Infection of the human cervix with certain papillomavirus subtypes is associated with the development of neoplastic squamous lesions that can progress to overt cervical malignancies. Recently, multistage squamous carcinogenesis has been achieved in K14-HPV16 transgenic mice, wherein expression of the human papillomavirus (HPV) type 16 early genes is targeted to basal squamous epithelial cells by regulatory elements of the human keratin-14 (K14) promoter. Immunostaining of the endothelial marker vWf revealed a parallel upregulation of angiogenesis during the early neoplastic stages in both human cervix and the epidermis of K14-HPV16 transgenic mice. Moreover, high-grade premalignant lesions and cancers in humans and transgenic mice were characterized by an additional increment in the number of new capillaries and close apposition of the microvasculature to the overlying neoplastic epithelium. Expression of the potent angiogenic factor VEGF was progressively up-regulated during carcinogenesis in both species, correlating with the increased density and altered distribution of the microvasculature. Thus, angiogenesis occurs during the premalignant stages of squamous carcinogenesis in both human cervical disease and a relevant transgenic model and may be controlled by similar molecular mechanisms in both species. These results validate the use of the transgenic model to elucidate the role of angiogenesis during HPV-associated neoplastic progression.

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K. S-M. acknowledges the support of the Irwin Foundation, a grant from the National Cancer Institute, and the past support of the Reproductive Scientist Development Program (NICHD) and the American Gynecological and Obstetrical Society. Support for J. M. A. was from grants from the American Cancer Society and the Simon Fund of the University of California at San Francisco. The work performed in the Hanahan laboratory was supported by grants to the National Cancer Institute, including one to D. H. and a second to J. F. and D. H.

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