The metabolic syndrome is composed of cardiovascular risk factors including increased body mass index/waist circumference, blood pressure, plasma glucose, and triglycerides, as well as decreased high-density lipoprotein cholesterol. The essence of the metabolic syndrome lies in the clustering of these risk factors, which are associated with cardiovascular disease. Interestingly, most of the components of the metabolic syndrome have individually been linked in some way to the development of cancer. However, epidemiological studies linking the metabolic syndrome to cancer are scarce. Nevertheless, two such studies indicate that the clustering of metabolic syndrome components significantly increases the risk of colon cancer mortality compared with the individual components. The purpose of this review is to further explore the potential relationship between the metabolic syndrome and cancer risk. Specifically, we examine the hypothesis that individual components of the metabolic syndrome contribute to the development of several processes, including insulin resistance, aromatase activity, adipokine production, angiogenesis, glucose utilization, and oxidative stress/DNA damage, which can work together to increase cancer risk beyond that of the individual components alone. We propose that the metabolic syndrome be considered as a high-risk state for certain types of cancer and that this relationship should be systematically explored across cancer types.

Mice overexpressing progastrin (PG) in intestinal mucosa (fatty acid-binding protein (Fabp)-PG mice) are at an increased risk of proximal colon carcinogenesis in response to azoxymethane. Here, we report a significant increase in the length of proximal colonic crypts in Fabp-PG mice, associated with potent antiapoptotic effects of PG, which likely contributed to the previously reported increase in colon carcinogenesis in Fabp-PG mice. Phosphorylation of kinase of IjBa (IKKa/b), inhibitor of jB (IjB)a and p65NF-jB was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of IjBa and nuclear translocation/activation of p65. Surprisingly, distal colonic crypt cells were not as responsive to elevated levels of PG in Fabp-PG mice. Annexin II, recently described as a high-affinity receptor for PG, strongly colocalized with PG intracellularly and on basolateral membranes of proximal crypt cells, providing evidence that annexin-II binds PG in situ in colonic crypt cells. Proliferative and antiapoptotic effects of PG on proximal crypts of Fabp-PG mice were attenuated to wild-type levels, on treatment with NEMO peptide (an inhibitor of nuclear factor-jB (NF-jB) activation), demonstrating for the first time a critical role of NF-jB in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-jB may significantly reduce the increased risk of colon carcinogenesis in response to PG.

Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearateinduced apoptosis for cancerous versus non-cancerous breast cells has not been examined and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time and dose dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer.

This study sought to determine if weekly X-ray exposure affected breast cancer cell metastasis to bone and to also evaluate the use of bioluminescent imaging (BLI) and microSPECT for detection of metastatic bone lesions. Five week old nude mice were randomly assigned to the CT exposed (n = 7) and no CT exposure (n = 6) treatment groups. Mice received an intracardiac injection of MDA-MB-435 human breast cancer cells transduced with luciferase, or a sham injection (saline). The CT exposed group of mice received CT irradiation once a week for 5 weeks. All mice underwent weekly BLI and select mice received Tc-99m-MDP followed by microSPECT imaging after 5 weeks. Pathological evaluation and histomorphometry were used to assess the affect of CT X-rays on bone metastasis and to evaluate BLI. BLI results found no significant difference in metastasis between animals that received CT and those that did not (P > 0.05); however, histomorphometry of the knee joints revealed a significant increase (P = 0.029) in tumor area of the leg bones in mice that received CT exposure (60% +/- 7%) compared to animals that did not receive CT scans (33% +/- 8%). Compared to histological analysis, BLI of the leg and spine was determined to have excellent sensitivity (100%), good specificity (80-90%) and accuracy (90-96%), a positive predictive value of 81-93% and a 100% negative predictive value. Thus, multi-modality imaging techniques can be very useful for monitoring bone metastasis, however microCT X-rays should be used judiciously in order to limit irradiation that may stimulate increased metastasis to specific regions of the skeleton. MicroSPECT imaging did not detect metastatic lesions in the legs of these young nude mice.

BACKGROUNDThe authors recently reported that gastrin gene knockout (GAS‐KO) mice had an increased risk for colon carcinogenesis in response to azoxymethane (AOM) compared with their wild type (WT) littermates. In the current report, the authors discuss the predisposition of GAS‐KO mice to develop obesity and metabolic hormonal changes that may contribute to their increased risk of colon carcinogenesis.METHODSThe weight and deposition of fat was monitored in the mice over a 14 month period, using magnetic resonance imaging and nuclear magnetic resonance techniques. Changes in plasma concentrations of ghrelin, leptin, insulin, and glucose were assessed using radioimmunoassay analysis and enzyme‐linked immunosorbent assays. Preneoplastic markers of colon carcinogenesis (aberrant crypt foci [ACFs]), in response to AOM, were measured in a subset of obese versus lean GAS‐KO mice and were compared with the markers in WT mice.RESULTSIncreases in visceral adiposity were evident by age 2 months in GAS‐KO mice, resulting in macroscopic obesity by age 7 months. Hyperinsulinemia and insulin:glucose ratios were increased significantly in GAS‐KO mice as young as 1 month and preceded alterations in nonfasting leptin and ghrelin levels. The number of ACFs per mouse colon were increased significantly in the following order: obese GAS‐KO mice > lean GAS‐KO mice > WT mice. Fasting plasma insulin levels were 0.88 ± 0.1 ng/mL, 1.45 ± 0.3, and 2.76 ± 0.9 ng/mL in the WT, GAS‐KO lean, and GAS‐KO obese mice, respectively.CONCLUSIONSThe current results suggest the novel possibility that loss of amidated gastrins may increase adipogenesis, hyperinsulinemia, and colon carcinogenesis in GAS‐KO mice. The increase in colon carcinogenesis may be due in part to hyperinsulinemia, increased obesity, and other associated hormone changes that were measured in GAS‐KO mice. Cancer 2005. © 2005 American Cancer Society.