Autophagy Enables Tumor Cells to Thrive in an Acidic Environment

Tumor cells forced to live in a hypoxic and acidic microenvironment have developed molecular pathways that activate autophagic activity within the cancer cells and provide them with the survival advantage they require to grow and spread.

Autophagy is a self-degradative cellular process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to nonapoptotic cell death. Autophagy can be either nonselective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully understood.

Usually autophagy is thought to be a cancer preventative process, as in addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability, and prevents necrosis. These functions give it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases, and infections.

Autophagy can also promote cancer cell survival, as has been described in a recent study conducted by investigators from the Moffitt Cancer Center (Tampa, FL, USA) and published in the August 15, 2012, issue of the journal Cancer Research.

To investigate how tumors adapt to an acidic environment they examined the effect of low pH (6.7) on human breast carcinoma cells. For this study they used the MDA-MB-231 human breast cancer cell line, which is highly invasive and metastatic both in vitro and in mouse models. Experiments were conducted under atmospheric oxygen so that all observations could be linked to acidosis and not confounded by oxygenation status.

The investigators detected elevated autophagic activity after acute and chronic exposure to acidosis, which promoted cell survival and continued proliferation similar to control cells. Pharmacological inhibition of autophagy resulted in reduced viability of cells grown at low pH. In vivo data showed spatial concordance between autophagic proteins and volumes expected to be acidic, and the expression of autophagic biomarkers was reversed with systemic buffers that raised tumor pH.

Although typically reported as an acute stress response, the data presented in this publication indicate that acid stress may lead to chronic maintenance of autophagy even during periods of adequate nutrient and oxygen supply. These results point toward a potential therapeutic strategy for treating tumors by using an autophagy inhibitor, one that does not affect cells under neutral conditions.

“Cancer progression is a multistep process strongly influenced by the physical properties of the tumor microenvironment,” said senior author Dr. Robert J. Gillies, director of imaging research at the Moffitt Cancer Center. “Both low oxygen and high acidity can be cytotoxic. Our research suggests that adaptation to these stressful conditions involves autophagy allowing cancer cells to survive, proliferate, and eventually metastasize to secondary sites.”

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Moffitt Cancer Center