The idea that angiogenesis is essential if solid tumors are to grow to clinically significant sizes has provided a powerful impetus for the development of therapeutic agents that block angiogenesis. These agents are now a part of the armamentarium that oncologists use against cancers; a cardinal example is bevacizumab, a monoclonal antibody that neutralizes VEGF activity and is approved for use in the treatment of multiple cancers. However, angiogenesis inhibitors have not been nearly as effective as was originally hoped; they can prolong life, but usually for only a few months and at high financial cost. The mechanisms that underlie the persistence and ultimate progression of cancers in the face of therapy with angiogenesis inhibitors are not yet clear. The modest benefit of anti-angiogenic therapy highlights the pernicious nature of advanced cancers, which can even elude therapies directed at stromal support cells such as endothelium.
Improvements are only possible with greater understanding of the “escape routes” through which tumor cells sidestep the effects of the angiogenesis inhibitors that are now in use.
Vascularizationoftumorsisessentialfortheirgrowthandiscontrolledbythebalancebetweenangiogenicandantiangiogenicfactorsthatareproducedbytumorandstromalcells.
HypoxiatriggersangiogenesisthroughtheactionsofHIF-1α onthetranscriptionoftheproangiogenicfactorVEGF.
Manyotherfactorsregulateangiogenesis;forexample,p53inducessynthesisoftheangiogenesisinhibitorthombospondin-1,whileRAS,MYC,andMAPKsignalingallupregulateVEGFexpressionandstimulateangiogenesis.
VEGFinhibitorsareusedtotreatanumberofadvancedcancersandprolongtheclinicalcourse,butarenotcurative.
Invasion, and metastasis, the major causes of cancer-related morbidity and mortality, result from complex interactions involving cancer cells, stromal cells, and the extracellular matrix (ECM). These interactions can be broken down into a series of steps consisting of local invasion, intravasation into blood and lymph vessels, transit through the vasculature, extravasation from the vessels, formation of micrometastases, and growth of micrometastases into macroscopic tumors (
Fig. 6.27 ). Predictably, this sequence of steps may be interrupted at any stage by either host-related or tumor-related factors. For the purpose of discussion, the metastatic cascade can be subdivided into two phases: (1) invasion of ECM and (2) vascular dissemination and homing of tumor cells.
Invasion of Extracellular Matrix
Human tissues are organized into a series of compartments separated from each other by two types of ECM: basement membranes and interstitial connective tissue (Chapter 1). Although organized differently, each type of ECM is composed of collagens, glycoproteins, and proteoglycans. Tumor cells must interact with the ECM at several stages in the metastatic cascade (see
Fig. 6.27 ). A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane. This process is repeated in reverse when tumor cell emboli extravasate at a distant site. Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several sequential steps (
Fig. 6.28 • Loosening of intercellular connections between tumor cells. As mentioned earlier, E-cadherins act as intercellular glues, and their cytoplasmic portions bind to β-catenin (see
Fig. 6.22 ). Adjacent E-cadherin molecules keep the cells together; in addition, as discussed earlier, E-cadherin can transmit anti-growth signals by sequestering β-catenin. E-cadherin function is lost in almost all http://ebooksmedicine.net