CROSS-SPECIES COMPARISON OF ANGIOGENESIS DURING THE PREMALIGNANT STAGES OF SQUAMOUS CARCINOGENESIS IN THE HUMAN CERVIX AND K14-HPV16 TRANSGENIC MICE

Infection of the human cervix with certain papillomavirus subtypes is associated with the development of neoplastic squamous lesions that ca n progress to overt cervical malignancies. Recently, multistage squamo us carcinogenesis has been achieved in K14-HPV16 transgenic mice, wher ein expression of the human papillomavirus (HPV) type 16 early genes i s targeted to basal squamous epithelial cells by regulatory elements o f the human keratin-14 (K14) promoter. Immunostaining of the endotheli al 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 a nd cancers in humans and transgenic mice were characterized by an addi tional increment in the number of new capillaries and close apposition of the microvasculature to the overlying neoplastic epithelium. Expre ssion of the potent angiogenic factor VEGF was progressively up-regula ted during carcinogenesis in both species, correlating with the increa sed density and altered distribution of the microvasculature, Thus, an giogenesis occurs during the premalignant stages of squamous carcinoge nesis in both human cervical disease and a relevant transgenic model a nd may be controlled by similar molecular mechanisms in both species, These results validate the use of the transgenic model to elucidate th e role of angiogenesis during HPV-associated neoplastic progression.