VHIR researchers verify the therapeutic potential of autophagy inhibition for certain tumours

An article in the journal Biological Reviews on the interaction between autophagy and tumorigenesis performed by the Biomedical Research in Cancer Stem Cells directed by Dr. Matilde Lleonart, reinforces the possibility of proposing the mechanism of autophagic inhibition as a part of the treatment of some types of cancer especially aggressive and/or with high metastatic capacity.

The aim of this review was to explain "the contradictory role of autophagy as a mechanism that both promotes and inhibits tumorigenesis (tumour formation process) using different models," explains Dr. Lleonart. It is also discussed the induction or inhibition of autophagy as a mechanism for the treatment of cancer.

In this sense, they proposed as a future objective to be able to predict which tumours would benefit from a therapeutic approach based on the autophagic inhibition, preferably in combination with standard radiotherapy or chemotherapy. They also proposed the potential of inhibition of autophagy as a mechanism for the treatment of certain types of cancer of an aggressive and metastatic nature such as TNBC (triple negative breast cancers and very aggressive tumours of the larynx).

To achieve this, standardized methods are needed to validate the presence of autophagy in human biopsies. Studies that allow the detection of new autophagic biomarkers in human biopsies to reveal cancer subtypes in which autophagic inhibition would be effective. Greater definition of the influence of the tumour's microenvironment of the whole tumour (including the contributions of other types of stroma cells and tumour associated macrophages). Drug screening studies to elucidate autophagy antagonists. And determination of the mechanisms responsible for the acquisition of individual resistance to the inhibitors of autophagy.

Four models of study

The researchers used four models for the review, depending on the characteristics of each tumour. The first model posed whether the tumour stroma may be key to "feeding" cancer cells by autophagy. The second, analysed inflammation as the key to the tumour’s fate. The third model reviewed whether genetic differences may explain variable cellular responses to autophagy inhibitors/stimulators. Finally, in the fourth model, tumour heterogeneity was studied as a determinant of the autophagic response.

The role of autophagy in cancer

Autophagy is a cellular recycling mechanism that allows to eliminate or clean the defective cells of our organism so that it stays stable. It occurs completely naturally in all cells of the body.

It is known that an alteration of the autophagic machinery increases genomic instability, DNA damage, oxidative stress and cancer stem cell expansion.

Specifically, in the case of cancer, the role of autophagy is dual since on the one hand, it allows the survival of cancer cells and, on the other hand, it participates in or incites cell death. And it goes even further, since in the different cells that constitute a single tumour can give rise to different results.

For example, in hypoxic tumour regions (supposedly where cancer stem cells have their niche), autophagy emerges as a protective mechanism and allows the survival of cancer cells.

In contrast, in cancer cells that surround the tumour mass (more differentiated), the induction of autophagy due to radiotherapy or chemotherapy may cause cell death and significantly reduce the tumour.