Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior

Abstract

One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

Molecular targets for therapeutic interventions in human papillomavirus-related cancers (Review)

“…Angiogenesis is an early event in the progression of HPVrelated cervical lesions (74). A strong association between higher VEGF expression in cervical cancer and worse prognosis has been observed (75,76).…”

“…In contrast, expression of the anti-angiogenic factors trombospondin (TSP)-1 and 2 were decreased in cells infected by HPV. It demonstrates that cervical cancer expression of HPV-16 integrated genes is able to contribute to a pro-angiogenic phenotype (referred as angiogenic switch) that might support tumor growth and invasion (22,74,80).…”

Relationship of common vascular endothelial growth factor polymorphisms and haplotypes with the risk of cervical cancer in Tunisians

“…Heightened VEGF expression was associated with tumor progression, increased micro-vessel http://dx.doi.org/10.1016/j.cyto.2014. 11.009 1043-4666/Ó 2014 Elsevier Ltd. All rights reserved. density, and with poor prognosis for various solid tumors, including CC [8,9].…”

Transcription Expression and Clinical Significance of mRNA of Vascular Endothelial Growth Factor and Endostatin in Liquid-Based Preparation Specimens from Patients with Cervical Dysplasia and Carcinoma

“…Expression of VEGF has been associated with increased microvessel density, tumor progression and a poor prognosis for various solid tumors, including cervical cancer [5,6,7,8]. In addition, increasing evidence suggests that HPV oncoproteins may enhance tumor angiogenesis via increased VEGF expression in cervical cancer [9,10]. Endostatin, a 20-kDa carboxyl-terminal fragment of the α 1 chain of collagen XVIII that inhibits endothelial cell migration and proliferation, and induces apoptosis of vascular endothelial cells, has been considered as the most potent inhibitor of angiogenesis.…”