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Introduction
Insulin-like growth factors (IGFs), especially IGF-1, are of interest because they may explain why many of the therapies that naturopathic doctors have traditionally relied upon with cancer patients may actually work. Understanding IGF function may allow us to optimize current dietary and lifestyle strategies in treating cancer as well as inform dietary recommendations for treating other conditions.
Background
Insulin-like growth factors 1 and 2 are proteins produced by the liver in response to growth hormone produced by the pituitary gland in the brain. These growth factors stimulate development of somatic tissues, in particular skeletal, muscle and bone. In the last 25 years, extensive research has focused on the role IGFs play in cancer and longevity.1
Salmon and Daughaday first hypothesized the existence of the IGFs back in 1957 as they searched for growth hormone (GH) mediators, initially naming the two IGFs "somatomedins A and C."2,3
Significant amounts of IGF are present in the blood, up to 1 mcg/ml, higher concentrations than other hormones. Most IGF is bound to one of six different IGF binding proteins (IGFBPs). These binding proteins regulate the amount of free IGF available to bind to IGF-receptors (IGFRs) on cells. This process is complicated; these binding proteins may lower free IGF serum levels but some also compete for IGF receptor sites and some amplify IGF function.
Both IGF-1 and IGF-2 bind to the IGF-1-receptors, while only IGF-2 binds to the IGF-2-receptor. This second receptor does not appear to do much so is generally ignored (and this may be a mistake).
IGFs mimic insulin in many ways; they increase glucose metabolism, increase glucose transport, inhibit fat breakdown, and increase lipid synthesis, all actions that are "like insulin" but always to a weaker degree than insulin.
IGF-1 plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early in life; it's why babies grow bigger.4
IGFs are curiously not essential for survival. Mice bred without IGF survive but are about half the size of their siblings.5 The drastic variation in size between dog breeds is because of IGF-1 polymorphisms.6
IGF-1 and Cancer Link
Two things pointed to a role of IGF-1 in cancer. People with a genetic disorder causing an IGF-1 deficiency have a very low risk of cancer. Second, epidemiologic data suggest that IGF-1 levels or IGF-1 binding protein levels may be predictive of cancer risk.
In 1966, Israeli endocrinologist Zvi Laron described a genetic condition, which has been since named after him, in which infants are born both deficient and resistant to IGF-1. These babies grow slowly and remain small; as in the IGF-1 deficient mice, about half the size of normal adults.7,8 A cluster of these patients living in a single village in Ecuador was discovered in the 1970s.9,10 Both the initial Israeli patient population that Laron first reported and these Ecuadorians are descendants of Spanish Jews driven out by the Inquisition. Researchers have now tracked the health of 100 of these Ecuadorian Laron syndrome patients for over 2 decades. These individuals do not get diabetes, and rarely if ever get cancer.11 This observation led Harvard researchers to examine epidemiological data, asking whether IGF-1 was predictive of cancer occurrence and prognosis.
In 1998, Chan reported that plasma IGF-1 concentrations were positively associated with development of prostate cancer. Chan also reported that IGFBP-3 levels were inversely associated. The more of this binding protein, the less free IGF-1 would be available to bind to and activate the IGF-1-receptors. Further studies reported a similar reciprocal association between IGF-1 and IGFBP-3 in other cancers including breast, colorectal, and lung.12 More studies quickly followed; high IGF-1 levels were associated with increased risk for most, if not all, cancers, including prostate, colorectal, multiple myeloma, breast, lung cancer, thyroid, bone, brain, and ovarian.13-22 This IGF-1 link to cancer explained why tall children are at greater risk for all types of cancer later in life.23,24 In people who have had cancer, low IGF-1 levels may predict longer survival.25 All this was exciting: IGF-1 and its pathways offered a clear target for cancer prevention and treatment.
Waning Benefit
This initial surge of excitement over the IGF-1 waned a bit in the early 2000s; not all studies found IGF-1 to be as strongly correlated as the first evidence suggested. In fact, it seems that in recent years, the stimulatory effect of IGF-1 on cancer weakened. (This writer suspects this may in part be due to changing dietary habits, in particular increasing carbohydrate intake and resultant increasing prevalence of metabolic syndrome and hyperinsulinemia may account for this shift, but has yet to find published data to support this theory.)
