Transforming growth factor (TGF-β).
TGF-β is a complex cytokine regulating a variety of biologic functions in healthy individuals including embryonic development, cellular proliferation and differentiation, angiogenesis, and wound healing. Among its properties, TGF-β is antiproliferative, promotes production and deposition of extracellular matrix proteins, inhibits production of enzymes that degrade extracellular matrix, stimulates angiogenesis, and dampens immune surveillance by inhibiting the function of lymphocytes. A multitude of evidence indicates that dysregulation of TGF-β production or signaling promotes tumorigenesis (42
). Along these lines, mutations in the TGF-β pathway can result in impaired cell cycle regulation resulting in uncontrolled proliferation while overproduction of TGF-β by tumor cells can promote angiogenesis, invasion and metastases. Suthanthiran and colleagues (43
) demonstrated that CS induces marked morphologic changes that confer an invasive phenotype on a nontransformed human pulmonary adenocarcinoma cell line, A-549. It was further demonstrated that CS-stimulated secretion of TGF-β by the A-549 cells, that anti-TGF-β antibodies could prevent the CS-induced morphologic changes, and that recombinant TGF-β could recapitulate the phenotypic changes induced by CS. In vivo
studies showed that CS enhanced invasion and increased metastases of murine renal cell adenocarcinoma (Renca) cells, murine Lewis lung carcinoma cells, and human bladder transitional carcinoma cells in an immunodeficient SCID-beige mouse model. Finally, anti- TGF-β antibodies could reverse the metastatic-promoting activity of CS in vivo
. The induction of TGF-β by CS may be a general property of calcineurin inhibitors since more recent studies indicate that tacrolimus also induces TGF-β production and promotes tumor progression in murine models of renal cell lung metastases (44
). Interestingly, the effect of the novel immunosuppressant Rapamycin appears to be the opposite of CS, that is, Rapamycin was found to suppress TGF-β and angiogenesis (19