Growth of Solid Tumors Depends on Development of New BloodVesseIs
Tumors, as with normal tissue, require blood vessels to supply them with oxygen and nutrients and to remove waste. Much attention has been focused on the development of tumor capillaries because it is a rate-limiting step in the tumors growth and progression.
Both primary and metastatic tumors require new vessels; without them the tumor remains too small to be visible or palpable, about 1 to 2 mm in diameter. Dormanl tumors of this size have been found in autopsies of people who did not die of cancer, so not all tumors develop the blood supply needed for growth. Thus the ability of tumors to stimulate new blood vessel development is a distinct and important step in tumor progression. As this suggests, it is also a relatively early step in tumor progression but is covered here after metastasis because most new vasculature arises from existing capillaries invading new regions of tissue, sharing some features with metastasis.The discussion of Starlings hypothesis in Chapter 1 notes that blood capillaries are composed primarily of a single layer of a specialized epithelial cell type, the endothelial cell. The first capillaries in the embryo are formed by Vasculogenesist the differentiation of precursor cells (angioblasts) to form a basic capillary network. However, most new capillaries are formed by angiogenesis, the sprouting and branching of existing capillaries to supply new tissue regions. Larger blood vessels, such as arterioles and veins, all develop from the subsequent growth of capillaries. In the adult, only angiogenesis normally occurs and depends on invasive cellular processes similar to those involved in metastasis: proliferation of existing endothelial cells; migration of the cells into the region to be supplied, involving changes in actin function and adhesion to the surrounding cells; and remodeling the surrounding ECM so the extending cells intercalate among the tissue cells, ultimately to form a hollow tube.
Although the cancer cells within a tumor are abnormal, the endothelial cells composing the new capillaries are normal. Thus, tumor capillaries can arise by Vasculogenesis (because of the abnormal environment of the tumor) or, and primarily, by angiogenesis. Similarly, the endothelial cells of tumor capillaries respond to the normal stimulatory and inhibitory signals for angiogenesis. Nevertheless, the pathological features of the tumor stimulate abnormal growth of blood vessels, whose pattern, composition, and function differ from normal capillaries.In normal adult tissue, except for the female reproductive tract, endothelial cells are among the most slowly proliferating cell type. Only 1 in 10,000 adult endothelial cells are in cell division at any one time, compared with about 10% of gut epithelial cells. Normal angiogenesis is under tight regulation by both stimulatory and inhibitory influences. Stimulatory influences include injury and hypoxia which in turn lead to the secretion of angiogenic growth factors such as vascular endothelial growth factor (VEGF, “vedge-eff"). This growth factor strongly stimulates endothelial cell proliferation and migration and suppresses apoptosis. VEGF also increases permeability of existing vessels. Inhibitory influences include thrombospondin-1, which is an ECM component that inhibits endothelial cell proliferation and motility. Inhibitory influences also include soluble factors such as angiostatin, which stimulates apoptosis in proliferating endothelial cells, and endostatin, which inhibits the migration of endothelial cells. The growth, stasis, or regression of capillaries, depends on the balance between pro- and anti-angiogenic stimuli, much as cellular life and death depends on the balance between pro- and anti-apoptotic signals discussed earlier.
The relative quiescence of normal capillaries is in sharp contrast to capillaries of tumors, which have been compared to “wounds that never heal," in that tumor capillaries undergo continuous growth and remodeling.
Tumor endothelial cells divide 20 to 40 times more frequently than normal endothelial cells, and tumors typically have a much higher density of vessels than normal tissue. As a result, tumor vasculature is abnormal in structure and function. Tumor vessels can exhibit strange combinations of capillary, venous, and arteriole structures and often incorporate cancer cells as part of the vessel wall. These vessels tend to be convoluted and dilated, follow tortuous paths, and even form dead ends. As a result, blood flow is equally abnormal, with the vessels leakier than normal vessels, and in some cases the blood flows back and forth rather than circulates.Perhaps the most important factor in this vascular pathology is the high concentration of VEGF in and around tumors. Most human tumors secrete large amounts of VEGF and also cause surrounding tissue to secrete VEGE Much evidence from experiments on mice supports the crucial role of VEGF in tumor angiogenesis and growth. Antibodies against VEGF suppress growth of existing tumors; cancer cells engineered to be incapable of expressing VEGF were unable to form tumors; and inhibition of the VEGF receptor inhibited the growth of a variety of tumors. In part, the secretion of VEGF by tumor cells seems to be the result of the initial hypoxic conditions of the avascular tumor. Hypoxia is normally a strong inducer of VEGF production, and the centers of many solid tumors show necrotic cells indicative of death from lack of oxygen. In addition, the genetic damage to cells in their progression to a cancer cell also seems to contribute to VEGF overexpression. Mutations of Ras and overexpression of Bcl-2, the anti-apoptotic factor, have been shown to play important roles in this regard.
Tumor vessels are also substantially more permeable than normal vessels, to the point of being almost hemorrhagic, which is also thought to be caused by overexpression of VEGF (which has an alternative name of “vascular permeability factor").
The leakiness of tumor vessels has several consequences with respect to tumor physiology, spread, and treatment. The high vascular permeability of tumors is believed to aid metastasis in that metastasis requires intravasation of tumor cells into the circulation, and leakier vessels makes this more likely. Leakier vessels also disrupt capillary fluid transport, as discussed in Chapter 1. Recall that capillary filtration and reabsorption depend on the balance between hydrostatic and oncotic forces across the capillary wall. The increased fluid leaking from tumor vessels distends the interstitial space, increasing its hydrostatic pressure and thus reducing the pressure gradient across the capillary wall. The oncotic pressure gradient is also reduced because the leak of proteins into the interstitial space means that the oncotic pressure of the interstitial space approaches that of the blood. The result is uncommonly high net interstitial fluid pressure. This can cause collapse of some vessels, leading to hypoxia of the surrounding tissue and further upregulation of VEGF expression. High interstitial fluid pressure also causes poor fluid transport out of the blood into the tumor. This poor Iluid exchange seems to inhibit the delivery of chemotherapeutic agents from the blood to the tumor. Studies on chemotherapy of breast cancer and melanoma show that tumors with high interstitial fluid pressure tended not to respond as well to the therapy.As with the other insights into tumor biology, the possibility of controlling tumor angiogenesis for therapy is being actively pursued. About a dozen antiangiogenesis compounds are being tested, and bevacizumab (an antibody to VEGF) is approved as a first-line therapy for metastatic colon cancer. Unlike most cancer therapy that targets the abnormal cancer cell, antiangiogenic therapy would be targeting normal endothelial cells. These cells are not genetically unstable, and therefore development of drug resistance may be less likely (sec following discussion). Also, because normal endothelial cells are unusually quiescent, inhibiting angiogenesis should produce fewer toxic side effects than standard chemotherapies. As with other Cellularly targeted therapies, however, antiangiogenesis inhibitors that showed dramatic results in preclinical studies have been much less successful in treating patients.