Paper of the Month - October 2016

Theriau CF, Shpilberg Y, Riddell MC, Connor MK.Voluntary physical activity abolishes the proliferative tumor growth microenvironment created by adipose tissue in animals fed a high fat diet. J Appl Physiol (1985). 2016 Jul 1;121(1):139-53. doi: 10.1152/japplphysiol.00862.2015. Epub 2016 May 5.

The incidence and number of deaths resulting from cancer are increasing, despite numerous advances in the fields of cancer detection and therapy.  Except in a few cases, cancer is a sporadic disease with many associated modifiable risk factors and very few direct known causes.  This makes determination of cancer incidence and the underlying mechanisms very difficult.  This also leads to a very unpredictable nature of disease development and even cancers of similar subtypes can have hundreds, if not thousands, of underlying root driving mechanisms.  Furthermore, cancers are highly mutagenic by nature and are continually changing during disease progression.  This makes targeting any specific cancer difficult as any tumour that presents itself at diagnosis will be potentially different six months later.  Taken together, cancers are very difficult to characterize and incredibly hard to eliminate therapeutically.  Interestingly, much of a cancer’s growth characteristics are controlled by elements of the external environment surrounding the tumour.    Although some of the factors contributing to this tumour growth environment are produced by the tumour itself, many of these elements are produced by stable and predictable components of patient physiology.

Obesity is one of the modifiable cancer risk factors and proteins secreted by adipose tissue, termed adipokines, have been shown to affect cancer cell growth.  Given the rapid rise in obesity over recent history and the fact that adipose tissue is a stable and predictable part of patient physiology, our lab focuses on the potential molecular mechanisms that link obesity to breast cancer progression.  Two adipokines, adiponectin (ADIPO) and leptin (LEP), have received much attention as mediating this link since they are secreted in large amounts by adipose tissue, they elicit cell growth effects on cancer cells and their productions are altered with obesity.  ADIPO is an inhibitor of cell proliferation via AMPK signaling whose production decreases with adiposity.  Conversely, LEP promotes cell cycle entry via AKT signaling and its levels increase with adiposity.  Thus, in an obese individual, the secretion pattern of ADIPO and LEP is one that will promote cancer growth, compared to a lean individual.

We showed that adipose tissue from obese high-fat diet fed animals alone can promote the growth of MCF7 breast cancer cells, while adipose from lean animals promoted cell cycle exit and quiescence.  These effects were a result, in part, of the antagonistic effects of ADIPO and LEP secreted by the adipose tissue.  These adipose-dependent effects were inhibited by voluntary physical activity in a volume dependent manner, with higher volumes of activity completely abolishing the effects of high fat diet feeding, mediated by predictable responses of adipose tissue to exercise.  The major notable alteration was a decreased LEP and an increased ADIPO secretion into the tumour growth microenvironment by isolated adipose tissue.  This paper was chosen as the APSselect paper of the month for July 2016 and for discussion in a podcast.

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