Transmissible tumors in animals: Two clonally transmissible cancers

After the discovery of tumor viruses in chickens during the first decades of the 20th century, a first mammalian tumor virus was discovered — by Richard E. Shope — in 1933. It was found in the cottontail rabbit.

The Shope papillomavirus was initially followed by the mouse mammary tumor virus (John Bittner, 1936) and murine polyomavirus (Ludwik Gross, 1954).

Various pathogens

The first human cancer virus, human herpesvirus 4/Epstein-Barr V tumor virus, was discovered at a later date, namely in 1964. Since then, various pathogens have been shown to be involved in transmissible tumors in animals and humans. Most of them are restrictively affecting a single species, but some, particularly of simian origin, were suspected to be of zoonotic potential. No transmissible cancer is known at present as being common to domestic animals and man. Addressing two transmissible tumor diseases within this veterinary-oriented column is exceptional in the sense of both not being zoonoses; they are brought forward from the perspective of comparative medicine.

The diseases to be addressed, canine transmissible venereal tumor (CTVT) and Tasmanian devil facial tumor disease (DFTD), are the only two known naturally occurring clonally transmissible cancers. These cancers are transmitted by the physical transfer of viable tumor cells that can be transplanted across histocompatibility barriers into unrelated hosts. Despite their common etiology, DFTD and CTVT have evolved independently and have unique life histories and host adaptations.

Canine transmissible venereal tumor

CTVT, also known as Sticker’s sarcoma, is an infectious genital tumor that affects dogs. Spread by the physical transfer of cancer cells during coitus, CTVT is characterized by the appearance of lesions around the external genitalia that can affect both sexes of any breed of dog. The disease has a global distribution and has been documented in six continents. The condition was first documented in 1876 by the Russian veterinarian Nowinsky, and the tumor subsequently became a popular model for cancer biologists. However, despite 130 years of research into CTVT, many features of this unusual transmissible cancer remain poorly understood.

CTVTs first appear as small, firm, localized nodules, typically at the base of the glans penis in males or in the vaginal vestibulum of females. Later-stage disease is characterized by pedunculated, exudative, ulcerating masses that can become as large as 10 cm or greater in diameter. They may be transplanted to adjacent skin and oral, nasal or conjunctival mucosae. The tumor may arise deep within the prepuce or vagina and be difficult to see during cursory examination. This may lead to misdiagnosis if genital bleeding is incorrectly assumed to be hematuria. The tumor is transplanted from site to site and dog to dog by direct contact with the mass. Initially, CTVTs grow rapidly. Metastasis is uncommon (5%). When metastasis occurs, it is usually to the regional lymph nodes, but kidney, spleen, eye, brain, pituitary, skin and subcutis, mesenteric lymph nodes and peritoneum may also be sites. One interesting feature of CTVT is that it sometimes undergoes spontaneous regression.

CTVT cells are generally easily recognized as uniform round- to polyhedral-shaped centrally nucleated cells with a prominent nucleolus and characteristic cytoplasmic vacuoles. The cells may be difficult to distinguish from other round cell tumors, particularly lymphosarcomas, when they occur in extragenital locations.

CTVTs are usually progressive and are treated accordingly. Complete surgical excision, radiation therapy and chemotherapy are effective treatments; however, chemotherapy is considered the treatment of choice. Vincristine is reported to be effective, except when the tumor is in the central nervous system or eye. Usually, total remission can be expected by the sixth treatment. Adriamycin also has been effective for those animals that do not respond to vincristine. The prognosis for total remission with chemotherapy or radiation therapy is good, unless there is metastatic involvement of organs other than skin. Complete surgical excision often cannot be achieved because of the anatomic location of many of these tumors. Recurrence is likely in such cases, unless adjunct radiation or chemotherapy is used.

CTVT has been proposed to be derived from the macrophage lineage. This is supported by the observation that CTVT cells themselves may be parasitized by Leishmania infantum, an organism that normally infects macrophages. Clonal transmission was first suggested for CTVT due to the success of tumor transplant experiments such as those pioneered by Nowinsky (1876) and Sticker (1906). These experiments revealed that CTVT could be transmitted between unrelated dogs by the direct transfer of cancer cells or tumor tissue.

Cytogenetic studies also supported the clonal transmission theory. Whereas the constitutive chromosome number of dogs is 78, the karyotypes of CTVTs from diverse geographical locations all confirmed a chromosome number of 57–59. The CTVT karyotype included 15 to 17 metacentric or submetacentric chromosomes, in contrast to two in the normal dog karyotype. The remarkable similarity between CTVT karyotypes from different continents, presumably from clones that have been geographically isolated for many years, suggests not only a common origin for globally distributed CTVT, but also highlights the fact that the clonal karyotype, despite its aneuploidy, is relatively stable. Phylogenetic analyses indicate that CTVT was probably founded by a single wolf that existed between 7,800 and 78,000 years ago; according to earlier studies, it most likely originated from a wolf or an East Asian breed of dog between 200 and 2,500 years ago. In recent times, a single clone has become dominant and has split into two clades, each with a broad global distribution. Thus, CTVT is one of the oldest known somatic cell line.

Tasmanian devil facial tumor

DFTD is a transmissible cancer affecting the Tasmanian devil (Sarcophilus harrisii), an endemic, spaniel-sized, Tasmanian marsupial carnivore. Transmitted when the animals bite one another’s faces during fights, DFTD is a rapidly fatal disease that culminates in large tumors, primarily on the face and mouth, which frequently metastasize to internal organs. The disease has already wiped out 60% of all Tasmanian devils since it was first observed in 1996 in northeastern Tasmania. There are no diagnostic tests, treatments or vaccines available for DFTD, and models predict that the disease could lead to a total extinction of wild Tasmanian devils within 25 to 35 years.

When the tumor disease was discovered, it was initially assumed that it was caused by a rapidly spreading virus. However, no virus could be demonstrated; DFTD appears to be a clonal cell line, transmitted (by biting) as an allograft between devils and may be similar in transmission to CTVT and a transmissible sarcoma affecting Syrian hamsters.

Studies of captive Tasmanian devils have suggested that the species is prone to developing tumors, particularly carcinomas. However, DFTD does not resemble previously described devil cancers, and determining its etiology is critical for developing management strategies for the disease. Cytologically, DFTD appears as a soft tissue neoplasm consisting of undifferentiated round to spindle-shaped cells with few defining ultrastructural features. Immunohistochemistry suggests that the tumor is derived from neuroectoderm.

Recent studies confirm that DFTD is a monophyletic clonally transmissible tumor and suggest that the disease is of Schwann cell origin. As Schwann cells and neuroendocrine cells are both derived from the neural crest and overlap in gene expression, the authors suggested that elements of both tissue types are possibly involved. A Schwann cell origin for DFTD contrasts with that of CTVT, the canine clonally transmissible cancer, which has been proposed to be of histiocytic origin.

On the basis of these results, the Australian investigators have generated a diagnostic marker for DFTD and identified a suite of genes relevant to DFTD pathology and transmission.

Arnon Shimshony, DVM, is Associate Professor at the Koret School of Veterinary Medicine Hebrew University of Jerusalem, Rehovot, and is the ProMED-mail Animal Diseases Zoonoses Moderator. Dr. Shimshony was Chief Veterinary Officer, State of Israel, from 1974 to 1999.

Murchison E. Science. 2010; 327: 84-87.