Autocrine and paracrine signaling through neuropeptide receptors in human cancer

Abstract

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common theme in human cancers. In addition to polypeptide growth factors such as EGF family members which signal through receptor tyrosine kinases, accumulating evidence supports the autocrine and paracrine involvement of speci®c neuropeptides with de®ned physiologic actions as neurotransmitters and gut hormones in lung, gastric, colorectal, pancreatic and prostatic cancers. These neuropeptides, including gastrin-releasing peptide, neuromedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric G proteins. Studies with human small cell lung cancer (SCLC) cells support a requirement for balanced signaling through G q and G 12/13 proteins leading to intracellular Ca 2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While speci®c neuropeptide antagonists o er promise for interrupting the single neuropeptide autocrine systems operating in pancreatic and prostatic cancers, SCLC is exempli®ed by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single speci®c antagonist. However, a novel class of neuropeptide derivatives based on the substance P sequence have been de®ned that exhibit broad speci®city for neuropeptide receptors and induce apoptosis in SCLC by functioning as biased agonists that stimulate discordant signal transduction. Thus, interruption of autocrine and paracrine neuropeptide signaling with speci®c antagonists or broad-spectrum biased agonists o er promising new therapeutic approaches to the treatment of human cancers. Oncogene (2001) 20, 1563 ± 1569.

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

“…Polypeptide growth factors such as stem cell factor (SCF) and fibroblast growth factor-2 (FGF-2) induce a variety of responses in human SCLC cells, including growth and proliferation, chemoresistance and motility (Heasley, 2001;Pardo et al, 2001Pardo et al, , 2002Arcaro et al, 2002). Activation of two major intracellular signalling pathways, the mitogen-activated Erk kinase (MEK)/ extracellular signal-regulated kinase (Erk) and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathways have been shown to mediate SCLC responses to polypeptide growth factors and thus represent attractive targets for the development of new drugs targeting SCLC in patients (Pardo et al, 2001(Pardo et al, , 2002Arcaro et al, 2002;Krystal et al, 2002).…”

Galanin and galanin receptor expression in neuroblastic tumours: correlation with their differentiation status

“…In animal models, direct paracrine effects have already been demonstrated in differentiating and regenerating neurones (Zigmond and Sun, 1997;Holmes et al, 2000), in the pituitary and in various brain nuclei (Todd et al, 1998). In several human cancers, autocrine or paracrine overactivation of neuropeptide G-protein-coupled receptors, including those of galanin, could contribute to neoplasia (Heasley, 2001;Marinissen and Gutkind, 2001). Moreover, some neuropeptide analogues induce apoptosis in cancer cells where neuropeptide autocrine and paracrine systems are involved (Heasley, 2001).…”

“…In several human cancers, autocrine or paracrine overactivation of neuropeptide G-protein-coupled receptors, including those of galanin, could contribute to neoplasia (Heasley, 2001;Marinissen and Gutkind, 2001). Moreover, some neuropeptide analogues induce apoptosis in cancer cells where neuropeptide autocrine and paracrine systems are involved (Heasley, 2001).…”

“…The different transduction pathways specifically associated with the different galanin receptors may selectively account for distinct biological activities, including cell-survival and neurite-outgrowth, and for neuropeptide-stimulated growth of cancer cells (Heasley, 2001). The biological activities of Gal-R1 and -R3 receptors are mediated by Gi/G0 G-proteins, leading to the inhibition of adenylate cyclase (Kolakowski et al, 1998).…”

“…Gal-R2 expression in GN indicates that its associated signalling pathway might also be involved in NT cell differentiation. Thus, galanin receptors may be a useful therapeutic target in neuroblastoma; in human cancers involving neuropeptide receptors system, novel molecules have been defined to selectively induce/inhibit one of the G-protein signalling (Heasley, 2001). …”