First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, although some of the steps in this process contain stochastic elements, metastasis as a whole favors the survival and growth of a few subpopulations of cells that pre-exist within the parent neoplasm. Thus, metastases can have a clonal origin, and different metastases can originate from the proliferation of different single cells. The prevascular stage of a tumor is associated with local, noninvasive, benign tumors, whereas the vascular stage is associated with aggressive, invasive, and metastatic tumors. Indeed, the extent of neovascularization in different malignancies, such as melanoma and breast and prostate cancers, is associated with their potential for invasion and metastasis.
Angiogenesis is a multistep process emanating from microvascular endothelial cells.
To generate capillary sprouts, endothelial cells must proliferate, migrate, and invade host stroma, the direction of migration generally pointing toward the source of angiogenic molecules. The capillary sprout subsequently expands and undergoes morphogenesis to yield a capillary. The induction of angiogenesis is mediated by multiple molecules that are released by some tumor cells and host cells. The extent of angiogenesis is determined by the balance between factors that stimulate and those that inhibit the process. In quiescent normal tissues, the inhibitory factors predominate.