Increased transforming growth factor beta expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells.
Several observations correlate increased expression of transforming growth factor (TGF) beta 1 with tumorigenesis, suggesting that expression of this multifunctional growth factor may provide an advantage in tumor formation. However, many tumor cells are inhibited in their proliferation by TGF-beta in vitro, thus suggesting that TGF-beta synthesis could exert an antiproliferative effect on tumor formation. To evaluate the physiological relevance of increased TGF-beta 1 synthesis in such tumor cells which are strongly inhibited in their proliferation by TGF-beta, we chose Meth A sarcoma cells as a model system. We established cell clones overexpressing TGF-beta 1 and determined its effect on tumor formation in mice that are not immunocompromised. Increased expression of biologically active TGF-beta 1 resulted in a profound growth inhibition in the transfected clones and increased adhesiveness in vitro. However, these cells were much more tumorigenic than Meth A cells that did not overexpress TGF-beta 1, as assessed by both tumor incidence and tumor growth. In addition, parental Meth A cells were inhibited in their tumor formation by neutralizing TGF-beta antibodies and stimulated by exogenous TGF-beta. Our results thus provide evidence that increased TGF-beta synthesis provides a major advantage for tumorigenesis, even if the cells are growth inhibited by their endogenous TGF-beta synthesis in culture. These results suggest that, in vivo, direct effects of TGF-beta on the tumor environment, such as increased extracellular matrix formation and cell-matrix interactions, and local suppression of the immune surveillance may provide a growth advantage which overrules any direct antiproliferative effects of TGF-beta, as suggested by the effects in culture.
Chang
H L
HL
Department of Cell Biology, Genentech Inc., South San Francisco, California 94080.
Gillett
N
N
Figari
I
I
Lopez
A R
AR
Palladino
M A
MA
Derynck
R
R
D000818:Animals; D002455:Cell Division; D005260:Female; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013163:Splenomegaly / Q000209:etiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D016212:Transforming Growth Factor beta; D008748:Methylcholanthrene