Autocrine and paracrine signaling through neuropeptide receptors in human cancer

Autocrine and paracrine signaling leading to stimulation of tumor cell grow th is a common theme in human cancers. In addition to polypeptide growth fa ctors such as EGF family members which signal through receptor tyrosine kin ases, accumulating evidence supports the autocrine and paracrine involvemen t of specific neuropeptides with defined physiologic actions as neurotransm itters and gut hormones in lung, gastric, colorectal, pancreatic and prosta tic cancers. These neuropeptides, including gastrin-releasing peptide, neur omedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bi nd seven transmembrane-spanning receptors that couple to heterotrimeric G p roteins. Studies with human small cell lung cancer (SCLC) cells support a r equirement for balanced signaling through G(q) and G(12/13) proteins leadin g to intracellular Ca2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While specific neuropeptide antagonists of fer promise for interrupting the single neuropeptide autocrine systems oper ating in pancreatic and prostatic cancers, SCLC is exemplified by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single specific antagonist. However, a novel class of neur opeptide derivatives based on the substance P sequence have been defined th at exhibit broad specificity for neuropeptide receptors and induce apoptosi s in SCLC by functioning as biased agonists that stimulate discordant signa l transduction, Thus, interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.