Predictive model of pro- and anti-angiogenic factors involved in breast cancer

描述(申请人提供)：癌症的发展、侵袭和转移在很大程度上依赖于血管生成，即从预先存在的血管形成新的毛细血管，这一过程受到促血管生成因子和抗血管生成因子的平衡的精确调节。血管生成的刺激因子包括生长因子，如血管内皮生长因子(VEGF)，它是血管生长的关键促进剂。此外，膜结合或细胞外基质蛋白，包括血栓反应蛋白-1(TSP1)，作为血管生成的内源性抑制因子发挥作用。在癌症的情况下，平衡被改变，导致过度血管生成的状态，并允许肿瘤建立自己的血液供应。定量描述血管生长的促进剂和抑制物的动态平衡将有助于我们理解肿瘤血管生成，并为测试控制这一过程的癌症治疗提供一个平台。这项拟议的研究旨在开发一个基于实验的乳腺癌血管生成计算模型，该模型包含内源性促血管生成通路和抗血管生成通路(目标1)。该模型将被用来探索TSP1抑制血管生长的机制，并量化血小板在血管生成中的作用(目标2)。此外，该模型将模拟和预测乳腺癌治疗的血管生成反应，包括血管内皮生长因子中和剂和TSP1衍生的抗血管生成多肽(目标3)。这项研究将进一步加深我们对血管生成相关病理生理学的理解，并有助于开发和优化抑制肿瘤血管生成的癌症治疗方法。 与公共卫生相关：每年有超过18万名妇女被诊断出患有乳腺癌。癌症的发展，导致侵袭和转移，在很大程度上取决于癌细胞促进新血管从原有血管生长的能力，这一过程被称为血管生成。本项目旨在开发一种定量模型来研究血管生成的促进剂和抑制物之间的平衡，并应用该模型来辅助癌症治疗的发展。

DESCRIPTION (provided by applicant): Cancer development, invasion, and metastasis is largely dependent on angiogenesis, the formation of new capillaries from pre-existing blood vessels, and this process is exquisitely regulated by a balance of pro- and anti-angiogenic factors. Stimulators of angiogenesis include growth factors, such as vascular endothelial growth factor (VEGF), a key promoter of vascular growth. Additionally, membrane-bound or extracellular matrix proteins, including thrombospondin-1 (TSP1), function as endogenous inhibitors of angiogenesis. In the case of cancer, the balance is altered, leading to a state of hyper-vascularization and allowing the tumor to establish its own blood supply. A quantitative description of the dynamic equilibrium of promoters and inhibitors of vascular growth would aid in our understanding of tumor angiogenesis and provide a platform to test cancer therapies that control this process. The proposed research aims to develop an experiment-based computational model of breast cancer angiogenesis that incorporates endogenous pro- and anti-angiogenic pathways (Aim 1). The model will be used to probe the mechanism by which TSP1 inhibits vascular growth and quantify the role of platelets in angiogenesis (Aim 2). Additionally, the model will simulate and predict the angiogenic response to breast cancer therapies, including VEGF-neutralizing agents and TSP1-derived anti- angiogenic peptides (Aim 3). This research will further our understanding of angiogenesis-related pathophysiology and facilitate the development and optimization of cancer therapies that inhibit tumor angiogenesis. PUBLIC HEALTH RELEVANCE: More than 180,000 women are diagnosed with breast cancer each year. Cancer development, leading to invasion and metastasis, is largely governed by the cancer cells' ability to promote the growth of new blood vessels from pre-existing ones, a process called angiogenesis. This project aims to develop a quantitative model to study the balance of promoters and inhibitors of angiogenesis and apply the model to aid in the development of cancer therapeutics.