Transforming growth factor-beta and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo

Liver cancer and gastric cancer are the most common solid tumors worldwide. Transforming growth factor-beta (TGF-beta) production and lack of response to TGF-beta growth inhibitory effects have been associated with tumor prog ression and therapeutic resistance. HepG2, Hep3B, and SK-HEP-1 human liver cancer lines produce 3, 5.7, and 2.5 ng TGF-beta 1; 1.4, 2, and 4 ng TGF-be ta 2 and 0.15, 0.2 and 0.22 ng TGF-beta 3 per 10(7) cells (24 h). Expressio n of the TGF-beta type I receptor is 20x, 1x, and 0.6x the level in mink lu ng MvLu1 cells in the HepG2, Hep3B, and SK-HEP-1 cells, respectively. HepG2 and Hep3B cells do not express the TGF-beta type II receptor while SK-HEP- 1 cells express 7x the level found in mink lung MvLu1 cells. Hs 746T, KATO III, RF-1, and RF-48 human gastric cancer cell lines produce 12.5, 0.35, 0. 4, and 0.4 ng TGF-beta 1; 2.6, 0.95, 0.5, and 0.52 ng TGF-beta 2 and 0.42, 0.17, 0.12, and 0.14 ng TGF-beta 3 per 10(7) cells (24 h). Expression of TG F-beta type I receptor is 0.7x, 0.7x, 0.8x, 0.6x the level in mink lung MvL u1 cells in the Ks 746T, KATO III, RF-1 and RF-48 cells, respectively. KATO III cells are lacking in the TGF-beta type II receptor while Hs 746T, RF-1 and RF-48 cells express 10x, 0.8x, and 1x the levels in mink lung MvLu1 ce lls. The IC50 for TGF-beta 1 is >>10 ng/ml in all of these lines except RF- 48 where TGF-beta 1 is mitogenic. The response of the cell lines to radiati on, doxorubicin, mitomycin C, cisplatin, 5-fluorouraciI, methotrexate, and gemcitabine showed that SK-HEP-1 was the most drug resistant liver cancer c ell line and KATO III was the most drug resistant gastric cancer cell line. Overall, there was no correlation between TGF-beta secretion in cell cultu re and sensitivity of the cells to anticancer agents. Increased TGF-beta 1 levels were detectable in the plasma of nude mice bearing Hep3B and Ks 746T xenografts. Those tumors which secreted greater amounts of TGF-beta were m ore therapeutically resistant in vivo.