REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER

重塑血管屏障中癌症引起的异常

基本信息

批准号：
10915752
负责人：
M. LUISA IRUELA-ARISPE
金额：
$ 12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10915752
关键词：
Address Affect Atrophic Blood Vessels Blood capillaries Body Weight Body Weight decreased Cachexia Cancer Etiology Cancer Patient Carcinoma Cells Cessation of life Chronic Clinical Compensation Complex Data Development Dietary Intervention Distant Early Diagnosis Endothelial Cells Endothelium Etiology Evaluation Failure to Thrive Fibrosis Food Functional disorder Genetically Engineered Mouse Goals Greater sac of peritoneum Growth Impairment Implant Individual Inflammation Inflammatory Intercellular Junctions Intervention Intervention Trial Intestines KDR gene Knowledge Lipids Liquid substance Location Lymphatic Lymphatic Endothelium Lymphatic function MAP3K7 gene Malabsorption Syndromes Malignant Neoplasms Measurable Metabolic Metabolic Diseases Molecular Mus Muscle Neoplasm Metastasis Nodule Normal tissue morphology Organ Patients Phenotype Phosphorylation Proteolysis Quality of life Recovery Regulation Research Personnel Risk Signal Pathway Signal Transduction Site Skeletal Muscle Skin Survival Rate Testing Therapeutic Time Treatment Efficacy Tumor Burden Tumor stage Tumor-Derived Vascular Endothelium Vascular Permeabilities Villus Weight absorption cancer cachexia cancer therapy carcinogenesis cytokine design dietary effective therapy efficacy evaluation experimental study extracellular vesicles food consumption improved innovation intestinal villi lacteal lymphatic dysfunction lymphatic vessel metabolic abnormality assessment mouse model muscle form preclinical trial prevent reduced food intake repaired response sarcopenia subcutaneous therapeutic evaluation trafficking treatment response tumor tumor progression

项目摘要

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.

概括众所周知，肿瘤会诱导遥远器官中独特的微环境的形成，以促进播种，存活和转移结节的生长。这些站点被称为中转移的壁ni，出现作为回应与肿瘤衍生因子和脱落细胞外囊泡的全身效应。除了预先转移性壁ni，远处的癌症受试者正常组织的遥远改变尚未确定。在评估含有肿瘤小鼠的全身脉管系统的同时，我们偶然发现皮下植入某些类型的癌对肠有害影响淋巴管和血管。这个令人惊讶的发现与严重的体重减轻直接相关，骨骼肌质量的逐步减少，这种疾病称为恶病质。重要的是，在癌症患者中恶病质对他们的反应和从治疗中恢复的能力具有有意义的负面影响，从而必须识别有风险的个体和有效治疗以扭转这种情况的方法。阻塞恶病质不仅可以显着改善这些患者的生活质量，而且还可以改善耐受性和对癌症治疗的反应，生存率可衡量。虽然是临床卡氏症的后果及其对治疗的积极反应是众所周知的，早期诊断的读出有效的治疗仍然具有挑战性。我们的初步发现发现了循环较高的特定炎症细胞因子的肿瘤肠道引起的血管和淋巴性屏障功能障碍。特别是毛细血管和中央肠绒毛的淋巴乳酸表现出延长和加剧的VEGFR2/3信号，TAK1 磷酸化和其他损害连接络合物的变化。反过来，我们记录了食物吸收的变化尽管食物消耗不变和相关的体重减轻。总体而言，研究结果表明，癌症引起的Vasculo淋巴舱的改变肠绒毛通过影响其吸收能力，从而有助于或可能触发卡希克西亚的发展脂质。该项目的目的是确定淋巴和血管内皮缺陷是否是一个癌症引起的恶病质的重要根本原因可以扭转疾病。我们的两个进步的方法将深入研究基础分子机制的进一步理解小鼠模型中的临床前试验测试旨在纠正血管缺陷的治疗途径。脉管系统作为卡希克西亚重要的罪魁祸首的贡献尚未得到认可，可能是具有变革性，因为它可能会通过关注于早期阶段提供前所未有的干预机会重新布线内皮屏障并阻止这种毁灭性的状况。