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

(PQA1)阿司匹林对结直肠癌作用的分子机制

• 批准号: 9246071
• 负责人: RAYMOND N. DUBOIS
• 金额: $ 38.67万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246071
• 关键词: Address; Adverse effects; Aspirin; Attenuated; Blood Platelets; Clinical; Colorectal Cancer; Data; Data Set; Development; Dinoprostone; Distant; Dose; Enzymes; Epidemiology; Epithelial Cells; Future; Gastrointestinal tract structure; Genetic Models; Growth; Health; Homing; Human; IL8RB gene; Immune; Immunologic Monitoring; Immunosuppression; Incidence; Infiltration; Inflammatory; Intestinal Mucosa; Intestinal Neoplasms; Lead; Ligands; Liver; Malignant Neoplasms; Mediating; Metformin; Modeling; Molecular; Mucous Membrane; Mutation; Myelogenous; Neoplasm Circulating Cells; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Organ; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Polyps; Preventive; Primary Neoplasm; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Reporting; Risk; Role; Signal Transduction; Solid; Suppressor-Effector T-Lymphocytes; System; Testing; Time; Tumor Tissue; angiogenesis; antitumor effect; cancer cell; cancer chemoprevention; cancer initiation; cancer prevention; cancer risk; cancer therapy; carcinogenesis; clinical care; colon cancer patients; colorectal cancer prevention; cyclooxygenase 1; design; in vivo; inhibitor/antagonist; mortality; neutralizing antibody; novel; novel therapeutic intervention; tumor; tumor initiation; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：阐明阿司匹林使用的分子机制降低了结直肠癌的风险和死亡率（CRC）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NSAID的抗肿瘤作用是由于促炎性前列腺素E2（PGE2）通过抑制环氧酶酶促活性而产生的。我们的初步数据通过表明阿司匹林减少息肉数量以及肿瘤前列腺素产生的减少来支持这一假设。但是，尚无直接证据表明，阿司匹林通过靶向COX酶来减少PGE2产生来抑制CRC的启动，进展和转移。此外，先前的研究集中在NSAID在消除肿瘤上皮细胞和抑制肿瘤相关血管生成中的作用。关于阿司匹林对CRC免疫逃避的影响知之甚少。 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通过针对新型COX-PGE2-CXCR2途径募集MDSC。 AIM 1旨在检验这一假设。该目标的结果不仅可以识别导致阿司匹林抗肿瘤作用的关键机制，而且还可以通过使用CXCR2拮抗剂和/或CXCR2中和抗体的抗体来开发新的治疗方法，以开发新的治疗方法，以颠覆APC突变和肿瘤诱导的免疫抑制。此外，我们的初步研究首次表明 肿瘤诱导了型前体器官中的免疫抑制，而用coxib进行治疗会减弱原发性肿瘤对肝脏前转移壁细分形成的影响。因此，可以想象通过通过靶向COX-PGE2-CXCR2途径来阻止异常壁ni的形成，可以假设阿司匹林抑制转移。 AIM 2旨在检查这一假设。这个目标的结果应为开发新型治疗方法提供基本原理来通过阻止质量前的细分市场形成来抑制CRC转移。最后，关于阿司匹林癌症预防作用的一种潜在解释可能是 由于抑制了血小板中的COX-1活性。但是，没有明确的证据支持这一想法。我们将测试血小板COX-1在AIM 3中的作用。该目标的结果将为开发新的治疗方法提供基本原理，以靶向血小板COX-1在未来的癌症预防和治疗工作中。总的来说，我们在此提案中识别的机制通常适用于其他固体癌症，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代表CRC患者的一种新型治疗方法。