Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer.
The autocrine hypothesis proposes that a cell produces and secretes a hormone-like substance that can interact with specific membrane receptors on its surface to induce effects such as proliferation. Thus, a cancer cell could act to stimulate its own growth. Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing peptide (GRP) cause various physiological responses in mammals, including stimulation of proliferation of 3T3 mouse fibroblasts and normal human bronchial epithelial cells in vitro and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats. Human small-cell lung cancer (SCLC) cell lines produce and secrete BLPs and can express a single class of high-affinity receptors for BLPs. Exogenously added BLPs can also stimulate the clonal growth and DNA synthesis of SCLC in vitro. These findings suggest that BLPs function as autocrine growth factors for this tumour. One way to test this hypothesis is to interrupt the function of the endogenously produced BLPs. Here, we demonstrate that a monoclonal antibody to bombesin binds to the C-terminal region of BLPs, blocks the binding of the hormone to cellular receptors and inhibits the clonal growth of SCLC in vitro and the growth of SCLC xenografts in vivo. These results demonstrate that BLPs can function as autocrine growth factors for human SCLC.
Cuttitta
F
F
Carney
D N
DN
Mulshine
J
J
Moody
T W
TW
Fedorko
J
J
Fischler
A
A
Minna
J D
JD
D000818:Animals; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006133:Growth Substances; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000494:pharmacology*; D018004:Receptors, Bombesin; D011956:Receptors, Cell Surface / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D006133:Growth Substances; D010455:Peptides; D018004:Receptors, Bombesin; D011956:Receptors, Cell Surface; D001839:Bombesin