Neurotensin and growth of normal and neoplastic tissues
Introduction
Neurotensin (NT), a tridecapeptide originally isolated from bovine hypothalamus extracts by Carraway and Leeman [12], is localized mainly in the central nervous system (predominantly hypothalamus and pituitary) and in endocrine cells (N cells) of the jejunum and ileum [64], [66]. NT is released in response to increased intraluminal fats [29] and has numerous physiologic functions in the gastrointestinal (GI) tract including effects on GI motility [4], [84], stimulation of pancreatic and biliary secretion [6], [72], [90], facilitation of fatty acid translocation from the intestinal lumen [5], [49], [77], [83], and growth stimulation of various GI tissues as well as other tissues such as the adrenal gland, hepatocytes, and fibroblasts. In the central nervous system (CNS), NT has a neurotransmitter function and is involved in inhibition of dopaminergic pathways [10], [49].
NT is produced from a single precursor, pre–pro-neurotensin, that contains both NT 1–13 and the related peptide, neuromedin N [8], [17], [49], [68]. Neuromedin N has a peripheral distribution similar to that of NT and, in fact, has subsequently been found to be tandemly positioned with NT near the carboxy terminus of the precursor protein [9], [17], [18], [48]. A better understanding of the effects of NT in the GI tract and CNS has been greatly facilitated by the cloning of the NT/neuromedin N (NT/N) gene [8], [9], [17], [18], [48], [68], the cloning of the high- and low-affinity NT receptors [56], [63], [80], [87], [88], [89], and the development of NT receptor antagonists [34], [35].
This overview focuses on the trophic effects of NT, both on normal and neoplastic tissues. Where appropriate, a discussion regarding signaling pathways will be included; however, a more in-depth discussion of second messenger systems affected by NT as well as the various NT receptors will be presented in other articles of this issue.
Section snippets
Proliferation of nonneoplastic tissues and cells
NT stimulates the proliferation of a number of nonneoplastic tissues. The most pronounced effects of NT on nonmalignant tissue growth are noted in the small bowel mucosa. In addition, NT has been reported to stimulate the growth of the colon, pancreas, stomach, adrenal cortex, as well as fibroblasts and hepatocytes.
Proliferation of neoplastic tissues
The endocrine control of certain cancers, most notably breast and prostate, has been well characterized and forms the basis of current therapies for these diseases. In a manner analogous to breast and prostate cancers, cancers of the GI tract and pancreas as well as the lung have been shown to possess receptors for various GI hormones including NT [27], [38], [83]. NT may have an effect on these tumors in a classic endocrine fashion, with secretion of endogenous NT leading to increased tumor
Conclusions
The NT peptide stimulates the growth of various nonneoplastic and neoplastic tissues, predominantly through the high-affinity NT receptor. The trophic effects of NT on normal intestinal mucosa suggest that NT may be useful in the stimulation of intestinal growth during periods of gut disuse, after small bowel resection, or with administration of chemotherapeutic agents. Furthermore, blocking NT receptors using potent receptor antagonists may be useful as adjuvant therapy in the treatment of
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