The evolution of a malignant dog

Abstract

What makes a dog? Well, it depends on whom you ask. The everyday person would probably say something like ‘‘a domestic animal with four legs and a tail, that eats meat and is not a cat.’’ The biologist would add the word ‘‘canine’’ to point to dogs’ phylogenetic position. Now, how do you define cancer? Well, it depends again on whom you ask. Our everyday person would say ‘‘an awful disease that may kill you.’’ The biologist would say ‘‘a tumor originating from a single cell that underwent a series of mutations in particular genes (oncogenes/tumor suppressor genes) causing it to get out of control.’’ The reader may wonder at this stage what these two questions have to do with each other and with evo-devo. The answer becomes clear after reading an extraordinary article published last year in Cell. Murgia et al. (2006) studied a special kind of cancer in dogs, called canine transmissible venereal tumor (CTVT), first described 131 years ago (Novinski 1876). A hallmark characteristic of ‘‘normal’’ cancers is that, in contrast to many pathogen-mediated diseases, cancers are mostly noncontagious. This is mainly because, having originated from one of one’s own normal cells, cancer still expresses self-markers (MHC) making the immune system of its original host believe it is ‘‘self,’’ and therefore ignoring it. Transplanting cancerous tissue to a healthy individual of the same species would normally result in T cell-mediated rejection of the graft, as happens following allogeneic organ transplantation among MHC-mismatching individuals. ‘‘Normal’’ cancer, thus, can only survive within its original host. CTVT is unusual in this regard, as it is transmissible either through coitus or by licking/biting tumor-affected tissues. How can cancer become transmissible? One could think of two possibilities: (1) the tumor is caused by an oncogenic agent (e.g., a virus), which is still present in the tumor and is transmissible; (2) the tumor possesses highly efficient immune suppressive capabilities. Murgia et al.’s findings point to the second alternative, but go far beyond it. The authors collected tumor material and healthy tissue samples from 16 unrelated, CTVT-affected dogs from Italy, India, and Kenya. They also analyzed additional 24 paraffin embedded archival tumors collected between 1976 and 2003 from Brazil, USA, Turkey, Spain, and Italy. Using several genetic markers (microsatellites, MHC, and mitochondrial DNA) they made two amazing discoveries: first, the cancer was in all cases genetically distinct from its host at all genetic loci tested; second, and even more surprising, all cancers from all around the world seemed to be genetically almost identical, indicating that they all originated from one single malignant cell. Phylogenetic analysis done with CTVT ‘‘individuals,’’ various dog breeds, and wolf DNA, detected two main clades within CTVT and placed it as a sister-group to wolves. Further, based on microsatellite divergence among CTVT samples, the authors estimated the last common ancestor of all CTVTs to have lived between 250 and 2500 years ago. Despite being aneuploid, CTVT’s karyotype seems to be remarkably invariant in tumors from different localities worldwide. It appears, thus, that CTVT’s genomes have been very stable ever since transformation and establishment as a tumor. Recall that the latter process occurred within a single dog’s (or wolf’s) lifespan. During these few years until first transmitted, CTVT has evolved mechanisms to evade not only its original host’s immune system, but also those of its conspecifics, a very uncommon evolution in cancer. CTVT is characterized by a ‘‘life cycle’’ that includes a progressive growth phase; however, in healthy dogs it eventually regresses and the host acquires immunity to subsequent infections. So what is CTVT? The answer would again depend on whom you ask. Our layperson would undoubtedly say ‘‘cancer.’’ Murgia and colleagues call it ‘‘a cellular parasite,’’ ‘‘allograft,’’ and ‘‘the oldest known somatic mammalian cell in continuous propagation.’’ And what do we, evo-devo’ists, say? Being genetically distinct from its host means that CTVT is not a tumor by definition. Is it perhaps a dog? If so, it’s definitely a very bizarre kind. But let’s explore this possibility; there are, after all, quite established criteria for the biological species concept. Sibling species are thought to have evolved from a common ancestor. So did contemporary dogs versus CTVT. Sibling species should reach reproductive isolation; also valid for dogs versus CTVT (its aneuploid genome would make sexual reproduction with an ordinary dog highly unlikely). What about sexual reproduction itself, is that EVOLUTION & DEVELOPMENT 9:6, 521 –522 (2007)