(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: 8685705
• 负责人: RAYMOND N. DUBOIS
• 金额: $ 39.95万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 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/8685705
• 关键词: Address; Adverse effects; Aspirin; Attenuated; Blood Platelets; Cancer Patient; Clinical; Colorectal Cancer; Data; Data Set; Development; Dinoprostone; Distant; Dose; Enzymes; Epidemiology; Epithelial Cells; Future; Gastrointestinal tract structure; Genetic Models; Growth; 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; cancer cell; cancer chemoprevention; cancer initiation; cancer prevention; cancer risk; cancer therapy; carcinogenesis; clinical care; colorectal cancer prevention; cyclooxygenase 1; design; in vivo; inhibitor/antagonist; mortality; neutralizing antibody; novel; novel therapeutic intervention; public health relevance; 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）：阐明阿司匹林使用降低结直肠癌（CRC）风险和死亡率的分子机制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通过抑制环氧合酶的酶活性减少促炎性前列腺素E2（PGE 2）的产生。我们的初步数据支持这一假设，表明阿司匹林减少息肉数量沿着肿瘤中前列腺素产生的减少。然而，没有直接证据表明阿司匹林通过靶向考克斯酶减少PGE 2的产生来抑制CRC的发生、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。我们的观察，以前从未报道过，表明阿司匹林通过抑制骨髓源性抑制细胞（MDSC）恢复宿主免疫监视，PGE 2通过诱导CXCR 2配体表达诱导MDSC浸润到肠肿瘤和粘膜中，这促使我们假设阿司匹林可能通过靶向新的COX-PGE 2-CXCR 2途径抑制MDSC募集来抑制肿瘤的发生、进展和转移。目标1旨在检验这一假设。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，而且可以为开发新的治疗方法提供理论基础，通过使用CXCR 2拮抗剂和/或CXCR 2中和抗体来破坏APC突变和肿瘤诱导的免疫抑制。此外，我们的初步研究首次揭示， 肿瘤在转移前器官中诱导免疫抑制，而用COXIB治疗减弱了原发性肿瘤对肝脏中转移前小生境形成的影响。因此，可以设想阿司匹林通过靶向COX-PGE 2-CXCR 2途径阻断转移前小生境的形成来抑制转移。目标2旨在检验这一假设。这一目标的结果应该为开发新的治疗方法提供理论基础，通过阻断转移前的小生境形成来抑制CRC转移。最后，阿司匹林预防癌症作用的一个潜在解释可能是 由于血小板中考克斯-1活性的抑制。然而，没有明确的证据支持这一想法。我们将在Aim 3中测试血小板考克斯-1的这种作用。这一目标的结果将为在未来的癌症预防和治疗工作中开发靶向血小板考克斯-1的新治疗方法提供理论基础。总的来说，我们在这项提案中确定的机制可能适用于其他实体癌，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患者的新治疗方法。