From Hypoxia Resistance to Cancer Tolerance: the Adaptations Evolved in the Blind Subterranean Mole Rats

Biodiversity that evolved on Earth created solutions for various biological challenges. In this regard, the study of natural resistance to cancer observed in some wild animals is a promising direction in the fight against cancer. We recently reported that the hypoxia-resistant long-lived subterranean blind mole rat (Spalax) possesses an outstanding cancer- tolerance to spontaneous and in vivo-induced carcinogens, and a direct inhibition of cancer cell growth by Spalax’s fibroblasts. Here we demonstrate that senescence with subsequent caspase-independent apoptosis is the predominant mode of cancer cell death in response to factors released by Spalax fibroblasts. Viability, colony formation and invasion assays were used to monitor cancer growth of cell of different species (MDA-MB-231, PC-3, Hep3B and HepG2 cells, as well as mouse- and Spalax-derived fibrosarcomas). Transwell migration assay was employed to evaluate chemotactic activity. In addition, effects of conditioned media generated by Spalax, rat or mouse fibroblasts on viability, nuclei and mitochondria integrity and cell cycle distributions were investigated. Spalax fibroblasts monolayer strongly reduced tumor growth while mouse, rat and Acomys fibroblasts had no effects or stimulated colony formation. Similarly, Spalax fibroblasts suppressed cancer cells migration. Medium conditioned by Spalax fibroblasts induced arrest of proliferation in different cancer cells. Protein expression profiling in Hep3B cells exposed to Spalax fibroblast conditioned medium revealed alterations in extracellular matrix signaling molecules and apoptotic proteins. Cancer microenvironment is an integral part of the tumorigenesis where cancer cells grow and invade. The scenario of cancer progression includes dynamic repression of natural host tolerance. We propose Spalax as a natural cancer-resistant model in which cancerous cells do not receive support from adjacent stroma, and wherein tumors fail to proliferate and metastasize.