Thursday, January 20, 2011

Excess Dietary Protein for Cancer Patients May Not Be Advised

Nutritional Determinants of IGF-1 Ligand Expression

As demonstrated in vitro, and given the theoretical propensity of the IGF-1 ligand to circumvent selective blockade in vivo, it becomes important to study potential determinants of elevated IGF-1 expression.

In prospective animal studies, caloric restriction has been shown to prolong overall survival.  Largely as a result of these trials, Caloric Restriction Societies have been created in many major cities.  Geared towards eating exactly 1800 calories per day, members religiously measure, weigh and monitor nutritional intake to ensure that they meet the recommended daily allowances of all important macro and micro nutrients (which is what distinguishes calorie restriction from anorexia).  As a general rule, calorie restrictors avoid refined and processed foods, given the low nutrient/calorie ratios present.

In calorie restricted mice, levels of serum inflammatory markers and IGF-1 levels are uniformly low, with an almost 50% reduction from normal seen in IGF-1 expression1.  Similarly, calorie restrictors show low levels of systemic inflammatory markers, as well as reduced body mass index measurements.  Paradoxically though, in contrast to their animal counterparts, their serum IGF-1  and IGF-1/IGFBP-3 ratios are markedly elevated2.

The same researchers then studied long term raw food vegans, who were age and sex matched to their calorie restricted counterparts.  Raw food vegans also avoid refined and processed foods, in addition to all forms of animal sourced foods (red meat, poultry, fish, and dairy). Though they ate an average of 600-700 more calories per day than their calorie restricted counterparts, this group had low levels of BMI, serum inflammatory markers, as well as systemic IGF-1 levels.

When looking more closely at the total macronutrient intake consumed by both groups, researchers found that the calorie restrictors consumed approximately 25% of their calories from protein2,3 while the vegan protein intake was only 10-12% of calories2.   As a result of this finding, calorie restrictors who then lowered their protein intake to 10% (for a total of 3 weeks, and not by completely vegan or vegetarian means) also saw normalization of their serum IGF-1 levels2. 

Both groups described represent extremes in dietary adherence, and may not reflect the general population consuming the standard american diet.   In normal weight patients without cancer, who consume a regular western diet, IGF-1 as well as IGF-1/IGFBP-3 ratio are elevated at baseline2,3.  In both normal and overweight/obese patients, weight loss by itself does not reduce these levels3-5. 

In an analysis of data from the National Health and Nutrition Examination Survey III (NHANES III), which studied a representative sample of healthy patients in the United States, total dietary protein intake was positive correlated with serum IGF-1 concentrations, and animal protein intake was more correlated with IGF-1 concentrations than vegetable protein, though this correlation was described as weak 6.

1.            Dunn SE, Kari FW, French J, et al. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res. 1997 Nov 1;57(21):4667-72.
2.            Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008 Oct;7(5):681-7.
3.            Racette SB, Weiss EP, Villareal DT, et al. One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci. 2006 Sep;61(9):943-50.
4.            Kaaks R, Bellati C, Venturelli E, et al. Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial. Eur J Clin Nutr. 2003 Sep;57(9):1079-88.
5.            Irwin ML, McTiernan A, Bernstein L, et al. Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors. Cancer Epidemiol Biomarkers Prev. 2005 Dec;14(12):2881-8.

Why IGF-1R Receptor Blockers May Not Work

The Importance of IGF-1 ligand expression in a setting of selective IGF-1R blockade

Though clinical trials are still accruing, the selective blockade of IGF-1R may not be as efficacious as intended.  As suggested by a growing body of basic science literature, IGF-1 ligand can potentially circumvent selective blockade through a number of different mechanisms.

Hybrid Receptors
Many tissues contain hybrid receptors assembled with one chain of the IGF-1R and one of the IR.  IGF-1R/IR-B hybrids have higher affinity for IGF-1, whereas IGF-1R/IR-A hybrids have an equal affinity for IGF-2 and insulin.

In vitro work at MDACC has shown that both IGF and Endothelial Growth Factor (EGF) can induce heterodimerization of the IGF-IR and the EGF Receptor (EGFR). 1 With heterodimerization, IGF can phosphorylate both the IGF-IR as well as EGFR (the converse was not true, in that EGF treatment did not phosphorylate IGF-IR). 1

Stimulation of Alternative Pathways

IGF-1 can also stimulate other pathways important in cancer biology. Stimulation of HNSCC SCC-9 cell lines with IGF-1 Ligand has been shown to upregulate vascular endothelial growth factor (VEGF) promotor activity and subsequent VEGF secretion2.

IRS-1 Deficiency
Some HNSCC cell lines, like those of other cancers, may potentially be IRS-1 deficient.  Without IRS-1, IGF-R sends a signal of differentiation, not mitogenesis.  Thus, IGF-IR blockers will not induce mitogenic downregulation in cells deficient in IRS-1, and in fact, may inhibit the differentiation and growth arrest signaling associated with IGF-1 in these situations. 3,4

Insulin Receptor
Insulin receptor shares 70% homology with IGF-1R.  The functions of the two, though physiologically distinct, are still partially overlapping, with IR capable of stimulating growth and IGF-1R able to regulate a metabolic response.  Activated by multiple IGF’s, IR can can also activate IRS-1, bypassing IGF-1R blockade4.

As demonstrated in vitro, and given the theoretical propensity of the IGF-1 ligand to circumvent selective blockade in vivo, it becomes important to study potential determinants of elevated IGF-1 expression.

1.            Barnes CJ, Ohshiro K, Rayala SK, El-Naggar AK, Kumar R. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res. 2007 Jul 15;13(14):4291-9.
2.            Slomiany MG, Black LA, Kibbey MM, Day TA, Rosenzweig SA. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun. 2006 Apr 14;342(3):851-8.
3.            Sun XJ, Pons S, Wang LM, et al. The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Mol Endocrinol. 1997 Feb;11(2):251-62.
4.            Baserga R. Customizing the targeting of IGF-1 receptor. Future Oncol. 2009 Feb;5(1):43-50.