Evaluation of the interaction between TGF beta and nitric oxide in the mechanisms of progression of colon carcinoma.
It is recognised that stromal cells determine cancer progression. We have previously shown that active TGFbeta produced by rat colon carcinoma cells modulated NO production in rat endothelial cells. To elucidate the role of TGFbeta and NO in the mechanisms of interaction of colon carcinoma cells with stromal cells and in cancer progression, we transfected REGb cells, a regressive colon carcinoma clone secreting latent TGFbeta, with a cDNA encoding for a constitutively-secreted active TGFbeta. Out of 20 injected rats only one tumour progressed, which was resected and sub-cultured (ReBeta cells). ReBeta cells secreted high levels of active TGFbeta. The adhesive properties of REGb and Rebeta cells to endothelial cells were similar, showing that the secretion of active TGFbeta is not involved in tumour cell adhesion to endothelial cells. ReBeta, but not REGb, cell culture supernatants inhibited cytokine-dependent NO secretion by endothelial cells, but inhibition of NO production was similar in co-cultures of REGb or ReBeta cells with endothelial cells. Therefore, secretion of active TGFbeta regulated endothelial NO synthase activity when tumour cells were distant from, but not in direct contact with, endothelial cells. However, only ReBeta cells inhibited cytokine-dependent secretion of NO in coculture with macrophages, indicating that the active-TGFbeta-NO axis confers an advantage for tumour cells in their interaction with macrophages rather than endothelial cells in cancer progression.
Lohm
Sylvia
S
University Institute of Pathology, Bugnon 25, CH-1011, Lausanne, Switzerland.
Peduto-Eberl
Lucie
L
Lagadec
Patricia
P
Renggli-Zulliger
Nicole
N
Dudler
Jean
J
Jeannin
Jean-François
JF
Juillerat-Jeanneret
Lucienne
L
D000818:Animals; D002277:Carcinoma / Q000378:metabolism* / Q000556:secondary; D002448:Cell Adhesion; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016212:Transforming Growth Factor beta; D009569:Nitric Oxide