Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

Abstract

BackgroundTumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment.MethodsTumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 μM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry.ResultsAdhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 μM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes.ConclusionWe conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.

Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas

“…However, not all immunosuppressants necessarily promote cancer development. While mycophenolate mofetil has some capacity to reduce tumor cell proliferation (15,16), rapamycin exhibits impressive inhibitory effects on cancer development. Rapamycin inhibits angiogenesis and tumor cell proliferation (15,17,18), leading to impaired inoculated tumor growth in mice and de novo tumor development in a p53-null mice (19).…”

Altered expression of β1 integrins in renal carcinoma cell lines exposed to the differentiation inducer valproic acid

“…Although integrin receptors undoubtly play a dominant role during tumor cell-endothelial cell interaction, the biphasic alterations verified in our study rule out that integrins exclusively serve as mechanistic adhesion elements. We have presented evidence in an earlier study that adhesion blockade of DU-145 prostate tumor cells is accompanied by a dose-dependent up-regulation of integrin ß1 subtypes (15). Consequently, down-regulation of ß1 integrin family members allowed prostate tumor cells to become more invasive and led to an increased propensity for metastasis (16).…”

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

“…Данные о проонкогенном и антионкогенном эффекте производ-ных микофеноловой кислоты противоречивы как по клиническим данным, так и в исследованиях in vitro. Если в одних исследованиях in vitro их применение усиливало митогенные процессы и инвазивность опухолевых клеток [51,52], то в других, напротив, предотвращало опухолевую диссеминацию [53,54]. Кроме того, известно, что микофенолаты усиливают противогерпетическую активность ацикловира и ган-цикловира, потенциально снижая вероятность ПТЛЗ, индуцированных вирусом Эпштейна-Барр [55].…”