Human Papillomavirus 16-Transgenic Mice as a Model to Study Cancer-Associated Cachexia.

Cancer cachexia is a multifactorial syndrome characterized by general inflammation, weight loss and muscle wasting, partly mediated by ubiquitin ligases such as atrogin-1, encoded by . Cancers induced by high-risk human papillomavirus (HPV) include anogenital cancers and some head-and-neck cancers and are often associated with cachexia. The aim of this study was to assess the presence of cancer cachexia in HPV16-transgenic mice with or without exposure to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Male mice expressing the HPV16 early region under the control of the cytokeratin 14 gene promoter (K14-HPV16; HPV) and matched wild-type mice (HPV) received DMBA (or vehicle) topically over 17 weeks of the experiment. Food intake and body weight were assessed weekly. The gastrocnemius weights and expression levels were quantified at sacrifice time. HPV-16-associated lesions in different anatomic regions were classified histologically. Although unexposed HPV mice showed higher food intake than wild-type matched group ( < 0.01), they presented lower body weights ( < 0.05). This body weight trend was more pronounced when comparing DMBA-exposed groups ( < 0.01). The same pattern was observed in the gastrocnemius weights (between the unexposed groups: < 0.05; between the exposed groups: < 0.001). Importantly, DMBA reduced body and gastrocnemius weights ( < 0.01) when comparing the HPV groups. Moreover, the gene was overexpressed in DMBA-exposed HPV compared to control mice ( < 0.05). These results show that K14-HPV16 mice closely reproduce the anatomic and molecular changes associated with cancer cachexia and may be a good model for preclinical studies concerning the pathogenesis of this syndrome.