Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer

Abstract

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.

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

“…4,5 In the present study, hASH1 expression was detected in 4/30 typical carcinoids, 11/13 atypical carcinoids, 38/67 large-cell neuroendocrine carcinomas and 56/78 small-cell carcinomas. Of the 50 non-smallcell lung cancers, only two adenocarcinomas expressed hASH1 in a patchy pattern.…”

“…[1][2][3] The neuroendocrine phenotypes may contribute to the virulence of large-cell neuroendocrine carcinoma and small-cell carcinoma via autocrine loops to promote cell growth and protect tumor cells from apoptosis. 4,5 However, the molecular mechanisms involved in the determination, regulation and maintenance of the neuroendocrine phenotypes of lung cancer remain to be further elucidated.…”

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

“…Particularly, bombesin, gastrin-releasing peptide (GRP), neuromedin B, bradykinin, cholecystokinin (CCK), galanin, neurotensin and vasopressin have been implicated in human small cell lung cancer (SCLC) (Cuttitta et al, 1985;Moody and Cuttitta, 1993;Schuller, 1991a,b;Sethi et al, 1992). Many of these neuropeptides are secreted by tumor-derived cells or by the solid tumor, suggesting an autocrine or paracrine mechanism of action (Sethi and Rozengurt, 1991).…”

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

“…BBS/GRP are neurotransmitters expressed mainly in nerve fibers throughout the mammalian gut and in the central nervous system. In addition to their physiological neuroendocrine actions, BBS/GRP have growth-promoting activity in various cancers, including pancreatic, prostate, mammary and small-cell lung carcinomas, which may secrete BBS/ GRP in an autocrine manner (Cuttitta et al, 1985). Conversely, BBS/GRP antagonists can effectively inhibit tumor growth and slow the progression of premalignant lesions (Iishi et al, 2003;Kanashiro et al, 2003;Yegen, 2003).…”