From a Horned Rabbit of Legend to a Tool of Cancer Research

In the folklore of North America and Europe, creatures such as the Jackalope and the Wolpertinger—rabbits said to bear antlers—are often regarded as bizarre mythical animals. Yet the image of a rabbit with horn-like growths may actually have originated from real observations in the wild. Early hunters occasionally reported capturing rabbits with unusual appearances, particularly animals whose faces and necks were covered with protruding growths resembling small horns. As early as the eighteenth century, the French naturalist Pierre Joseph Bonnaterre recorded such observations in Tableau encyclopédique et méthodique.

Illustration of the Jackalope（Image source：Dr Von Drake， CC BY-SA 4.0 ）

It was not until the twentieth century that the true cause of these strange growths was uncovered. The American virologist Richard Edwin Shope investigated wart-like lesions found on the skin of cottontail rabbits and demonstrated that they were caused by a virus. This pathogen later became known as the Shope papillomavirus, or cottontail rabbit papillomavirus (CRPV). In the United States, infections have been reported mainly in regions extending from Minnesota and North Dakota southward to Texas.

Rabbit with papillomatous growths（Courtesy of Gunnar Boettcher）

Viruses of the family Papillomaviridae are small, non-enveloped viruses with an icosahedral capsid and a DNA genome. The most widely known members of this group are the human papillomaviruses (HPV). Certain HPV types, particularly HPV16 and HPV18, are capable of causing cancers such as cervical cancer, anal cancer, and cancers of the head and neck.

Papillomavirus under an electron microscope (human papillomavirus as an example)（Image source：Laboratory of Tumor Virus Biology，CC0 1.0 ）

The cottontail rabbit papillomavirus that infects rabbits also possesses carcinogenic potential. Transmission typically occurs through the bites of arthropods such as ticks, assassin bugs, or mosquitoes. Among these, the rabbit tick Haemaphysalis leporispalustris is one of the most common vectors. After a bite, the virus infects epithelial cells in the rabbit's skin and begins to replicate within those cells.

One viral protein, E6, interferes with the rabbit tumor-suppressor protein hDlg/SAP97. Under normal conditions, this protein helps maintain cellular polarity and regulates cell proliferation. When the viral E6 protein binds to hDlg/SAP97, its function becomes disrupted. Infected epithelial cells gradually lose their polarity and begin proliferating uncontrollably. As a result, wart-like lesions form in the epithelium and may eventually progress into squamous cell carcinoma. In domestic rabbits (Oryctolagus cuniculus), malignant transformation can occur in as many as about 70% of cases. By contrast, the Eastern cottontail rabbit (Sylvilagus floridanus) is the virus's natural host, and in this species papillomas usually remain benign and rarely progress to cancer.

Infected epithelial tissues initially develop small reddish raised areas. These gradually evolve into papillomatous growths with rough, rounded surfaces and may later develop into large keratinized protrusions. If the lesions remain benign, they usually regress within roughly six months. However, if malignant transformation occurs and squamous cell carcinoma develops, cancer cells often invade nearby lymph nodes first, particularly those in the axillary region. During this stage, many rabbits exhibit systemic physiological changes, including amyloid deposition in organs such as the renal glomeruli, the splenic red pulp, and the hepatic sinusoids. As the disease progresses, tumor cells metastasize to other organs—especially the lungs—ultimately leading to death.

Because cottontail rabbit papillomavirus belongs to the same viral family as human papillomaviruses and shares many biological features with them, it has become an important experimental model for studying papillomavirus-induced cancers. Researchers infect rabbits experimentally to investigate the mechanisms of viral oncogenesis and tumor pathology, thereby gaining insights relevant to HPV-associated cancers in humans.

This line of research has also led to the development of several tumor cell lines derived from CRPV-induced cancers. Among them, the VX2 cell line is particularly well known. VX2 originates from squamous cell carcinoma triggered by CRPV infection and exhibits high transplantability. When introduced into rabbits, these cells can form solid tumors in multiple anatomical locations and frequently metastasize to regional lymph nodes and the lungs. These characteristics closely resemble those seen in human head and neck cancers, making the VX2 model widely used in animal experiments aimed at understanding cancer mechanisms and evaluating potential therapeutic approaches.

Thus, what began as a peculiar skin growth on rabbits—once inspiring fantastical creatures of folklore—has ultimately become a valuable scientific model in modern cancer research. It represents an intriguing journey from myth and misinterpretation to a deeper understanding of viral oncogenesis and experimental oncology.

Author: Shui-Ye You

References:

1. Bette M and Mandic R. (2024). Cottontail Rabbit Papillomavirus (CRPV) Related Animal Models for Head and Neck Cancer Research: A Comprehensive Review of the Literature. MDPI.

2. Brabb T and Di Giacomo RF. (2012). The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents. Chapter 14 - Viral Diseases. Academic Press.