PTEN link between cancer and diabetes

Abstract

New research has linked mutations in tumour suppressor PTEN to enhanced insulin sensitivity, and suggests that mutations paradoxically cause an increased risk of obesity and cancer while decreasing risk of type 2 diabetes. Aparna Pal and colleagues (Oxford, UK) show just how intimately linked pathways involved in metabolism and cell growth might be. They support the idea that epidemiological and genetic associations between cancer and type 2 diabetes could be based on common signalling pathways linking tumour-suppressor genes to metabolic pathways involved in insulin action. PTEN antagonises the PI3K pathway and has a role in both the cell cycle and metabolic pathways. Loss-offunction mutations in PTEN cause the rare cancer-predisposition Cowden syndrome, and, via the PI3K pathway, PTEN has also been implicated in type 2 diabetes. Pal and colleagues measured insulin sensitivity in 15 patients with Cowden syndrome and 15 matched controls. Insulin signalling was measured in muscle and adipose tissue from fi ve patients and fi ve matched controls. Insulin resistance was reduced in the patients compared with controls, with mean fasting plasma insulin levels of 29 pmol/L in patients compared with 74 pmol/L in controls (p=0·001). This reduction was due to increased activity in the insulin signalling pathway. The eff ect of PTEN haploinsuffi ciency on obesity was also assessed. PTEN carriers were obese (mean BMI of 32), whereas controls were not (26; p<0·001). Christos Mantzoros, from Harvard Medical School (MA, USA) believes the research contributes signifi cantly to furthering understanding of molecular mechanisms linking metabolism and cell growth. “It not only improves our understanding of the pathophysiology but also potentially off ers new opportunities for cancer detection and treatment,” he said. Pier Paolo Pandolfi , (Harvard Medical School) concurs, “This study lends further support to the notion that pharmacologic approaches geared at achieving systemic PTEN elevation should be rigorously pursued and thoroughly tested [for] the prevention of cancer and obesity”. Development of PTEN inhibitors to treat type 2 diabetes has been considered, but study investi gator Anna Gloyn thinks the study discourages this viewpoint by showing adverse “on target” eff ects of possible therapeutic interven tion on this particular pathway. “The evidence is now very strong that manipulation of this pathway leads to oncogenic side eff ects”, she said, suggesting insulin sensitiser metformin might be a safer option.