Galloping Towards a Better Understanding of Cancer

White horses have trotted through human culture as symbols of power, purity, and the divine: from Pegasus soaring through Greek lores to Uchchaihshravas, a seven-headed horse, rising from the churning ocean in Hindu legends. Over centuries, storytellers picked up the mythological symbolism, crafting fairytales about heroic princes riding white horses.

“Humans are really fascinated by these white horses,” said Leif Andersson, an animal geneticist at Uppsala University. “And what has been known for 100 years is that they tend to get a type of melanoma.”

Up to 80 percent of horses with a light coat color are susceptible to skin cancer.¹ Using histological and genetic methods, researchers showed that equine melanomas resemble some forms of human skin cancers, supporting the use of horses as a model to study the disease.² On the other hand, despite having mammary gland development and functions similar to humans, horses rarely get mammary cancer, offering a comparative oncology study platform.³

Most white-looking horses are born colored, but a genetic mutation causes premature hair coat depigmentation, turning the foals gray and eventually lighter. Such horses are more prone to melanoma, which appears as jet-black nodules. “For a long time, it was a mystery why [skin color and melanoma] were linked,” said Andersson. “That was the reason I wanted to study their genetics.”

A white-colored horse with a few black patches near its jaw. — Horses with a light coat color are prone to getting melanoma (black patches) around the jaw.
Leif Andersson

Andersson and his colleagues screened the genetic profiles of more than 700 horses with light coat colors and observed that animals with a mutation in the gene encoding agouti-signaling protein (ASIP), involved in melanin pigment distribution, have a higher incidence of melanoma.¹ They also observed that melanoma cells in the animals overexpressed the transcription factor NR4A3. Other researchers have found a role of both ASIP and NR4A3 in human melanomas.^4,5

“It is possible that maybe they need additional mutations besides this basic mutation that we have identified,” noted Andersson. But studying cancer in horses has revealed mechanisms relevant to human melanomas, such as mutations in a tumor-suppressor gene, he added.⁶

While horses are prone to getting melanoma, they rarely develop cancer of the mammary glands. As a veterinary student at Ghent University, Gerlinde Van de Walle often encountered small animals like cats and dogs with mammary cancers. “When I would be on clinics for large companion animals, or just large animals in general, I would never hear about mammary cancer,” recalled Van de Walle, now a stem cell biologist at the University of Edinburgh.

This discrepancy prompted her to investigate the molecular players that may protect horses from the disease with the hopes of leveraging the knowledge to develop better human breast cancer treatments. Since other researchers demonstrated that mammary stem cells can give rise to tumors, Van de Walle and her team examined their role in equine cancer.

picture of Megan Fahey in a blue shirt next to a brown horse. — Van de Walle studies wound healing in horses in addition to mammary cancers. Her lab member, Megan Fahey, with one of the horses they used for this study.
Gerlinde Van de Walle

The researchers isolated stem cells from mammary glands of horses.⁷ Treating the cells with polycyclic aromatic hydrocarbons, known carcinogens, resulted in DNA damage and cell death. In contrast, mammary stem cells from dogs, which are prone to mammary cancer, repaired the carcinogen-induced DNA damage. This led Van de Walle to hypothesize that horses eliminate stem cells with impaired DNA, reducing the risk of potential tumor-initiating mutations.

Further, Van de Walle and her team explored the potential of secreted products, or secretome, from equine mammary stem and progenitor cells to protect against cancer.⁸ Treating cultured human breast cancer cells or mammary tumor-bearing mice with the secretome triggered cell death in vitro and tumor reduction in vivo. Identifying the exact factors responsible for tumor cytotoxicity could help design a treatment for humans, said Van de Walle.

However, working with such large animals is not logistically or financially simple. So, Van de Walle and other researchers rely on organoids derived from equine mammary cells.⁹ Alternatively, researchers are also turning to xenotransplantation models. Last year, Van de Walle and her colleagues transplanted equine mammary cells into mice for in vivo experiments.¹⁰ “And then that would allow us to actually study how the horse mammary gland reacts to a carcinogen by actually exposing the mouse to the carcinogen,” explained Van de Walle.

While horses can offer a complementary system to study cancer biology, these animals cannot replace traditional mouse models, which are easier to handle and genetically manipulate, noted Andersson. Van de Walle agreed. “But there is more than just the mouse model, and we actually have a lot of nontraditional model species that can provide so much additional information,” she added. “And I feel that slowly but steadily, it is being recognized.”