Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
Like normal tissues, tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide. The tumor-associated neovasculature, generated by the process of angiogenesis, addresses these needs. During embryogenesis, the development of the vasculature involves the birth of new endothelial cells and their assembly into tubes (vasculogenesis) in addition to the sprouting (angiogenesis) of new vessels from existing ones. Following this morphogenesis, the normal vasculature becomes largely quiescent. In the adult, as part of physiologic processes such as wound healing and female reproductive cycling, angiogenesis is turned on, but only transiently. In contrast, during tumor progression, an «angiogenic switch» is almost always activated and remains on, causing normally quiescent vasculature to continually sprout new vessels that help sustain expanding neoplastic growths.
A compelling body of evidence indicates that the angiogenic switch is governed by countervailing factors that either induce or oppose angiogenesis. Some of these angiogenic regulators are signaling proteins that bind to stimulatory or inhibitory cell-surface receptors displayed by vascular endothelial cells. The well-known prototypes of angiogenesis inducers and inhibitors are vascular endothelial growth factor-A (VEGF-A) and thrombospondin-1 (TSP-1), respectively.
The VEGF-A gene encodes ligands that are involved in orchestrating new blood vessel growth during embryonic and postnatal development, and then in homeostatic survival of endothelial cells, as well as in physiological and pathological situations in the adult. VEGF signaling via three receptor tyrosine kinases (VEGFR-1–3) is regulated at multiple levels, reflecting this complexity of purpose. Thus, VEGF gene expression can by upregulated both by hypoxia and by oncogene signaling. Additionally, VEGF ligands can be sequestered in the extracellular matrix in latent forms that are subject to release and activation by extracellular matrix-degrading proteases (e.g., MMP-9). In addition, other proangiogenic signals, such as members of the fibroblast growth factor (FGF) family, have been implicated in sustaining tumor angiogenesis when their expression is chronically upregulated. TSP-1, a key counterbalance in the angiogenic switch, also binds transmembrane receptors displayed by endothelial cells and thereby evokes suppressive signals that can counteract proangiogenic stimuli.
The blood vessels produced within tumors by chronically activated angiogenesis and an unbalanced mix of proangiogenic signals are typically aberrant: tumor neovasculature is marked by precocious capillary sprouting, convoluted and excessive vessel branching, distorted and enlarged vessels, erratic blood flow, microhemorrhaging, leakiness, and abnormal levels of endothelial cell proliferation and apoptosis.
Angiogenesis is induced surprisingly early during the multistage development of invasive cancers both in animal models and in humans. Histological analyses of premalignant, noninvasive lesions, including dysplasias and in situ carcinomas arising in a variety of organs, have revealed the early tripping of the angiogenic switch. Historically, angiogenesis was envisioned to be important only when rapidly growing macroscopic tumors had formed, but more recent data indicate that angiogenesis also contributes to the microscopic premalignant phase of neoplastic progression, further cementing its status as an integral hallmark of cancer.
The past decade has witnessed an astonishing outpouring of research on angiogenesis. Amid this wealth of new knowledge, we highlight several advances of particular relevance to tumor physiology.
Градации ангиогенного переключения
Once angiogenesis has been activated, tumors exhibit diverse patterns of neovascularization. Some tumors, including such highly aggressive types as pancreatic ductal adenocarcinomas, are hypovascularized and replete with stromal «deserts» that are largely avascular and indeed may even be actively antiangiogenic. Many other tumors, including human renal and pancreatic neuroendocrine carcinomas, are highly angiogenic and consequently densely vascularized.
Collectively, such observations suggest an initial tripping of the angiogenic switch during tumor development that is followed by a variable intensity of ongoing neovascularization, the latter being controlled by a complex biological rheostat that involves both the cancer cells and the associated stromal microenvironment. Of note, the switching mechanism can vary in its form, even though the net result is a common inductive signal (e.g., VEGF). In some tumors, dominant oncogenes operating within tumor cells, such as Ras and Myc, can upregulate expression of angiogenic factors, whereas in others, such inductive signals are produced indirectly by immune inflammatory cells, as discussed below. The direct induction of angiogenesis by oncogenes that also drive proliferative signaling illustrates the important principle that distinct hallmark capabilities can be coregulated by the same transforming agents.
Эндогенные ингибиторы ангиогенеза представляют естественные барьеры канцерному ангиогенезу
Research in the 1990s revealed that TSP-1 as well as fragments of plasmin (angiostatin) and type 18 collagen (endostatin) can act as endogenous inhibitors of angiogenesis. The last decade has seen reports of another dozen such agents. Most are proteins, and many are derived by proteolytic cleavage of structural proteins that are not themselves angiogenic regulators. A number of these endogenous inhibitors of angiogenesis can be detected in the circulation of normal mice and humans. The genes encoding several endogenous angiogenesis inhibitors have been deleted from the mouse germline without untoward physiological effects; the growth of autochthonous and implanted tumors, however, is enhanced as a consequence. By contrast, if the circulating levels of an endogenous inhibitor are genetically increased (e.g., via overexpression in transgenic mice or in xenotransplanted tumors), tumor growth is impaired; interestingly, wound healing and fat deposition are impaired or accelerated by elevated or ablated expression of such genes. The data suggest that such endogenous angiogenesis inhibitors serve under normal circumstances as physiologic regulators that modulate transitory angiogenesis during tissue remodeling and wound healing; they may also act as intrinsic barriers to induction and/or persistence of angiogenesis by incipient neoplasias.
Перициты — важные компоненты опухолевой неоваскулатуры
Pericytes have long been known as supporting cells that are closely apposed to the outer surfaces of the endothelial tubes in normal tissue vasculature, where they provide important mechanical and physiologic support to the endothelial cells. Tumor-associated vasculature, in contrast, was portrayed as lacking appreciable coverage by these auxiliary cells. However, careful microscopic studies conducted in recent years have revealed that pericytes are associated, albeit loosely, with the neovasculature of most if not all tumors. More importantly, mechanistic studies discussed below have revealed that pericyte coverage is important for the maintenance of a functional tumor neovasculature.
Множество костных мозг-дериватных клеток способствует канцерному ангиогенезу
It is now clear that a repertoire of cell types originating in the bone marrow play crucial roles in pathological angiogenesis. These include cells of the innate immune system—notably macrophages, neutrophils, mast cells, and myeloid progenitors—that infiltrate premalignant lesions and progressed tumors and assemble at the margins of such lesions; the peri-tumoral inflammatory cells help to trip the angiogenic switch in previously quiescent tissue and to sustain ongoing angiogenesis associated with tumor growth, in addition to facilitating local invasion, as noted below. In addition, they can help protect the vasculature from the effects of drugs targeting endothelial cell signaling. Additionally, several types of bone marrow-derived “vascular progenitor cells” have been observed in certain cases to have migrated into neoplastic lesions and become intercalated into the neovasculature as pericytes or endothelial cells.