Tumor growth and
metastasis are angiogenesis-dependent. Virtually all solid
tumors are neovascularized by the time they are detected. However, there is a prevascular phase during early
tumor development where few or no
tumor cells are angiogenic and expansion of the
tumor is restricted to a few mm3. When enough
tumor cells become angiogenic, the
tumor can expand progressively and shed metastatic cells. This angiogenic switch has recently been quantitated for human
breast cancer, as well as for
prostate cancer. We have studied the problem of how
tumors switch to the angiogenic phenotype by using transgenic mice in which
tumors develop at a predictable time and in discrete prevascular and vascular stages. When the transgene is the bovine
papilloma virus (BPV) genome, angiogenic
fibrosarcomas develop from non-angiogenic precursors called
fibromatoses. The
fibrosarcomas secrete
growth factors for capillary endothelial cells. In contrast, the
fibromatoses do not secrete endothelial cell
growth factors. When the transgene consists of the
large "T" antigen of SV40 under the control of the rat
insulin promoter, 70% of pancreatic islets become hyperplastic and 4-10% of these become angiogenic at 6-7 weeks.
Tumors arise from these neovascularized hyperplastic islets and reach > 1000 x the volume of the preangiogenic islets. The onset of angiogenic activity coincides with the secretion of
acidic fibroblast growth factor (aFGF) and other
growth factors not fully identified at this writing. These studies help to explain the switch to the angiogenic phenotype during
tumorigenesis and provide models to discover antiangiogenic
therapies directed at the source of angiogenic activity. Such
therapy, when developed, may be co-administered with currently available
angiogenesis inhibitors which are directed at the target of angiogenic activity, vascular endothelial cells.