Transforming growth factor-ß1 and -ß2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro.

ABSTRACT

Transforming growth factor-ß1 (TGF-ß1) and -ß2 are correlated with poorer prognosis in gastric cancer (GC), which act in both tumor and immune cells. However, their expressions in precancer and tumor-cell interactions with peripheral blood mononuclear cells (PBMCs) remain unclear. Protein levels of TGF-ß1 and -ß2 were analyzed by immunohistochemistry and corresponding mRNA levels were determined by quantitative real-time polymerase chain reaction in 93 surgical and biopsy specimens. Serum TGF-ß concentration was detected by enzyme-linked immunosorbent assays. AGS and MKN45 cell lines were directly or indirectly cocultured with PBMCs in vitro. TGF-ß and Smad molecules were detected after cocultures and the growths of GC cells and PBMCs were assessed by cell proliferation assay. The results showed positive staining for TGF-ß1 was detected in 20% of control samples, 52.3% of precancer, 59.1% of early GC and 66.7% of advanced GC samples, correlated with lesion progression (χ²â€Š= 9.487, P = 0.002). All tissues were positive for TGF-ß2. TGF-ß1 mRNA levels were increased in advanced cancers, while TGF-ß2 increased earlier. TGF-ß1 mRNA levels were higher in tumor than in peritumor, which positively correlated with Smad2 and Smad7. Serum TGF-ß levels were significantly higher in patients with early and advanced cancers compared to controls (TGF-ß1∶50.08±4.38 and 45.76±5.00 vs. 27.78±6.11 ng/mL; TGF-ß2∶133.61±21.90 and 111.34±15.76 vs. 59.41±15.42 ng/mL, both P<0.05). The levels of TGF-ß1 mRNA and cytokine secretion were higher in GC cells after direct coculture compared to indirect culture. TGF-ß1 was decreased and TGF-ß2 was increased in PBMCs after cocultures. Moreover, TGF-ß1 inhibited the viability of PBMCs but not cancer cells. Collectively, neoplastic transformation may be an early event involving the increase of TGF-ß1 in the general and local environment. TGF-ß1 production is promoted by the direct interaction between GC cells and PBMCs, which might facilitate cancer development.