Sethi, Tariq Jabbar; (1993) Small cell lung cancer cells: Stimulation by multiple neuropeptides and inhibition by broad spectrum antagonists. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Human small cell lung cancer (SCLC) constitutes 25[percent] of lung cancers and follows an aggressive clinical course. SCLC is characterised by the presence of intracytoplasmic neurosecretory granules and by its ability to secrete many hormones and neuropeptides. Only bombesin-like peptides, which include gastrin-releasing peptide (GRP), have been shown to act as autocrine growth factors for certain SCLC cell lines. This thesis focused on other neuropeptides and particularly their ability to mediate SCLC growth. The neuropeptides bradykinin, cholecystokinin (CCK), GRP, neurotensin and vasopressin at nanomolar concentrations stimulated an increase in the intracellular concentration of calcium ([Ca2+]i), inositol phosphate hydrolysis, and increased colony formation in semi-solid medium in responsive SCLC cell lines. These results suggest that multiple Ca2+-mobilising neuropeptides stimulate SCLC growth by an extensive network of autocrine and paracrine interactions. With tumour progression these neuropeptides have increased potency. Galanin a 29 amino-acid peptide opposes Ca2+ signals and modulates the action of other neuropeptides in various cellular systems. Thus the effect of galanin in SCLC cell lines was investigated. Surprisingly, galanin increased rather than decreased [Ca2+]i, and stimulates the production of inositol phosphates in certain SCLC cell lines. In view of the Ca2+-mobilizing actions of galanin, the effect on SCLC growth was tested. Galanin stimulates clonal growth in SCLC cells, further supporting the proposition that SCLC growth is stimulated by multiple autocrine/paracrine interactions involving Ca2+ mobilizing neuropeptides. This is the first time that galanin is shown to evoke inositol phosphate, Ca2+ mobilisation and growth responses in any cell type. Gastrin, CCK and CCK-related peptides have identical carboxy-terminal amino-acid structure. SCLC cells are shown to express two distinct functional CCK receptor subtypes, CCKA and gastrin/CCKB receptors, both of which increase [Ca2+]i and stimulate clonal growth. The cDNA of the gastrin/CCKB receptor was cloned and sequenced. Northern blot analyses revealed a single transcript of 2.4 kb in SCLC. The levels of RNA expression match directly with the ability of these SCLC cells to respond to gastrin. This is the first time that CCKA and gastrin/CCKB receptors are shown to stimulate growth outside the gastointestinal system. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D- Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) block bradykinin, CCK, galanin, gastrin, GRP, neurotensin and vasopressin mediated signals and growth in SCLC cell lines, and inhibit SCLC growth in vitro and in vivo. Thus, broad spectrum neuropeptide antagonists constitute potential anticancer agents.

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