Elucidating the role of microbiota-driven “Tumor-elicited inflammation” in colorectal cancer progression

阐明微生物群驱动的“肿瘤引发的炎症”在结直肠癌进展中的作用

• 批准号: 442076297
• 负责人: Dr. Sophia Chikhladze
• 金额: --
• 依托单位: Klinik für Allgemein- und Viszeralchirurgie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/442076297?language=en
• 关键词: Elucidating; role; microbiota; driven; Tumor

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer mortality. In 2014, over 60.000 new colorectal carcinoma cases were diagnosed in Germany and over 24,000 cancer deaths were reported. The majority of these deaths are caused by metastatic relapse. Inflammation seems to have an important role in colorectal cancer prognosis. Presence of certain chemokines, cytokines and myeloid cell subsets correlates with poor prognosis in CRC. CRC tumors after their formation induce frank inflammatory reaction termed “Tumor-elicited inflammation” (TEI). The mechanisms of TEI in CRC, especially in CRC malignant progression, are unknown. Important and unresolved questions include: 1) What are the tumor-specific signals, which activate TEI? 2) What are molecular and cellular mechanisms of TEI action? 3) How does TEI promote CRC invasion and metastasis? The colon is rich in microbes and hypothetically, bacterial products are excellent candidates for TEI induction. We will examine to which extent microbiota influence/control CRC progression. Here, we will establish parameters of tumor-adherent microbiota and of cellular types involved in TEI. We will define how individual microbiota and inflammatory states affect cancer growth and metastasis. We will further explore in a reductionist mouse model how differences in microbiota-driven intratumoral immune responses influence murine CRC. We will further identify tumor-associated bacteria in human CRC and explore their relevance. We will calculate and interpret correlations between overall survival and the aforementioned parameters, which potentially reflect a role of tumor mucosa adherent microbes and TEI in resistance to anti-cancer therapy. We expect that chemotherapy-treated patients with higher abundance of adherent microbes and enhanced expression of TEI inflammatory genes will demonstrate earlier clinical relapse, harboring tumors with enhanced proliferation and with a “pro-tumorigenic” environment increased numbers of myeloid cells and a lack of activated cytotoxic T cells. This work will allow the creation of a prediction tool for metastatic relapse and resistance to therapy, based on microbiota and TEI responses.

结直肠癌（CRC）是全球第三大常见癌症，也是癌症死亡的主要原因。2014年，德国诊断出6万多例新的结直肠癌病例，报告的癌症死亡人数超过2.4万。这些死亡大多是由转移性复发引起的。炎症似乎在结直肠癌预后中起着重要作用。某些趋化因子、细胞因子和骨髓细胞亚群的存在与结直肠癌的不良预后相关。结直肠癌肿瘤形成后会诱发直接的炎症反应，称为“肿瘤诱发炎症”（TEI）。TEI在结直肠癌中的机制，特别是在结直肠癌恶性进展中的机制尚不清楚。重要的和未解决的问题包括：1)激活TEI的肿瘤特异性信号是什么？2) TEI作用的分子和细胞机制是什么？3) TEI如何促进结直肠癌的侵袭和转移？结肠富含微生物，假设细菌产物是TEI诱导的极好候选者。我们将研究微生物群影响/控制结直肠癌进展的程度。在这里，我们将建立肿瘤粘附菌群和细胞类型参与TEI的参数。我们将定义个体微生物群和炎症状态如何影响癌症的生长和转移。我们将在一个简化的小鼠模型中进一步探索微生物群驱动的肿瘤内免疫反应的差异如何影响小鼠CRC。我们将进一步鉴定人类结直肠癌中的肿瘤相关细菌并探讨其相关性。我们将计算和解释总生存率与上述参数之间的相关性，这些参数可能反映肿瘤粘膜粘附微生物和TEI在抗癌治疗耐药中的作用。我们预计，接受化疗的患者具有更高丰度的附着微生物和增强的TEI炎症基因表达，将表现出更早的临床复发，具有增殖增强和“致瘤性”环境的肿瘤，骨髓细胞数量增加，缺乏活化的细胞毒性T细胞。这项工作将允许创建一个基于微生物群和TEI反应的转移性复发和治疗耐药性的预测工具。