Role of Angiogenesis in Human Tumor Dormancy: Animal Models of the Angiogenic Switch

Tumor progression depends on sequential events, including a switch to the angiogenic phenotype (i.e., initial recruitment of blood vessels). Failure of a microscopic tumor to complete one or more early steps in this process may lead to delayed clinical manifestation of the cancer. Microscopic human cancers can remain in an asymptomatic, non-detectable, and occult state for the life of a person. Clinical and experimental evidence suggest that human tumors can persist for long periods of time as microscopic lesions that are in a state of dormancy (i.e., not expanding in tumor mass). Because it is well established that tumor growth beyond the size of 1-2 mm is angiogenesis-dependent, we hypothesized that presentation of large tumors is attributed to a switch to the angiogenic phenotype in otherwise microscopic, dormant tumors. Although clinically important, the biology of human tumor dormancy is poorly understood. The development of animal models which recapitulate the clinically observed timing and proportion of dormant tumors which switch to the angiogenic phenotype are reviewed here. The contributing molecular mechanisms involved in the angiogenic switch and different strategies for isolation of both angiogenic and non-angiogenic tumor cell populations from otherwise heterogeneous human tumor cell lines or surgical specimens are also summarized. Several imaging techniques have been utilized for the qualitative and quantitative detection of microscopic tumors in mice and their strengths and limitations are discussed. The animal models employed here permitted further studies of the angiogenic switch. These models also allowed development of an angiogenesis-based panel of blood and urine biomarkers that can be quantified and used to detect microscopic tumors before or during the angiogenic switch. If the information obtained from these animal models is translatable to the clinic, it may be possible in the future to liberate the management of cancer from a dependency on anatomical site years before it becomes symptomatic and detectable.