Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster.

Dear Editor, The question we address here is what drives cancer to grow in an accelerated fashion as it evolves. Various proposals have been made regarding the possible drivers of cancer growth such as driver mutations and autonomous growth signaling. While these are clearly relevant, they rely too much on specific types of genomic mutations or molecular abnormalities by chance across different cancer types, which makes the probability for cancer to occur/progress significantly lower than what we have witnessed about the current cancer occurrence rates worldwide, hence making them less probable to be the ultimate drivers of cancer growth (Loeb, 1998). We present here a model for the (accelerated) growth of a cancer based on the discovered gene-expression patterns derived from genome-scale transcriptomic data of seven solid carcinoma types, namely breast, kidney, liver, lung, ovary, pancreatic, and stomach cancers. Our data analysis clearly indicates that as a cancer advances, (i) its percentage of cells in the G0 phase of the cell cycle tends to become increasingly lower, indicating accelerated cell proliferation; (ii) when the hypoxia level goes up, the activity level of oxidative phosphorylation as the main energy (ATP) producer goes down and that of glycolysis goes up, which triggers cancer cells to accelerate the uptake of glucose from the blood circulation to make up for the lost efficiency in energy production, needed for them to stay viable; (iii) this switch in energy metabolisms leads to accelerated cell proliferation and further increased hypoxia, forming a vicious cycle of (accelerated) growth of cancer; (iv) this cycle breaks down when the new angiogenesis takes place triggered by the high hypoxia level, which decreases the hypoxia level and switches back to oxidative phosphorylation as the main energy producer and continues until the cells become too hypoxic again; and (v) the cellular hypoxia level goes up and down ‘periodically’ that coincides with the increasing cancer mass and new angiogenesis, respectively, while its overall trend is going up. Hypoxia has long been linked to cancer growth, including its link to the activation of glycolysis and angiogenesis, de-acidification of cancer cells, tumor promotion, and the emergency DNA repair mechanism. The relationship between hypoxia and the (gradual) switch in energy metabolisms from oxidative phosphorylation to glycolysis has been widely studied and well established (Harris, 2002). However, there have not been any published studies aimed to explain how hypoxia drives the growth and accelerated growth of a cancer, to the best of our knowledge. Glycolysis has been a focus of cancer study since 1920s when Warburg (1956) discovered that glycolysis is active in cancer cells even in the presence of oxygen. The current understanding about this is that aerobic glycolysis provides a powerful way to generate carbon skeletons for biosynthesis of amino acids and lipids needed for rapid cell proliferation, and it is substantially faster in ATP generation than oxidative phosphorylation when glucose is abundant (DeBerardinis et al., 2007; Koppenol et al., 2011). The key contribution made in this study is that our model represents the first one for explaining what possibly drives cancer growth/accelerated growth and how, which is supported by genome-scale transcriptomic data of seven solid cancer types. A key internal driver, that we found, is that the reduced energy efficiency (caused by hypoxia and/or possibly other factors) triggers increased uptake and accumulation of glucose, leading to cell proliferation. Our model does not require genomic mutations but it allows the growing process of a cancer to positively select mutations that may give the cells a competitive edge, such as multiplications of oncogenes and deleterious mutations of tumor suppressor genes. Previous studies have suggested that cancer tends to grow increasingly faster as it evolves (Hanahan and Weinberg, 2011). To check whether this is purely due to the exponential growth with a stable cell-division rate or compounded with accelerated cell division, we have examined whether the cell division of a cancer is accelerated or not as the hypoxia level increases. We first estimated the relative cell cycle rate and its change versus cancer stages by checking the percentage of cells in a cell population (e.g. a tumor sample) in the G0 phase, using a marker gene VRK1 for phase transition from G0 to G1 (Valbuena et al., 2008), as well as the cyclin genes that are involved in the subsequent phase transitions of cell cycle. From Figure 1A, we can clearly see overall up-going trends of the expression levels of these cell cycle genes with high statistical significance as a cancer evolves for each cancer type, indicating increased cell cycle rates in all the seven cancers. We have also checked the change of these expression levels versus the change of the hypoxia level. Here we used the expression level of the hypoxia marker gene HIF1A to reflect the level of hypoxia. All the seven cancers show an 174 | Journal of Molecular Cell Biology (2012), 4, 174–176 doi:10.1093/jmcb/mjs017 Published online April 20, 2012