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11.1 INTRODUCTION: THE TUMOR-VASCULAR INTERFACE
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An important feature of malignancies is the emergence of new and abnormal contact points between cancer cells and the host vascular system (Folkman, 2007). Prior to transformation, many epithelial tissues (eg, in the gut, skin, and exocrine glands) are anatomically separated from the vasculature by basement membranes and/or connective tissue layers. These barriers are compromised during the malignant process, resulting in abnormal interactions between vascular components (endothelial cells, blood cells, plasma, or lymph) and cancer cells at this new tumor-vascular interface (Rak, 2009).
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Tumor-vascular interactions are important for disease progression, because of several “outside-in” effects, such as supply of oxygen, nutrients, growth factors, metabolites, and paracrine (angiocrine) effects of endothelial cells (Rafii et al, 2016). This progression also includes adhesive tumor-vascular interactions, formation of a vascular stem cell niche (Gilbertson and Rich, 2007), recruitment/retention of host immune, inflammatory, and bone marrow–derived progenitor cells, as well as delivery of drugs, hormones, and regulatory molecules (Fig. 11–1). The vascular interface also mediates important “inside-out” processes, notably, through intravasation of metastatic cancer cells, release into the circulation of angiogenesis-regulating, proinflammatory, procoagulant, hormonal, immunomodulatory and metabolic (eg, cachexia-inducing) signals, as well as shedding of tumor-related extracellular vesicles (exosomes) containing biologically active molecules (Rak, 2009). The dynamic nature of the tumor-vascular interface is influenced by a succession of genetic and epigenetic alterations in cancer cells, microenvironmental influences (hypoxia, inflammation), as well as the host’s genetic background, accompanying diseases (comorbidities), aging, and other processes (Folkman, 2007).
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The term angiogenesis was first used by John Hunter in 1787, and reintroduced in 1935 by Artur Tremain Hertig, to describe non-cancer-related blood vessel growth processes. Investigations led gradually to a description of vascular expansion associated with a developing cancer, along with pioneering experimental methods (Roy-Chowdhury and Brown, 2007). In the early 1970s, the concept of targeting angiogenesis for therapeutic purposes (antiangiogenesis) was proposed by Judah Folkman (Folkman, 1971). This form of therapy is now a part of the ...