by ecancer reporter Clare Sansom


Autophagy (from 'self-eating') is a catabolic process in which cells degrade their own components using their lysosomal machinery. Its role in tumour development has caused controversy, as both molecules that block autophagy (e.g. chloroquine) and those that promote it (e.g. rapamycin) are known to block tumour development.

A group of researchers from Thomas Jefferson University, Philadelphia, USA have recently proposed a solution to this apparent paradox. This new model has been termed “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumor Growth”. It suggests that autophagy in fibroblasts adjacent to the tumour (the tumour stroma) recycles nutrients that can be used to grow the tumour, independently of angiogenesis; the stroma is acting as a “battery” fueling tumour growth elsewhere. Thus, both promoting and inhibiting autophagy throughout the tumour can, at times, prevent tumour growth by interrupting this cycle and “starving” it of nutrients.

The development of the model was based on the discovery of a biomarker, calveolin-1, in tumour stromal cells. Calveolin-1 loss in some tumours can be predictive of oxidative stress and autophagy, and of poor clinical outcome. The researchers have now proven some aspects of their model experimentally using data from calveolin-1 null mice, which can be taken as a pre-clinical model for a “lethal tumour micro-environment”, and from human tumour xenografts.  Transcriptional analysis and metabolic profiling of cells from the calveolin-1 null mice revealed a catabolic phenotype consistent with the induction of oxidative stress. A series of inhibitor-based studies in tumour models showed that hypoxia and oxidative stress induced genes such as HIF1 and NFkB that drive the loss of calveolin-1 and autophagy. Whereas expression of these genes in tumour-associated fibroblasts was associated with tumour growth, their expression in tumour tissue itself was associated with suppression of that growth. The researchers suggest that patients whose tumours exhibit calveolin-1 loss may respond to inhibitors of NFkB and HIF1, or to anti-oxidants.

Many cancer patients suffer from cachexia (wasting) and this is known to be due to an increase in metabolic rate and a transfer of energy to the tumour, rather than to decreased energy intake. The autophagic tumour stroma model of cancer presented here suggests that the process that leads to cachexia may start locally to the tumour, with stromal cell autophagy, before becoming systemic. This fits with earlier proposals of a link between oxidative stress and cachexia, and with the suggestion that it may be treated successfully with anti-oxidants. Furthermore, the model provides a rational explanation for the lack of success of drugs that block angiogenesis, by suggesting that these drugs induce hypoxia and thus autophagy in the tumour stroma, and that this drives tumour growth. In contrast, the researchers propose a close link between local oxidative stress, stromal cell autophagy and cancer development, and suggest that anti-oxidants, many of which are available as prescription or over-the-counter drugs, may reverse this process and thus be effective in treating cancer.

Reference

Martinez-Outschoorn, U.E., Whitaker-Menezes, D.,  Pavlides, S. and 16 others (2010). The autophagic tumor stroma model of cancer or “battery-operated tumor growth”, a simple solution to the autophagy paradox. Cell Cycle  9:21, 4297-4306.