A transforming giant virus discovered in Canine Transmissible Venereal Tumour: Stray dogs and Tasmanian devils opening the door to a preventive cancer vaccine.

Abstract

BackgroundCanine Transmissible Venereal Tumour (CTVT) along with Tasmanian Devil Facial Tumour and transmissible leukaemia in Mya Arenaria soft shell-clams are the only examples of contagious cancers occurring in nature. In particular, CTVT is the oldest contagious cancer present in the wild world. The attempts to detect a transmissible virus as a causative agent in these forms of contagious cancer proved conflicting and the current consensus view is that a transformed somatic cell itself is transmitted and starts the tumor in a new animal, as a parasitic allograft. We modify this perception and report for the first time the isolation of an acutely transforming agent from CTVT. MethodsLarge particles were successfully isolated from CTVT specimens through a sucrose gradient, examined at electron microscopy, fully sequenced, used for transformation tests on NIH-3T3 cells and tumorigenic experiments in dogs. A neutralizing therapeutic vaccine was also administered in dogs with natural, not-induced CTVT. ResultsThe particles, isolated from CTVT, are infectious living entities with large dimension. Electron Microscopy reconstructed an organic wall assemblage pattern typical of early life fossils from the Precambrian age, time at which Earth began to form 4.6 billion years ago. Astonishingly, our agents are not fossils, but unicellular organisms biologically active and acutely transforming. They transformed NIH-3T3 cells in vitro and initiated the typical CTVT lesions in healthy dogs, just one week post-infection. Only the fraction containing these infectious entities were able to induce cancer, while a filtered supernatant did not. This ruled out the presence of conventional filterable viruses. RNA sequencing and bioinformatics analyses disclosed a large genome composed by an almost complete Orphan genes dataset, with retro-elements distinct from the host genome. Five doses of a neutralizing vaccine against these oncogenic organisms, drastically reduced the neoplastic mass in dogs with natural, not-induced CTVT. Analogous infectious agents, acutely transforming were also isolated from several human neoplasms. ConclusionsModifying the current believe that contagious cancers are transmitted by a somatic cells allograft, we identified a living agent that infects and starts the typical CTVT in healthy dogs, while its neutralization with a vaccine induces cancer regression in animals with cancer. Significance StatementThese infectious living single-cell agents establish a new family of oncogenic organisms that resist current classifications and affect humans and animals in the wild. While only a dozen of proteins compose a classic virus, these organisms are small infectious cells, but very distinct from somatic eukaryotic cells. The identification of causative unicellular organisms that start cancer in healthy subjects and the possibility to induce cancer regression with a neutralizing vaccine change some perspectives in cancer. The Precambrian features and the genetic composition suggest that these unicellular entities are infectious living RNA protocells that finally gives form to what was considered only a hypothesis drafted by the Nobel laureate Walter Gilmore: the RNA world, the origin of life and RNA protocells.