(PQA1)The Molecular Mechanisms Underlying Effects of Aspirin on Colorectal Cancer

描述(申请人提供)：阐明使用阿司匹林降低结直肠癌风险和死亡率的分子机制(S)可能导致癌症化学预防和治疗领域的重大突破。迄今为止最令人信服的证据表明，阿司匹林和其他非甾体抗炎药的抗肿瘤作用是由于抑制环氧合酶活性而减少了促炎前列腺素E2(PGE2)的产生。我们的初步数据表明，阿司匹林减少了息肉数量，同时减少了肿瘤中前列腺素的产生，从而支持了这一假设。然而，没有直接证据表明阿司匹林通过靶向COX酶来减少PGE2的产生来抑制结直肠癌的发生、进展和转移。此外，以前的研究主要集中在NSAIDs在清除肿瘤上皮细胞和抑制肿瘤相关血管生成方面的作用。人们对阿司匹林对结直肠癌免疫逃避的影响知之甚少。我们以前从未报道过的观察表明，阿司匹林通过抑制髓系抑制细胞(MDSCs)恢复宿主的免疫监视，PGE2通过诱导CXCR2配体的表达诱导MDSCs渗入肠道肿瘤和粘膜。这促使我们假设阿司匹林可能通过靶向COX-PGE2-CXCR2途径抑制MDSCs的募集，从而抑制肿瘤的启动、进展和转移。AIM 1就是为了检验这一假设而设计的。这一目标的结果不仅可以确定阿司匹林抗肿瘤作用的关键机制，而且可能为开发新的治疗方法提供理论基础，通过使用CXCR2拮抗剂和/或CXCR2中和抗体来逆转APC突变和肿瘤诱导的免疫抑制。此外，我们的初步研究首次显示，初选 肿瘤诱导了转移前器官的免疫抑制，而柯昔布治疗减弱了原发肿瘤对转移前肝脏生态位形成的影响。因此，可以设想阿司匹林通过靶向COX-PGE2-CXCR2途径来抑制转移的形成，从而抑制转移。AIM 2的设计就是为了检验这一假设。这一目标的结果应该为开发新的治疗方法提供理论基础，通过阻断转移前的利基形成来抑制结直肠癌转移。最后，阿司匹林防癌作用的一个潜在解释可能是 由于抑制了血小板中COX-1的活性。然而，没有明确的证据支持这一观点。我们将在目标3中测试血小板COX-1的这一作用。这一目标的结果将为在未来的癌症预防和治疗中开发针对血小板COX-1的新的治疗方法提供理论基础。总的来说，我们在这项建议中确定的机制可能适用于其他实体癌症，并且肯定可以在其他系统中进行测试。此外，靶向宿主免疫监视或血小板也可能是结直肠癌患者的一种新的治疗方法。

DESCRIPTION (provided by applicant): Elucidating the molecular mechanism(s) by which aspirin use reduces the risk and mortality of colorectal cancer (CRC) could lead to major breakthroughs in the field of cancer chemoprevention and treatment. The most compelling evidence to date indicates that the anti-tumor effects of aspirin and other NSAIDs are due to reduction of pro-inflammatory prostaglandin E2 (PGE2) production via inhibiting cyclooxygenase enzymatic activity. Our preliminary data supports this hypothesis by showing that aspirin reduced polyp numbers along with a decrease of prostaglandin production in tumors. However, no direct evidence has been developed that aspirin inhibits CRC initiation, progression, and metastasis by reduction of PGE2 production via targeting COX enzymes. In addition, previous studies have focused on the roles of NSAIDs in eliminating tumor epithelial cells and suppressing tumor-associated angiogenesis. Little is known about the impact of aspirin on CRC immune evasion. Our observations, never before reported, indicate that aspirin restores host immunosurveillance by inhibition of myeloid-derived suppressor cells (MDSCs) and PGE2 induces an infiltration of MDSCs into the intestinal tumor and mucosa via induction of CXCR2 ligand expression prompted us to postulate that aspirin might inhibit tumor initiation, progression, and metastasis by suppressing recruitment of MDSCs via targeting a novel COX-PGE2-CXCR2 pathway. Aim 1 is designed to test this hypothesis. The results from this aim could not only identify key mechanisms responsible for anti-tumor effects of aspirin, but also may provide a rationale for development of new therapeutic approaches to subvert APC mutation- and tumor-induced immunosuppression by using CXCR2 antagonists and/or CXCR2 neutralizing antibodies. Moreover, our preliminary studies revealed for the first time that primary tumor induced immunosuppression in pre-metastatic organs, whereas treatment with a COXIB attenuated the effects of the primary tumor on pre-metastatic niche formation in the liver. Thus, it is conceivable to hypothesize that aspirin inhibits metastasis by blocking the formation of pre-metastatic niches via targeting the COX-PGE2-CXCR2 pathway. Aim 2 is designed to examine this postulation. The results from this aim should provide a rationale for developing novel therapeutic approaches to inhibit CRC metastasis by blocking the pre-metastatic niche formation. Finally, one potential explanation for the cancer-preventive effects of aspirin could be due to inhibition of COX-1 activity in platelets. However, there is no clear evidence supporting this idea. We will test this role of platelet COX-1 in Aim 3. The results from this aim will provid a rationale for development of new therapeutic approaches to target platelet COX-1 in future cancer prevention and treatment efforts. Collectively, the mechanisms we identify in this proposal might be applicable for other solid cancers in general and can certainly be tested in other systems. In addition, targeting host immunosurveillance or platelets may also represent a novel therapeutic approach for CRC patients.