The tumor-suppressive role of mesenchymal stem cells in cancer-resistant and long-lived subterranean rodent,Spalax

Author(s): Manov Irena

The capacity to resist cancer varies widely between and within species. Hypothetically, the risk of cancer should increase in long-lived animals with large body weight because the increased number of cells and cell divisions and the subsequent high probability to accumulate mutations. However, long-lived and large bodied organisms, such as elephants and whales do not show higher cancer occurrence, vice versa, these mammals demonstrate strong cancer resistance, a phenomenon known as “Peto’s Paradox”. The large-bodied and/or long-lived animals have evolved many times across the tree of life independently, therefore there is no single strategy to prevent cancer in wild animals. In each case, it’s an evolutionary strategy that favors reproductive success. Among small body mammals naked mole rats and blind mole rats (Spalax) developed unusual for small-bodied species longevity and cancer resistance. Investigations carried out in our laboratory on Spalax demonstrated that not only a high DNA integrity appears to suppress malignant transformation, but also the behavior of host stromal cells throughout a microenvironment that does not support tumor development. Spalax adopt molecular strategy to prevent penetration of adipose-derived stem cells (ADSC) into the tumor and thus inhibit intratumoral abnormal angiogenesis. By tracking EdU-labeled ADSCs injected into tumor-bearing nude mice, we found reduced Spalax ADSC migration towards tumor cells and a poor intratumoral angiogenesis compared with rat ADSCs that migrated intensively, penetrated the tumors and actively incorporated in the newly formed intratumoral vessels. Using time-lapse microscopy and in vitro scratch assay, we demonstrated an impaired motility and low polarization ability of Spalax ADSCs. Molecular analysis of the factors involved in Spalax ADSCs reduced migration revealed sustained myosin light chain phosphorylation which, in turn, disrupted cell polarization and motility. The lack of basic property of ADSCs, namely homing to cancer cells, makes Spalax ADSCs unable to promote cancer.