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Adrenocortical carcinoma (AC) is a rare tumor with poor prognosis. Twenty-two patients (14 F, 8 M; age 22 to 59 years; median, 43 years) with AC were evaluated prospectively in a single center: tumor stage was I-II in 12 cases and III-IV in 10. The overall survival in our cohort was 41.6 +/- 42 months; 16 subjects are still alive. Curative surgery was followed by longer survival than debulking or no surgery (p < 0.0001). The first relapse was highly predictive for further recurrences. Recurrent ACs were progressively more aggressive, and they occurred with variable but ever shorter intervals. At diagnosis, 14 patients (63.5%) presented with features of clear adrenocortical hyperactivity. Despite the absence of clinical signs of hormonal excess, all other patients presented some abnormalities of steroid secretion. The most common clinical finding was a recent diagnosis of moderate-to-severe hypertension (68%), poorly controlled by pharmacological treatment, often associated with multiple cardiovascular risk factors. High mitotic rate and undifferentiated polymorph cellular pattern were associated with worse prognosis. Response to treatments other than surgery (mitotane chemotherapy) was better in patients treated early after the first surgery. In conclusion, curative surgery was the most effective treatment. Monitoring arterial pressure, endocrine parameters, and metabolic parameters can be helpful for the early detection of AC recurrences.

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We recently demonstrated in an immortalized thyroid cell line that integrin stimulation by fibronectin (FN) simultaneously activates two signaling pathways: Ras/Raf/MAPK kinase (Mek)/Erk and calcium Ca2+/calcium calmodulin-dependent kinase II (CaMKII). Both signals are necessary to stimulate Erk phosphorylation because CaMKII modulates Ras-induced Raf-1 activity. In this study we present evidence that extends these findings to normal human thyroid cells in primary culture, demonstrating its biological significance in a more physiological cell model. In normal thyroid cells, immobilized FN-induced activation of p21Ras and Erk phosphorylation. This pathway was responsible for FN-induced cell proliferation. Concurrent increase of intracellular Ca2+ concentration and CaMKII activation was observed. Both induction of p21Ras activity and increase of intracellular Ca2+ concentration were mediated by FN binding to alphavbeta3 integrin. Inhibition of the Ca2+/CaMKII signal pathway by calmodulin or CaMKII inhibitors completely abolished the FN-induced Erk phosphorylation. Binding to FN induced Raf-1 and CaMKII to form a protein complex, indicating that intersection between Ras/Raf/Mek/Erk and Ca2+/CaMKII signaling pathways occurred at Raf-1 level. Interruption of the Ca2+/CaMKII signal pathway arrested cell proliferation induced by FN. We also analyzed thyroid tumor cell lines that displayed concomitant aberrant integrin expression and signal transduction. These data confirm that integrin activation by FN in normal thyroid cells generates Ras/Raf/Mek/Erk and Ca2+/CaMKII signaling pathways and that both are necessary to stimulate cell proliferation, whereas in thyroid tumors integrin signaling is altered.