression to a more aggressive phenotype causes the production of sMIC. The long-term goal of this proposed research is to delineate the relationship between levels of sMIC and prostate cancer progression and to define and validate strategies to counteract tumor production of sMIC. To achieve this long-term goal, this proposed research aims specifically at establishing an animal model to further study these clinical observations in prostate cancer. Outcomes from this proposed research would potentially have direct clinical implication for treatment of prostate cancer. Furthermore, as studies have shown that sMIC was also produced in other epithelial tumors, such as breast, lung, and colon cancers, the outcomes of this proposed research will also have broad clinical implications in other epithelial tumors.