Neuroendocrine tumors of the digestive system : Modulation of apoptosis and factors associated with growth regulation during biotherapies

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Neuroendocrine tumors of the gut have the potential to create life-threatening syndromes which become difficult to treat. Tumor mass reduction, by medical therapy, is one of the choices of treatments. Induction of apoptosis and modulation of factors related to apoptosis as well as different growth regulatory factors by treatment, alters tumor growth and improves symptoms.Interferon-α (IFN-α), somatostatin analogs and combination of both were used for medical treatment. Increased apoptosis was observed in 62% of patients who demonstrated a biochemical response to the treatment of high dose (12mg/day) of somatostatin analog, lanreotide. There was no significant change in apoptotic index with neither IFN-α, low dose somatostatin analog nor combination treatment. The xenographated tumors (BON-1 cell line) and in vitro test showed increased tumor growth inhibition with combination therapy of IFN-α and somatostatin analog even at a low dose (p=0.0011 & p<0.001 respectively). IFN-α did not increase apoptosis but induced the bcl-2 gene in patients responding to the treatment. This finding correlates with the inhibition of cell cycle progression, a described function of IFN-α. Carcinoid tumors, in patients with stable disease condition, expressed another apoptosis modulator bcl-xL, which is suitable as a prognostic marker. In endocrine pancreatic tumors, the adhesion molecule CD44 expression was analyzed. Variant isoforms of CD44, v6 and v9 expression were inversely correlated to malignant transformation (p=0.0352 and 0.0266 respectively) which are suitableas prognostic indicators.Interferon induced protein, MxA, expression was studied in 122 patients with neuroendocrine tumors. All of the patients were treated with IFN-α and showed MxA expression at the mRNA level with no correlation to the clinical outcome of the treatment and thus MxA is not suitable as a predictive marker for treatment response.

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