A 2004 meta-analysis by Andrew Renehan, including 21 eligible studies and comparing 3609 cases against 7137 controls, reported that high IGF-1 levels were associated with only a modest increased risk for prostate cancer (odds ratio: 1.49) and for premenopausal breast cancer (OR: 1.65). IGFBP-3 levels were associated with increased risk of premenopausal breast cancer (OR: 1.51) but not postmenopausal.26 In a second meta-analysis two years later, Renehan again only found modest associations, still finding IGF-1 and IGFBP-3 useful in predicting premenopausal but not postmenopausal breast cancer. In 2006 Rinaldi, using data from the EPIC cohort, reported no association in younger women but a positive association for both IGF-1 and IGFBP-3 in women older than 50 years. Eva Schernhammer, using data from the Nurses Health Study II, found no significant associations. In a 2006 commentary, Renehan pointed out that the association between IGF-1 and diagnosis of cancer appeared to be weakening with the passage of time. Still, even in their 2006 analysis, women with high IGF-1 had a 69% greater risk of being diagnosed with breast cancer.27 Roddam, in a 2008 meta-analysis, reported that doubled circulating IGF-I levels, were associated with only a 35% increased risk for prostate cancer.28
Recent studies still do suggest benefits of low IGF-1 for cancer patients. Duggan et al. in 2013 reported that a high IGF-1/IGFBP-3 ratio in women with a history of breast cancer was associated with nearly triple the risk of dying from any cause.29
Unlike some other carcinogenic pathways (such as HER2), mutations of the IGF-1 receptor are not linked to particular cancers. IGF-1 is not oncogenic itself; rather, IGF1-receptor "… signaling appears to be necessary but not sufficient for cancer growth."30 IGF1-receptor signaling appears more important in the growth of carcinomas than in adenomas, particularly in carcinomas that have become resistant to HER2 or EGFR inhibitors.31,32 In speaking with patients I often employ an analogy and liken IGF-1 to Miracle-Gro Plant Food: "It makes what is already there grow faster."
Drugs
IGF-1 receptors became an obvious and exciting target cancer drug development.33-35 Over two dozen monoclonal antibodies targeting IGF-1-receptors have been developed and researched against a range of cancers, including sarcoma prostate, thymus, colorectal, pancreatic, brain, lung, squamous cell, and breast.36,37 Many of these have already reached human trial, including figitumumab, ganitumab, conatumumab, cixutumumab, and dalotuzumab.38-42
While the concept of attacking these IGF pathways looked so exciting in preclinical experiments, results of the "… human clinical trials have been less promising. Despite evidence of some activity in early phase trials, randomized phase III studies have thus far been unable to show a benefit of blocking IGF signaling in combination with conventional strategies. ... This inability to translate the preclinical findings into useful clinical strategies calls attention to the need for a deeper understanding of this complex pathway."43
Researchers used the word futile in describing their attempt to improve outcome in a clinical trial of figitumumab in NSCLC patients when they announced they were discontinuing the trial last year.44,45
"The optimal strategy for targeting IGF signaling in patients with cancer is not clear. The modest benefits reported thus far underscore the need for a better understanding of IGF signaling, which would enable clinicians to identify the subset of patients with the greatest likelihood of attaining benefit from this targeted approach." 46
While the IGF theory sounds great, the drugs have not delivered the expected or promised results.47,48 This may be due to several reasons. First, the drugs may just work too well; IGF-1 plays an important role in preserving health and totally blocking its activity may backfire. Second, the IGF receptors are also sensitive to insulin; and unless insulin is lowered in tandem with IGF-1, something that the drug trials have not considered, we may not see benefit.
Diet needs to not only be considered when attempting to influence IGF-1's role in cancer, it may actually be the more effective way to address this pathway. We can use dietary interventions to lower IGF-1, and we should at the same time also use diet to lower insulin production.
Serum IGF-1 levels increase with animal protein consumption and decrease as consumption is lowered. Dairy protein appears to have the greatest impact. Moderate decreases in animal protein may have greater impact on IGF-1 levels than extreme decreases. Many patients appreciate the news that they need not become absolute vegans.
Two recent studies of particular interest related to IGF-1 are Levine's 2014 paper on animal protein consumption and longevity and Millman's on IGF-1 levels in old age.
Levine reported that high dietary protein intake during middle age increases morbidity and mortality; high-protein diets are associated with a 75% increase in overall mortality and a 4-fold increase in risk of cancer death. Low protein during middle age is associated with lower mortality. The authors attribute all these effects to dietary protein raising IGF-1.49
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