Dual role for p16 in the metastasis process of HPV positive head and neck cancers

Abstract

Several studies show that human papillomavirus (HPV) positive head and neck cancers (HNSCC) are typically characterized by low tumor and high regional node stages, intrinsically indicating high local metastatic potential. Despite this, the distant metastasis rates of HPV positive and negative HNSCC are similar. To date, majority of the studies focus on molecular characterization of HPV positive disease and on treatment outcome. Here we assessed the biological mechanisms of metastasis by combining in vitro and in vivo head and neck carcinoma xenograft models with patient data. We provide experimental evidence for a dual role of p16, a surrogate marker for HPV infections, in the metastasis process of HNSCC. We found that p16 regulates the invasiveness and metastatic potential of HNSCC cells by impairing angiogenesis. In parallel, we found that p16 is regulating the nodal spread by mediating lymphatic vessel formation through the upregulation of integrins. These findings not only provide understanding of the biology of the different dissemination patterns but also suggest that inhibition of lymphangiogenesis in HPV positive cancers and inhibition of angiogenesis in HPV negative cancers can form a treatment strategy against metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0678-8) contains supplementary material, which is available to authorized users.

Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression

“…Phosphoinositide 3-kinase (PI3K) pathway alterations are also associated with improved survival [ 58 ]. Moreover, in vitro and in vivo HNSCC xenograft models combined with patient data have revealed two different ways by which p16, the surrogate marker for HPV infection, contributes to different dissemination patterns: (1) regulating vascular invasiveness and angiogenesis and (2) stimulating nodal spread by increasing lymphatic vessel formation via alpha4 beta1 integrin upregulation [ 59 ].…”

Acquired lymphangioma circumscriptum in high-grade penile intraepithelial neoplasia

“…10 Moreover, p16 INK4a stimulates lymphangiogenesis via upregulation of integrins in HPV-induced head and neck cancer. 11 These observations might argue for a supportive role of HPV66induced high-grade PeIN in the development of LC in our patient. HPV66 is classified as a probable high-risk HPV-type.…”

“…12 In a study on penile HPV infection in 2460 men from Denmark, HPV66 was among the three most frequent HPV types (HPV51: 8.7%, HPV16: 5.8%, HPV66: 5.1%; overall HPVprevalence: 22.2%). 13 The nonavalent HPV-vaccine protects against infections with the HPV-types 6,11,16,18,31,33,45,52, and 58. Accordingly, prophylactic HPV-vaccination would not have prevented the HPV66-induced PeIN lesion of our patient.…”

Expression of human papillomavirus oncoproteins E6 and E7 inhibits invadopodia activity but promotes cell migration in HPV‐positive head and neck squamous cell carcinoma cells

“…HPV − SCC‐25, SCC‐61, and SCC‐1 cells are frequently used as cell line models for studying invadopodia . HPV + SCC‐47 and SCC‐104 cells are common cell line models for studying the effects of HPV‐16 . We performed invadopodia assays on these cell lines and quantitated invadopodia numbers and ECM degradation of a fluorescently labeled ECM (Figure B‐D).…”