Genetic mechanism in mole rats can be targeted in cancer research

Mar 15 2009

"When we understand how the subterranean mole rat developed these mechanisms for survival, we may be able to understand why they are so destructive in humans," Prof. Aaron Avivi of the University of Haifa said.

Cellular mechanisms that subterranean mole rats have developed in order to survive the low levels of oxygen in their underground habitat are similar to the mechanisms used by tumors to survive and progress in humans. This landmark discovery was revealed in a new study carried out by researchers from the Institute of Evolution at the University of Haifa and the Functional Genomics Center at the University of Illinois.

The biological significance of the blind subterranean mole rat was recognized about 50 years ago by Prof. Eviatar Nevo, who also pioneered biological studies of the organism. The current study, led by Prof. Aaron Avivi from the Institute of Evolution at the University of Haifa and Dr. Mark Band from the University of Illinois, is supported by a grant from the U.S-Israel Binational Science Foundation (BSF), and has just been published in the online FASEB Journal .

Based on the new study, the mole rat can represent the human tumor in research, and the gene targeted in mole rats can be targeted for possible development of anti-cancer drugs. It is therefore predicted that understanding the survival mechanism in the blind subterranean mole rat can help in the advancement of cancer research. "When we understand how the subterranean mole rat developed these mechanisms for survival, we may be able to understand why they are so destructive in humans," Prof. Avivi of the University of Haifa pointed out.

Experiments were conducted on groups of hypoxia-tolerant mole rats and hypoxia-intolerant "regular" rats. A group of each species was exposed to normal levels of oxygen while other groups were exposed to low oxygen levels, ranging from 3 to 10 percent. The gene BNIP3, which becomes active in the regular rats to protect their bodies from low oxygen and to prevent resulting damage, was shown to be active in heart and skeletal muscles. On the other hand, in the mole rats that tolerate low levels of oxygen, the gene was less expressed and less active, suggesting and supporting previous findings by these scientists that on a physiological level their cells and tissues do not become hypoxic.

The hypoxia-regulated pattern of BNIP3 expression and the gene's activity in the mole rat echoes its behavior in cancer cells. In both cases waves of normal oxygen levels and hypoxic levels lead to changes in the regulation of hypoxia-induced genes behavior. In mole rats this fluctuation is due to rainfalls that flood their underground tunnels, limiting the availability of oxygen and, moreover, forcing them to rebuild the tunnels and exhaust the limited oxygen; in tumor cells it occurs as they divide faster than blood vessels, which supply oxygen, sprouting into new cells.

Among a growing list of hypoxia-induced genes that were studied in the mole rat by Prof. Avivi and his colleagues and collaborators, this is the third gene that shows a similar pattern of expression as in cancer. In the past it has also been revealed that VEGF (Vascular Endothelial Growth Factor - a major growth factor that regulates the growth of new blood vessels) and p53 (a "master" gene, responsible for activating a battery of other genes engaged in either programmed cell death [apoptosis] or DNA-repair in cells) exhibit a similar mode of action in mole rats and in cancer growths, which is why they are so destructive in human cancer growths, Prof. Avivi pointed out.