Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Subterranean blind mole rats<jats:italic>(Spalax)</jats:italic>are hypoxia tolerant (down to 3% O<jats:sub>2</jats:sub>), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of<jats:italic>Spalax</jats:italic>research, spontaneous tumors have never been recorded among thousands of individuals<jats:italic>.</jats:italic>Here we addressed the questions of (1) whether<jats:italic>Spalax</jats:italic>is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from<jats:italic>Spalax</jats:italic>possess tumor-suppressive activity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Treating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-<jats:italic>O</jats:italic>-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed<jats:italic>Spalax</jats:italic>high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among<jats:italic>Spalax</jats:italic>no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2<jats:italic>Spalax</jats:italic>individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment.<jats:italic>In vitro</jats:italic>experiments showed an extraordinary ability of normal<jats:italic>Spalax</jats:italic>cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated<jats:italic>Spalax</jats:italic>3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with<jats:italic>Spalax</jats:italic>fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to<jats:italic>Spalax</jats:italic>, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or<jats:italic>Acomys</jats:italic>.<jats:italic>Spalax</jats:italic>fibroblast conditioned media had no effect on proliferation of noncancerous cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This report provides pioneering evidence that<jats:italic>Spalax</jats:italic>is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of<jats:italic>Spalax</jats:italic>normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia,<jats:italic>Spalax</jats:italic>has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing<jats:italic>Spalax</jats:italic>to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.</jats:p></jats:sec>