Anticancer mechanisms in a longest-lived rodent,
the naked mole-rat

A. Seluanov1, C. Hine1,2, J. Azpurua1,
M. Feigenson1,2, V. Gorbunova1
1Department of Biology, University of Rochester, Rochester, NY 14627
2Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14627

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we demonstrated that naked mole-rat fibroblasts require more "hits" for malignant transformation than the mouse cells. Interestingly, naked mole-rat cells constitutively express telomerase and do not become senescent in culture. Replicative senescence is an important anticancer mechanisms that limits cell proliferation. The presence of active telomerase may provide an advantage by allowing for better cell renewal in the naked mole-rat tissues, but on the other hand, active telomerase is often associated with tumorigenesis. These observations make the cancer resistance of naked mole-rats even more intriguing, and suggest that naked mole-rats evolved alternative telomere-independent tumor-suppressor mechanisms. We identified one such mechanism, termed early contact inhibition (ECI). Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways, and is associated with upregulation of p16INK4A. Recently, we identified that ESI is triggered by an extracellular signal, a very high molecular weight hyaluronic acid (HA) secreted by naked mole-rat cells. Cancer-prone mouse models are valuable for development of cancer treatments. However, to find ways to prevent cancer before it occurs it would be extremely useful to study cancer-resistant models such as the naked mole-rat. We anticipate that these unusual rodents have evolved multiple novel anticancer adaptations which would pave the way for development of novel therapies for cancer treatment and prevention.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010