REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER

总结 已知肿瘤在远端器官中诱导形成独特的微环境， 存活和转移性结节的生长。这些部位被称为转移前小生境， 肿瘤衍生因子和脱落细胞外囊泡的联合全身效应。除了预- 转移性小生境，携带癌症的受试者的其他正常组织中的远处改变还没有被发现。 鉴定在评估荷瘤小鼠的全身血管系统时，我们偶然发现， 皮下植入的某些类型的癌的存在对肠上皮细胞具有有害作用。 器官和血管。这一令人惊讶的发现与严重的体重减轻直接相关， 骨骼肌质量逐渐减少，即恶病质。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具有有意义的负面影响， 必须查明处于危险中的个人，并采取有效的治疗方法来扭转这种状况。阻挡 恶病质不仅显著改善了这些患者的生活质量， 对癌症治疗的耐受性和反应，以及可测量的存活率增加。虽然临床 恶病质的后果及其对治疗的积极反应是众所周知的， 有效的治疗仍然具有挑战性。 我们的初步研究发现，具有高循环水平的特定炎症细胞因子的肿瘤， 导致肠内血管和淋巴屏障功能障碍。特别是毛细血管和中央 肠绒毛的淋巴管显示VEGFR 2/3信号、TAK 1 磷酸化和其他改变产生受损的连接复合物。反过来，我们记录了 尽管食物消耗水平不变，但食物吸收发生变化，并伴有体重减轻。 总的来说，研究结果表明，癌症引起的血管淋巴室的变化， 肠绒毛通过影响其吸收的能力而促进或触发恶病质的发展， 脂质。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个 癌症引起的恶病质的重要潜在原因，可以靶向逆转病情。我们俩- 一种有计划的方法将深入了解潜在的分子机制，同时追求 在小鼠模型中进行临床前试验，以测试旨在纠正血管缺陷的治疗途径。 脉管系统作为恶病质的重要原因的贡献还没有被认识到， 它可能提供前所未有的机会，在早期阶段进行干预， 重新连接内皮屏障并阻断这种毁灭性的疾病。

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.