Predictive experiment-based multiscale models of angiogenesis in breast cancer

项目概述/摘要肿瘤是依赖血管生成的，因为它们需要血液供应来生长和转移。血管生成受多种刺激物和抑制剂的调节，这些刺激物和抑制剂在生理条件下维持血管稳态。这种血管生成平衡倾向于促血管生成因子在癌症中的作用。促血管生成因子包括多种生长因子，其中血管内皮生长因子（VEGF）起着突出的作用。在内源性抗血管生成因子中，已经确定了一些完整的蛋白质，例如血栓反应蛋白-1和蛋白质片段；大多数已知的片段存在于细胞外基质中。目前还缺乏对这些因素如何相互作用导致脉管系统生长以及如何控制这种生长的定量理解。为了更好地理解这些过程，发展基于预测实验的肿瘤血管生成的分子详细多尺度计算模型是必要的。这项研究的重点是乳腺癌。该项目的长期目标是开发这种乳腺癌血管生成生理组模型。计算技术的发展将与动物模型在分子、细胞、微血管和组织水平上的乳腺癌成像技术紧密结合。侵袭性人乳腺癌细胞系MDA-MB-231和侵袭性较低的人乳腺癌细胞系MCF-7将用于在雌性严重联合免疫缺陷（SCID）小鼠的乳腺脂肪垫中产生原位异种移植物。测量将包括肿瘤发展不同阶段受体和配体表达的表征和定位；肿瘤生长过程中缺氧与微血管的时空发展肿瘤微血管的功能特征，如血容量和血管通透性，以及细胞外基质。这些数据的一部分将作为计算模型的输入，而其他数据将作为验证模型的手段。这些模型将扩展到人类疾病。该研究将有助于更好地了解肿瘤血管生物学的基础，并有助于设计新的治疗方法和临床数据的定量解释。计算和实验研究的协同结合应该提供对疾病性质的重要见解。

DESCRIPTION (provided by applicant): Project Summary/Abstract Tumors are angiogenesis-dependent as they require blood supply to grow and metastasize. Angiogenesis is regulated by a multitude of stimulators and inhibitors that maintain vascular homeostasis under physiological conditions. This angiogenic balance is tipped in favor of proangiogenic factors in cancer. The proangiogenic factors include many growth factors among which vascular endothelial growth factor (VEGF) plays a prominent role. Among endogenous antiangiogenic factors several whole proteins, e.g. thrombospondin-1, as well as protein fragments have been identified; most of the known fragments reside in the extracellular matrix. A quantitative understanding of how these factors interact to result in a growing vasculature and how to control this growth is presently lacking. To achieve a better understanding of these processes, the development of predictive experiment-based molecular-detailed multiscale computational models of tumor angiogenesis is necessary. This research will focus on breast cancer. The long-term goal of this project is to develop such models of the breast cancer angiogenesis physiome. The computational developments will be tightly coupled to state of the art breast cancer imaging at the molecular, cellular, microvascular, and tissue levels using animal models. The invasive human breast cancer cell line MDA-MB-231 and the less invasive human breast cancer cell line MCF-7 will be used to generate orthotopic xenografts in the mammary fat pad in female severe combined immune deficient (SCID) mice. The measurements will include the characterization and localization of receptor and ligand expression at the different stages of tumor development; temporal and spatial development of hypoxia and microvasculature in growing tumor; and functional characteristics of the tumor microvasculature such as blood volume and vascular permeability, and the extracellular matrix. Part of these data will serve as input to the computational models whereas other data will serve as a means for their validation. The models will be extended to human disease. The research will contribute to a better fundamental understanding of the tumor vascular biology and to the design of novel therapeutics and quantitative interpretation of clinical data. The synergistic combination of computational and experimental studies should provide significant insights into the nature of the disease.