Metabolic Aspects of Cancer
Tumor development is influenced by the endocrine and metabolic environment. This section reviews the potential role of hyperglycemia and the insulin/IGF axis. Cancers rely on anaerobic glycolysis for their energy needs, but are normally able to extract all the glucose they need at normoglycemic levels. Consistent with this, glucose control has not been shown to modify cancer risk in diabetes. Both diabetes and obesity are associated with hyperinsulinemia and increased IGF levels. Many cancers overexpress receptors for insulin, including the insulin receptor A (normally found only in fetal life), together with the IGF-1 receptor and hybrid insulin/IGF-1 receptors. Increased insulin/IGF signalling harnesses the proproliferative actions of the two hormones to maximize cell reproduction. Insulin is not required for glucose entry or utilization in cancer tissues, but anaerobic glycolysis allows glucose to be used as a substrate for synthesis of (e.g.) nucleotides as well as meeting the energy requirents of the cell. Cancer cells thus hijack metabolic pathways needed for growth and reproduction and use glucose as a substrate as well as a fuel. The high levels of insulin and IGFs seen in diabesity are thought to play an important role in promoting cancer development; hyperglycemia appears less important.
Endocrine, metabolic and paracrine influences upon cancer development
Cancer cells often develop the ability to appropriate cell signalling mechanisms for their own growth and development. These signals may derive from circulating hormones or local growth factors.
Increasing age is the most consistent risk factor for cancer development, and almost certainly represents the accumulation over time of cascades of somatic mutations predisposing to cancer. Cancer research in recent decades has focused largely upon these mutations, but there is increasing awareness that, although mutations accumulate in the aging population in stochastic fashion, their progression is largely dependent upon environmental influences.
Autopsy studies have revealed that initiating mutations are common in the aging population; examples include prostate, breast, colon and pancreatic cancer. The progression of such potentially malignant cell foci to clinical cancer is heavily depended upon the environment. Environmental influences in their turn impact upon cancer cells by modulating the metabolic and endocrine milieu within which these cells develop.
Almost all cancers, for example, are less likely to develop in those taking a low calorie diet; conversely, about 40% of cancers are associated with overnutrition and obesity. Type 2 diabetes, an obesity-related condition, is associated with a similar increase in risk. This page of Diapedia will consider the potential role of glucose, insulin and the IGFs in cancer growth and progression.
Hyperglycemia and Cancer
The first issue to consider is the role of glucose, the hallmark of diabetes, in mediating the growth of diabetes-related cancers. Two considerations appear to support a causal role for hyperglycemia:
The first derives from epidemiologic observations linking blood glucose levels to cancer risk, even within the non-diabetic range.
The second lies in the observation that cancer cells are glucose-dependent and obtain their energy requirements from fermentation; in other words they perform anaerobic glycolysis in the presence of oxygen. It might therefore be anticipated that such cells would grow faster in a high glucose environment.
The switch to an anaerobic pattern of glucose metabolism is indeed advantageous for rapidly proliferating cells, since it enables them to convert nutrients into biomass efficiently, but glucose transport into cancer cells is already maximal at normal levels of circulating glucose. This implies that such cells will gain no further advantage from hyperglycemia.
In support of these pathophysiological observations, meta-analysis of clinical trials of glucose-lowering therapies in type 2 diabetes has shown no diminution of cancer risk. See Hyperglycemia and cancer
Hyperinsulinemia and Cancer
There is a strong overlap between the risks of cancer conferred by diabetes and obesity. The risk of cancer is also increased in those with other featurs of the metabolic syndrome. Since hyperinsulinemia is also strongly associated with all these conditions, it has been proposed that that this might be the common soil from which cancer risk is derived.
The "hyperinsulinemia" or "insulin-cancer" hypothesis proposes that chronic hyperinsulinemia, as seen in type 2 diabetes and other conditions associated with insulin resistance, may influence cancer development both directly (by acting as a growth factor for cancer cells) and indirectly by reducing the binding of IGF1 and IGF2 to their carrier proteins, thus increasing local tissue availability of these peptides.
The hypothesis is strongly supported by the observation that diabetes and obesity-related cancers typically over-express both the insulin and IGF receptors, profiting from the growth signals which each of these can deliver.
The hyperinsulinemia hypothesis is supported by epidemiological data showing that hyperinsulinemia, raised C-peptide and markers of insulin resistance are all associated with increased cancer risk.
The insulin/IGF-1 receptors share a common ancestry, and there is minor overlap between their actions
The metabolic actions of insulin are mediated by the PI3 kinase route, and the growth actions by MAP kinase
The PI 3-kinase route is predominantly affected in insulin resistance, and hyperinsulinemia produces greater activity via the MAP-kinase route
Overexpression of insulin and IGF-1 receptors on tumor cells
Role of the Insulin-like Growth Factors
IGF1 and its receptor share a common ancestry with insulin, differentiating early in vertebrate evolution in order to subserve specialized growth functions. Unlike insulin, the IGFs are constitutionally secreted by liver and other cells, and are bound to specialized carrier proteins.
The IGF axis is complex and incompletely understood. This is because they act both as local growth factors, whose effects in any given tissue is influenced both by local concentrations and tissue-specific effects, and as hormones available to the body as a whole.
IGF2 plays a key role in fetal life and early childhood, but pituitary growth hormone drives production of IGF1 as the pituitary develops, and this assumes a more prominent developmental role. Levels of IGF1 vary widely with age, nutrition, physiological condition and disease, whereas IGF2 is relatively invariant.
How strong is the evidence?
At levels of obesity BMI >28 concentrations of IGFBP1 and IGFBP2 begin to fall and free IGF1 levels in the serum increase. Increasing total IGF1 levels predict prostate, breast and colorectal cancers. Acromegaly is associated with a two-fold increase in the risk of colorectal cancer. Associations between free IGF1 levels, or circulating levels of IGFBP-1 and IGFBP-2 are however weak and inconsistent.
There is thus good circumstantial evidence to support the insulin-cancer hypothesis, but the mechanisms linking hyperinsulinemia and/or raised levels of the IGFs with cancer remain undefined and their clinical relevance is unclear5. Nonetheless, the insulin/IGF axis has attracted considerable research interest as a potential route to novel cancer therapies 1.
^ Holly JMP. Cancer as an endocrine problem. Best Pract Res Clin Endocrinol Metab 2008;22:539-550
^ Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841
^ Vander Heiden MG et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33
^ Renehan AG et al. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 2006;17:328-336
^ Pisani P. Hyperinsulinemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem 2008;114:63–70.
^ Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nature Reviews Cancer 2009;8:915-28
^ Holly JMP, Perks C. IGF what we have learned from human studies. Endocrinol Metab Clin North Am. 2012 Jun;41(2):249-63