Autophagy – the dark side of Cancer

Autophagy is a cellular clean-up process that removes waste from cells. It is generally thought to be a wonderful, built in, maid service to healthy cells to keep everything tidy.

However, tumor areas can experience episodes of limited nutrient supply due to poor perfusion to the degree that nutrient availability is insufficient for maintaining tumor growth or even survival. Also, some tumors tend to be poorly perfused due to low vascularization and high interstitial pressure; a good example of this is pancreatic ductal adenocarcinoma (PDAC) (Koong et al., 2000; Neesse et al., 2011).

Unfortunately, this is where the ‘dark side of autophagy’ plays against us. A well-described alternative mode of nutrient acquisition during these periods of starvation is autophagy or ‘self-cannibalism’ (Rabinowitz and White, 2010). It is a catabolic pathway used by cells to recycle cell content and organelles, and reuse their components. The process utilizes autophagosomes (enzymes that gobble-up waste) that eventually fuse with lysosomes (one of the organelles in the cell) for content degradation and the subsequent release of the breakdown products. When a growing cancer, with its ferocious appetite, experiences nutrient starvation, the breakdown products generated by autophagy (amino acids, fatty acids, sugars, and nucleosides) help sustain energy production and synthesis of essential cellular building blocks. In tumor cells, autophagy has been found to be particularly important for maintaining survival during nutrient stress (Guo et al., 2011; Yang et al., 2011) – UGH!

Although it can support cell survival during episodes of starvation, autophagy is inherently incapable of facilitating tumor growth, as it only recycles or consumes the intracellular biomass. To support proliferation, exogenous (from outside the cell) substrates are required. Recently, it was found that cancer cells, particularly those with a Ras mutation, can internalize proteins in the spaces between the cells through macropinocytosis (Commisso et al., 2013). This is a process by which extracellular fluid and its components are engulfed by the plasma membrane, leading to the budding of macropinosomes in the cytoplasm. Like autophagosomes, macropinosomes also fuse with lysosomes and the degraded content is released to support metabolism.

In a study by Commisso et al., cell consumption of albumin, a blood protein, was found to reduce the dependence on free glutamine (Commisso et al., 2013), and a later study also confirmed that macropinocytosis occurs commonly in human tumors (Kamphorst et al., 2015). Additionally, this process enables pancreatic cancer cells to proliferate in medium lacking essential free amino acids (Kamphorst et al., 2015).

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From a treatment perspective, nothing pharmaceutical has yet been developed to conquer such a process. Nutritionally, fasting for periods throughout the day or doing what is called a fasting mimicking diet (FMD) has been an approach that seems to be the most helpful to reduce self-cannibalization to feed a growing cancer. The FMD diet reduces mTOR and can limit autophagy.

In summary, some cancer cells survive and even grow during primary nutrient starvation by maintaining metabolic activity through catabolizing both intracellular and extracellular macromolecules. This metabolic ‘scavenging’ appears important for the growth of a subset of tumors, such as PDAC. Conceivably, it can also form a general mechanism of resistance to antiangiogenic therapies or other nutrient deprivation-based strategies. The use of FMD diets and/or limited daily fasting may prove our greatest defense against this process.