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

Abstract

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 <i>Fbxo32</i>. 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 <i>Fbxo32</i> 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 (<i>p</i> < 0.01), they presented lower body weights (<i>p</i> < 0.05). This body weight trend was more pronounced when comparing DMBA-exposed groups (<i>p</i> < 0.01). The same pattern was observed in the gastrocnemius weights (between the unexposed groups: <i>p</i> < 0.05; between the exposed groups: <i>p</i> < 0.001). Importantly, DMBA reduced body and gastrocnemius weights (<i>p</i> < 0.01) when comparing the HPV⁺ groups. Moreover, the <i>Fbxo32</i> gene was overexpressed in DMBA-exposed HPV⁺ compared to control mice (<i>p</i> < 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.