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


METHODS
Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 microM 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.


RESULTS
Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 muM 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.


CONCLUSIONS
We 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.
Engl
Tobias
T
Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. engl@em.uni-frankfurt.de <engl@em.uni-frankfurt.de>
Makarević
Jasmina
J
Relja
Borna
B
Natsheh
Iyad
I
Müller
Iris
I
Beecken
Wolf-Dietrich
WD
Jonas
Dietger
D
Blaheta
Roman A
RA
D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D039222:Integrin alpha1beta1 / Q000378:metabolism; D038982:Integrin alpha2beta1 / Q000378:metabolism; D039201:Integrin alpha3beta1 / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D019038:Platelet Glycoprotein GPIb-IX Complex; D012333:RNA, Messenger / Q000378:metabolism
D007166:Immunosuppressive Agents; D039222:Integrin alpha1beta1; D038982:Integrin alpha2beta1; D039201:Integrin alpha3beta1; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D019012:Integrin beta1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D012333:RNA, Messenger; C094990:adhesion receptor; D009173:Mycophenolic Acid