Human oral cancers associated with papillomavirus also target the back of the tongue
Text by Nancy M. Cladel
Papillomaviruses are ubiquitous and are typically either cutaneotropic or mucosotropic. Most of the infections resolve over time but some do not. When infections persist, significant pathology can occur. Nearly all cases of cervical cancer result from infections with one or another of these viruses and oropharyngeal cancers are increasingly associated with papillomaviruses. Because the viruses are species specific, human papillomaviruses cannot be studied in an animal model. Since the viruses require differentiating cells to complete their life cycles, cell culture studies also pose significant limitations. We have found that the recently–described mouse papillomavirus 1 (MmuPV1) infects the oral cavity of the HSD: NU–Foxnu mouse and specifically targets the circumvallate papilla and associated glands at the back of the tongue. The back of the tongue is a preferred site for HPV-associated oral cancers. The mouse model will provide a powerful tool for the study of papillomavirus-associated disease and progression.
We began our work with MmuPV1 shortly after the report of its discovery and sequence in 2011. The impetus for this work came from our desire to supplement our rabbit/cottontail rabbit papillomavirus (CRPV) model with a smaller animal model. Although many animal papillomaviruses have been described, until the announcement of the discovery of MmuPV1, no papillomavirus infecting a common laboratory mouse had been discovered. We had some reservations about focusing on this virus as it was reported to be “strictly cutaneous” but CRPV is also cutaneous and that has not prevented our learning many interesting things about papillomavirus virus life cycle and immunology.
We used the published sequence of MmuPV1 as a template for the synthesis of the viral DNA and, using direct DNA inoculations, we achieved our initial infections. The resulting viral stock allowed us to begin studies that have led to unanticipated and fascinating discoveries. One of the seminal observations was that the virus exhibits mucosal as well as cutaneous tropism. This observation ultimately led to the establishment of models to study both cervicovaginal and anal disease.
We have now found that the oral cavity is also susceptible to the virus. In fact, the back of the mouse tongue exhibits particular susceptibility and this is the part of the anatomy favored by human papillomavirus associated oropharyngeal cancers. We are now poised to begin studies that we anticipate will shed light on factors contributing to these cancers. This was farthest from our minds when we began this work.
Mouse papillomavirus1 has been found to preferentially target the circumvallate papilla and associated Von Ebner’s glands of the caudral dorsal mouse tongue (two examples shown). Lesions become hyperproliferative. These findings introduce a powerful new pre-clinical model to explore development and progression of back of tongue papillomavirus-associated lesions and, potentially, cancers.
Introducing the authors
The research team from left to right: Lynn Budgeon (seated), our superb histotechnologist; Karla Balogh, animal technician, par excellence; Neil Christensen, our most supportive P.I.; Nancy Cladel, author and molecular biologist; Jiafen Hu, research associate whose skills are legion. Not present: Tim Cooper, board certified veterinary pathologist
About the research
Nancy M. Cladel, Lynn R. Budgeon, Karla K. Balogh, Timothy K. Cooper, Jiafen Hu, Neil D. Christensen
Virology, Volume 488, 15 January 2016, Pages 73–80