Discovery of Novel Mechanism by Which Senescence is Evaded in Tumour Cells

Novel study findings on senescence in cancer

A team of researchers from the Institute of Research in Oncology in Bellinzona, Switzerland, led by Dr Andrea Alimonti has identified a novel mechanism by which senescence is evaded in tumour cells. They identified a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy according to results published in Nature on 24 August 2014.

For about a decade, scientists involved in cancer research have tried to unveil the mechanisms that trigger senescence evasion in tumour cells. Senescence is a stable cell growth arrest that opposes tumour formation. Paradoxically, aberrant activation of oncogenes or loss of tumour suppressor genes, causative events of cancer, have been shown to activate senescence, making it very difficult for the scientists to understand how tumours form and progress.

Anti-cancer chemotherapy also inhibits tumour growth by triggering senescence. However, cancer cells find ways to continue to proliferate driving tumour relapse. If over-expression of oncogenes or losses of tumour suppressor genes induce a stable growth arrest then, why do tumours form? Similarly, why do tumours relapse if chemotherapy induces a strong senescence response in cancer cells? A common understanding of this phenomenon is that cancer cells bypass senescence by acquiring secondary genetic mutations.

Novel findings demonstrate that tumour cells can also by-pass senescence in the absence of genetic mutations

“What we’ve found is that myeloid cells, a type of cells of the immune system that infiltrate a majority of tumours, are able to inhibit senescence driven by loss of tumour suppressor genes or induced by chemotherapy, thus promoting tumour formation and diminishing chemotherapy effectiveness”. The paper demonstrates that tumour cells bypass senescence and continue to proliferate indefinitely because of the interaction with myeloid cells. “This discovery is of a great relevance and opens up new and unexpected scenarios in cancer therapy", explained Dr Alimonti.

The most interesting finding of Dr Alimonti's team is indeed, that by inhibiting the recruitment of myeloid cells in prostate tumours, senescence induced by chemotherapy is highly enhanced and tumours strongly responds to treatments.

The team also unveiled the mechanism by which this phenomenon occurs. Tumour-infiltrating myeloid cells release lL1RA in the tumour microenvironment, a protein known to be a potent inhibitor of interleukin-1 receptor alpha (IL1α). IL1α is a protein released by senescent tumour cells that was previously shown to be essential for the regulation of senescence in tumours.

"During chemotherapy, senescent cells secret IL1α which induces senescence in proliferating tumour cells, through a chain reaction” said Dr Alimonti. “Unfortunately, this chain reaction is interrupted by the release of IL1RA by myeloid cells infiltrating the tumour. IL1RA binds to the receptor for IL-1 on cancer cells thus blocking the binding of IL1α, and therefore preventing the activation of the signal responsible for the induction of senescence".

“As a result, tumour cells continue to proliferate and the tumour does not respond or respond only partially to chemotherapy" concluded Dr Alimonti.

These results demonstrate that tumour cells can also by-pass senescence in the absence of genetic mutations and point towards treatments that blocks myeloid cells as novel promising therapies for cancer patients subjected to chemotherapy.

These findings were made possible thanks to the contribution of two talented collaborators of Dr Alimonti’s group, Dr Diletta Di Mitri and Dr Alberto Toso, first authors of the paper just published in Nature.

The results were also accomplished thanks to the collaboration of Swiss, Spanish and American research centres and to the financial support of the European Research Council, the Swiss National Fund and the Swissbridge foundation.

Reference

Di Mitri D, Toso A, Chen JJ,et al.Tumour-infiltrating Gr-11 myeloid cells antagonize senescence in cancer. Nature 2014; Published online 24 August. doi:10.1038/nature13638