Intertumoral angiogenic heterogeneity: biologic and therapeutic implications

Abstract

It has been largely assumed that tumors within a given histological type induce angiogenesis via the same mechanisms. While such concepts neatly compartmentalize angiogenesis, it is not consistent with other critical tumor phenotypes. The literature contains numerous references describing heterogeneity for tumor phenotypes, including cell proliferation, invasiveness, metastatic potential, and response to therapies. At this time, data regarding angiogenic heterogeneity are limited. In order to investigate this possibility, normal, dysplastic, and malignant oral keratinocytes were harvested using laser capture microdissection (LCM). Total RNA was extracted and subjected to RTQ-PCR analysis. IL-8 and VEGF messages were highly variable within the tumor samples. Validation of the RTQ-PCR data via immunohistochemistry on human tumor samples also found highly variable expression of VEGF and IL-8. Finally, using mouse tumor xenografts, anti-VEGF treatment of HNSCC lines secreting VEGF markedly inhibited the growth of the tumor xenografts. Conversely, anti-VEGF treatment had no effect on the growth of xenografts tumors containing cells that do not produce VEGF. These findings underscore the concept of tumor angiogenic heterogeneity. They imply that there are differences with regard to the specific mechanism by which individual tumors within the same histologic type induce angiogenesis. Moreover, they demonstrate the need for a more in-depth understanding of the variability of the angiogenic phenotype within a given type of neoplasm when designing antiangiogenic therapies.