Mechanisms of VEGF-A regulated tumor lymphangiogenesis

VEGF-A调节肿瘤淋巴管生成的机制

• 批准号: 7194794
• 负责人: Sophia Ran
• 金额: $ 21.68万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194794
• 关键词: Affect; Angiogenic Factor; Angiopoietin-2; Angiopoietins; Antibodies; Blood; Blood Vessels; Breast Cancer Model; Breast Carcinoma; CMV promoter; Cancer Patient; Cells; Complex; D factor; Data; Dependence; Disease; Distant; Endothelial Cells; Engineering; Event; Family; Fatty acid glycerol esters; Female; Generations; Goals; Health; Immunoprecipitation; Implant; In Vitro; Laboratories; Lead; Literature; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic Metastasis; Lymphatic Vessel Tumors; Lymphatic vessel; Malignant Neoplasms; Mammary gland; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metastatic to; Migration Assay; Molecular; Monitor; Mus; Neoplasm Metastasis; Numbers; Organ; Outcome; Pathway interactions; Patients; Process; Production; Proteins; Regulation; Reporting; Risk; Role; SCID Mice; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Testing; Thinking; Transcriptional Activation; Translations; Up-Regulation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Week; Western Blotting; angiogenesis; autocrine; bevacizumab; design; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; leukemia inhibitory factor; lymph nodes; member; mortality; neoplastic cell; neutralizing antibody; novel; outcome forecast; prevent; receptor; reconstruction; research study; size; tool; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): Lymphatic metastasis is the main dissemination pathway in many solid tumors. The prerequisite for this process is generation of new lymphatic vessels accessible to tumor cells. The formation of new lymphatic vessels, i.e., lymphangiogenesis, is thought to be induced primarily by two factors, VEGF-C or VEGF-D. We recently discovered that an antibody against another member of the VEGF family, VEGF-A, inhibits both tumor lymphangiogenesis and lymphatic metastasis without affecting expression of VEGF-C or VEGF-D. This observation identifies VEGF-A, a potent angiogenic factor, as a regulator of tumor lymphangiogenesis, suggesting that anti-VEGF-A therapies could be useful for preventing lymphatic metastasis in cancer patients. This finding also provides a unique opportunity to better understand the process of lymphangiogenesis and its relevance to metastatic spread. Our in vivo data showed that anti-VEGF-A treatment suppressed expression of three pro- lymphangiogenic mediators: angiopoietin-2 (Ang-2), its receptor Tie-2 and VEGFR-3, a main receptor transmitting VEGF-C signals. The functional association among these mediators and their dependence on VEGF-A is strongly supported by both literature reports and our preliminary data. However, the mechanisms underlying VEGF-A induced and Ang-2 mediated regulation of lymphangiogenesis are largely unknown. We hypothesize that the main VEGF-A-dependent events that regulate lymphangiogenesis are: 1) transcriptional up- regulation of Ang-2, which subsequently increases expression of VEGFR-3 in lymphatic endothelium through Tie-2 activation; and 2) autocrine amplification of its own receptor in lymphatics, VEGFR-2, known to functionally enhance VEGFR-3 signaling. By increasing a number of VEGF-C receptors and enhancing their transduction activity, these VEGF-A and Ang-2 dependent events pre-sensitize lymphatics to VEGF-C and accelerate the translation of VEGF-C signals into robust formation of the new lymphatic vessels. To test these hypotheses, we propose to determine: 1) a regulatory effect of VEGF-A on the expression of VEGFR-2 in lymphatic endothelial cells in vitro; 2) a regulatory effect of Ang-2 on the expression of Tie-2 and VEGFR-3 in lymphatic endothelial cells in vitro; and 3) Ang-2 mediated, VEGF-A-independent, regulation of tumor lymphangiogenesis in breast carcinoma model in vivo. Unraveling these mechanistic details is crucially important for optimizing the existing anti-VEGF-A targeted strategy and for identifying new targets to counteract lymphatic metastasis in cancer patients. We propose to delineate the molecular events mediating inhibition of tumor lymphatics by anti-VEGF-A therapy in experimentally defined in vivo and in vitro models. The significance of these studies is two-fold: 1) they will establish a new paradigm of cross- talk among angiogenic and lymphangiogenic mediators, which would lead to a novel understanding of the formation of the lymphatic vessels in health and disease; and 2) they will define specific roles of VEGF-A and Ang-2 in the regulation of tumor lymphangiogenesis, thus providing a strong impetus for applying VEGF-A and Ang-2 inhibitors to cancer patients with a high risk of lymphatic metastasis. Because metastasis is a primary cause of mortality from cancer, these studies have the potential to significantly improve health outcomes in a large number of cancer patients.

