W389Fighting Cancer Underground: Hypoxia Tolerant Spalax Hides the Key for Treatment
Time: 12:15 PM
Imad Shams, Irena Manov, Assaf Malik*, Mark Band, Aaron Avivi
Evolution Institute, Haifa University, Haifa 31095, Israel and * Comparative and Functional Genomics, University of Illinois, Urbana, Illinois 61801, USA
The subterranean blind mole-rat (Spalax) is a long-lived (>20 years), wild, solitary rodent of the Mediterranean region. Spalax inhabits a system of poorly ventilated, dark, sealed underground tunnels and has evolved unique adaptive complex mechanisms for surviving underground, including coping with extreme hypoxia and hypercapnia. Spalax is able to maintain intensive aerobic work down to 3% O2.
Hypoxia can result in a failure to maintain essential cellular functions and contributes to heart and lung diseases, brain strokes and cancer, which together are the primary sources of morbidity in the Western world. A long and growing list of genes exhibits hypoxia-related adaptations in structure and function in Spalax, among them major genes directly related to cancer development: VEGF, a major angiogenic growth factor, is constitutively maximally expressed in Spalax like in tumors; p53 , an important cancer-suppressor, harbors mutations in its DNA-binding domain, identical to the most common inactivating mutations of tumors- p53, which in Spalax abrogate apoptosis but favor cell cycle arrest/DNA repair; and heparanase, a protein highly affecting cancer progression, that in Spalax has a unique splice variant decreasing tumor size in mice by a factor of 7 and reducing metastatic activity compared to native heparanase. Furthermore, assessment of Spalax transcriptome assembly and expression data revealed enrichment of genes overlapping cancer-resistance and hypoxia-tolerance.
During 50 years studying thousands of animals, we have never observed spontaneous tumors in Spalax. An attempt to induce cancer in Spalax with chemical carcinogens that induced cancer in 100% of mice and rats identically treated, demonstrated that Spalax is extremely resistant also to induced cancer. Furthermore, fibroblast cells from Spalax, regardless of the subspecies, sex and age inhibit growth and kill cancer cells from various tissues and species, importantly including human. This is exhibited in both co-culture system or by exposure to conditioned media harvested from Spalax fibroblasts. Cancer cell death was accompanied by decreased cancer cell viability and proliferation, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation, nuclei deformation and mitochondrial fragmentation.
Many renowned cancer scientists have already stated that “The classical mice model for cancer research has little predictive value and a negligible relation to that of human. Far more than anything else, the lack of good experimental animals has become the rate-limiting step in human cancer research” Therefore, it would be extremely useful to study naturally cancer-resistant animals. Our results may lead to a breakthrough in the conservative paradigm of cancer research, completely dependent on laboratory, inbred rodents, and place Spalax as the ‘missing’, appropriate candidate animal for such studies. We anticipate that the long lived, hypoxia- and cancer-tolerant Spalax will turn out to be a significant biological resource to biomedical research as an organism for treatment and prevention of cancer in humans.