11.1 INTRODUCTION: THE TUMOR–VASCULAR INTERFACE
An important feature of malignancies is the associated emergence of new and abnormal contact points between cancer cells and the various facets of the host vascular system (Folkman and Kalluri, 2003; Kerbel, 2008). Prior to transformation many normal epithelial tissues (eg, in the gut, skin, and exocrine glands) are functionally linked to, but often anatomically separated from, the vasculature, for instance, by basement membranes and connective tissue layers (Rak, 2009). These barriers are compromised during the course of the malignant process, resulting in abnormal, often direct and reciprocal interactions between vascular components (endothelial cells, blood cells, plasma, or lymph) and cancer cells at this new tumor–vascular interface.
Tumor–vascular interactions are important for disease progression, because of several "outside-in" effects, such as supply of oxygen, nutrients, growth factors, metabolites, paracrine and adhesive tumor–vascular interactions, recruitment/retention of the host immune, inflammatory, and bone marrow-derived progenitor cells, as well as delivery of drugs, hormones, and regulatory molecules. The vascular interface also mediates important "inside-out" processes, notably, intravasation of metastatic cancer cells, emission of angiogenesis-regulating, proinflammatory, procoagulant, hormonal, and metabolic (eg, cachexia-inducing) signals, as well as shedding of tumor-related microvesicles (exosomes) containing biologically active molecules (Rak, 2009). The 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 host genetic background, accompanying diseases (comorbidities), ageing, and other factors (Kerbel, 2008).
The term angiogenesis and its evolving meaning have a long history. The term was first used by John Hunter in 1787, and later reintroduced in 1935 by Artur Tremain Hertig, to describe non-cancer-related blood vessel growth processes (Roy-Chowdhury and Brown, 2007). Works of Lewis (1927), Sandison (1928), Ide (1939), and Algire (1945), as well as Greenblatt and Shubik (1968) gradually led to a description of vascular expansion associated with a developing cancer, along with some of the first experimental approaches to study the related processes. It was not until the early 1970s that 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 clinical management in several malignancies. Further development of these approaches depends on improving our understanding of mechanisms governing the response of the vascular system to an emerging malignancy, and the relationships, both local and systemic, between cancer cells and the vascular and non-vascular host tissues (Folkman, 2007).
11.2 CONSTITUENTS OF THE VASCULAR SYSTEM
11.2.1 Blood Vessel and Lymphatic Networks
Blood circulation ensures the delivery of oxygen, nutrients, macromolecules, hormones, and cells (eg, immune, inflammatory, or stem cells), to the vicinity of every living cell, while removing catabolites and waste products. To remain viable, each mammalian cell must be located no further than 100 to 180 μm from the nearest functional (perfused) blood vessel capillary. Directionality, efficiency, and ...