描述（申请人提供）：淋巴转移是许多实体瘤的主要传播途径。这一过程的先决条件是生成可供肿瘤细胞使用的新淋巴管。新淋巴管的形成，即淋巴管生成，被认为主要由两个因素诱导：VEGF-C 或 VEGF-D。我们最近发现，针对 VEGF 家族另一成员 VEGF-A 的抗体可抑制肿瘤淋巴管生成和淋巴转移，而不影响 VEGF-C 或 VEGF-D 的表达。这一观察结果确定了 VEGF-A（一种有效的血管生成因子）作为肿瘤淋巴管生成的调节剂，表明抗 VEGF-A 疗法可用于预防癌症患者的淋巴转移。这一发现还为更好地了解淋巴管生成过程及其与转移扩散的相关性提供了独特的机会。我们的体内数据表明，抗 VEGF-A 治疗抑制了三种促淋巴管生成介质的表达：血管生成素-2 (Ang-2)、其受体 Tie-2 和 VEGFR-3（传递 VEGF-C 信号的主要受体）。这些介质之间的功能关联及其对 VEGF-A 的依赖性得到了文献报告和我们的初步数据的有力支持。然而，VEGF-A 诱导和 Ang-2 介导的淋巴管生成调节的机制在很大程度上尚不清楚。我们假设调节淋巴管生成的主要 VEGF-A 依赖性事件是：1）Ang-2 转录上调，随后通过 Tie-2 激活增加淋巴内皮中 VEGFR-3 的表达； 2) 淋巴管中自身受体 VEGFR-2 的自分泌扩增，已知该受体可在功能上增强 VEGFR-3 信号传导。通过增加大量 VEGF-C 受体并增强其转导活性，这些 VEGF-A 和 Ang-2 依赖性事件使淋巴管对 VEGF-C 预先敏感，并加速 VEGF-C 信号转化为新淋巴管的稳健形成。为了检验这些假设，我们建议确定：1）VEGF-A对体外淋巴管内皮细胞中VEGFR-2表达的调节作用； 2) Ang-2对体外淋巴内皮细胞Tie-2和VEGFR-3表达的调节作用； 3) 体内乳腺癌模型中Ang-2介导的、不依赖于VEGF-A的肿瘤淋巴管生成的调节。阐明这些机制细节对于优化现有的抗 VEGF-A 靶向策略以及确定对抗癌症患者淋巴转移的新靶点至关重要。我们建议在实验定义的体内和体外模型中描述抗 VEGF-A 疗法介导肿瘤淋巴管抑制的分子事件。这些研究的意义有两方面：1）它们将建立血管生成和淋巴管生成介质之间交互作用的新范式，这将导致对健康和疾病中淋巴管形成的新理解； 2）他们将明确VEGF-A和Ang-2在调节肿瘤淋巴管生成中的具体作用，从而为将VEGF-A和Ang-2抑制剂应用于高淋巴转移风险的癌症患者提供强大动力。由于转移是癌症死亡的主要原因，这些研究有可能显着改善大量癌症患者的健康结果。

项目成果

Lymphangiogenesis and lymphatic metastasis in breast cancer.

• DOI: 10.1016/j.pathophys.2009.11.003
• 发表时间: 2010-09
• 期刊: Pathophysiology : the official journal of the International Society for Pathophysiology
• 作者: Ran S;Volk L;Hall K;Flister MJ
• 通讯作者: Flister MJ