Transforming growth factor-β1 and -β2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro.
Transforming growth factor-β1 (TGF-β1) and -β2 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-β1 and -β2 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-β concentration was detected by enzyme-linked immunosorbent assays. AGS and MKN45 cell lines were directly or indirectly cocultured with PBMCs in vitro. TGF-β 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-β1 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 (χ² = 9.487, P = 0.002). All tissues were positive for TGF-β2. TGF-β1 mRNA levels were increased in advanced cancers, while TGF-β2 increased earlier. TGF-β1 mRNA levels were higher in tumor than in peritumor, which positively correlated with Smad2 and Smad7. Serum TGF-β levels were significantly higher in patients with early and advanced cancers compared to controls (TGF-β1∶50.08±4.38 and 45.76±5.00 vs. 27.78±6.11 ng/mL; TGF-β2∶133.61±21.90 and 111.34±15.76 vs. 59.41±15.42 ng/mL, both P<0.05). The levels of TGF-β1 mRNA and cytokine secretion were higher in GC cells after direct coculture compared to indirect culture. TGF-β1 was decreased and TGF-β2 was increased in PBMCs after cocultures. Moreover, TGF-β1 inhibited the viability of PBMCs but not cancer cells. Collectively, neoplastic transformation may be an early event involving the increase of TGF-β1 in the general and local environment. TGF-β1 production is promoted by the direct interaction between GC cells and PBMCs, which might facilitate cancer development.
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Gui-Fen
GF
Ma
Qing
Q
Miao
Xiao-Qing
XQ
Zeng
Tian-Cheng
TC
Luo
Li-Li
LL
Ma
Yi-Mei
YM
Liu
Jing-Jing
JJ
Lian
Hong
H
Gao
Shi-Yao
SY
Chen
D000328:Adult; D000368:Aged; D002460:Cell Line; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000097:blood / Q000378:metabolism*
D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2