Diabetes and cancer are two heterogeneous, multifactorial, severe, and chronic diseases. Because of their frequency, reciprocal influences – even minor influences – may have a major impact. Epidemiological studies clearly indicate that the risk of several types of cancer (including pancreas, liver, breast, colorectal, urinary tract, and female reproductive organs) is increased in diabetic patients. Mortality is also moderately increased. Several confounding factors, having general or site-specific relevance, make it difficult to accurately assess cancer risk in diabetic patients. These factors include diabetes duration, varying levels of metabolic control, different drugs used for therapy, and the possible presence of chronic complications. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic but also mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. Obesity, hyperglycemia, and increased oxidative stress may also contribute to increased cancer risk in diabetes. While anti-diabetic drugs have a minor influence on cancer risk (except perhaps the biguanide metformin that apparently reduces the risk), drugs used to treat cancer may either cause diabetes or worsen a pre-existing diabetes. In addition to the well-known diabetogenic effect of glucocorticoids and anti-androgens, an increasing number of targeted anti-cancer molecules may interfere with glucose metabolism acting at different levels on the signaling substrates shared by IGF-I and insulin receptors. In conclusion, diabetes and cancer have a complex relationship that requires more clinical attention and better-designed studies.
Paolo Vigneri, Francesco Frasca, Laura Sciacca, Giuseppe Pandini, and Riccardo Vigneri
Roberta Malaguarnera, Angelo Mandarino, Emanuela Mazzon, Veronica Vella, Piero Gangemi, Carlo Vancheri, Paolo Vigneri, Alessandra Aloisi, Riccardo Vigneri, and Francesco Frasca
Inactivation of p53 and p73 is known to promote thyroid cancer progression. We now describe p63 expression and function in human thyroid cancer. TAp63α is expressed in most thyroid cancer specimens and cell lines, but not in normal thyrocytes. However, in thyroid cancer cells TAp63α fails to induce the target genes (p21Cip1, Bax, MDM2) and, as a consequence, cell cycle arrest and apoptosis occur. Moreover, TAp63α antagonizes the effect of p53 on target genes, cell viability and foci formation, and p63 gene silencing by small interfering (si) RNA results in improved p53 activity. This unusual effect of TAp63α depends on the protein C-terminus, since TAp63β and TAp63γ isoforms, which have a different arrangement of their C-terminus, are still able to induce the target genes and to exert tumour-restraining effects in thyroid cancer cells. Our data outline the existence of a complex network among p53 family members, where TAp63α may promote thyroid tumour progression by inactivating the tumour suppressor activity of p53.