REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER

摘要 众所周知，肿瘤可以在远处器官中形成独特的微环境，便于播种， 转移结节的存活和生长。这些位置被称为转移前的壁龛，作为一种反应出现。 肿瘤衍生因子和脱落细胞外小泡的综合作用。除了Pre- 在携带癌症的受试者的其他正常组织中，转移的壁龛和远处的改变没有被发现 已确认身份。在评估荷瘤小鼠的全身血管系统时，我们偶然发现 某些类型的癌症皮下种植会对肠道产生有害影响 淋巴管和血管。这一令人惊讶的发现与严重的体重减轻直接相关 骨骼肌块进行性减少，一种称为恶病质的情况。重要的是，在癌症患者中， 恶病质对他们的反应能力和从治疗中恢复的能力有重大的负面影响，因此 确定处于危险中的个人并采取有效的治疗来扭转这一状况势在必行。阻止 恶病质不仅显著改善了这些患者的生活质量，而且还改善了 对癌症治疗的耐受性和反应，存活率显著提高。虽然临床上 恶病质的后果及其对治疗的阳性反应是众所周知的，读出以便于早期诊断 有效的治疗仍然具有挑战性。 我们的初步发现发现，循环中特定炎症细胞因子水平较高的肿瘤 引起肠道血管和淋巴屏障功能障碍。尤其是毛细血管和中央 肠绒毛淋巴液中VEGFR2/3信号转导通路TAK1表达延长和加重 磷酸化和其他产生受损连接复合体的改变。反过来，我们记录了 食物吸收的变化，尽管食物消费水平和相关的体重减轻没有改变。 总而言之，这些发现表明，癌症引起的血管淋巴室的改变 肠道绒毛通过影响恶病质的吸收能力而促进或触发恶病质的发展。 脂类。这个项目的目标是确定淋巴管和血管内皮细胞的缺陷是否是一种 癌症引起恶病质的重要潜在原因，可以有针对性地逆转这种情况。我们的两个- Progued方法将深入了解潜在的分子机制，同时追求 在小鼠模型上进行临床前试验，以测试旨在纠正血管缺陷的治疗途径。 血管系统作为恶病质的重要罪魁祸首的作用还没有被认识到，它可能是 变革性，因为它可能为早期阶段的干预提供前所未有的机会，通过专注于 重新连接内皮细胞屏障，阻止这种毁灭性的状况。

Summary Tumors are known to induce the formation of unique microenvironments in distant organs that facilitate seeding, survival, and growth of metastatic nodules. These sites, known as pre-metastatic niches, emerge as a response to the combined systemic effects of tumor-derived factors and shed extracellular vesicles. Aside from pre- metastatic niches, distant alterations in otherwise normal tissues of cancer-bearing subjects have not been identified. While evaluating the systemic vasculature of tumor-bearing mice, we serendipitously found that presence of certain types of carcinomas implanted subcutaneously have a deleterious effect on intestinal lymphatics and blood vessels. This surprising finding was directly correlated with severe weight loss and progressive reduction of skeletal muscle mass, a condition known as cachexia. Importantly, in cancer patients, cachexia has a meaningful negative impact in their ability to respond and recover from therapy and thus identification of individuals at risk and effective treatments to reverse this condition are imperative. Blocking cachexia offers not only a significant improvement in the quality of life for these patients, but it also improves tolerance and response to cancer treatment, with measurable increase in survival rates. Although the clinical consequences of cachexia and its positive response to therapy are well known, read-outs for early diagnosis and effective treatment remain challenging. Our preliminary findings uncovered that tumors with high circulating levels of specific inflammatory cytokines induced vascular and lymphatic barrier dysfunction in the intestine. In particular, the capillaries and central lymphatic lacteal of intestinal villi showed prolonged and exacerbated levels of VEGFR2/3 signaling, TAK1 phosphorylation and other alterations that yield compromised junctional complexes. In turn, we documented changes in food absorption despite unaltered levels of food consumption and associated weight loss. Collectively, the findings indicate that cancer-induced alterations in the vasculo-lymphatic compartment of intestinal villi contribute to, and perhaps trigger, the development of cachexia by affecting their ability to absorb lipids. The goal of this project is to determine whether deficiencies in lymphatic and vascular endothelium are a significant underlying cause of cancer-induced cachexia that can be targeted to reverse the condition. Our two- progued approach will delve into further understanding of the underlying molecular mechanisms while pursuing pre-clinical trials in mouse models to test therapeutic avenues aimed at correcting the vascular deficiencies. The contribution of the vasculature as an important culprit in cachexia has not been recognized and it could be transformative as it may offer an unprecedented opportunity for intervention at early stages by focusing on rewiring endothelial barrier and blocking this devastating condition.