Nerve Growth Factor as a Mitogen for a Pancreatic Carcinoid Cell Line

Abstract: Carcinoid tumors are a group of neuroendocrine neoplasms distributed widely throughout the body but most commonly occurring in the gut. These tumors retain many characteristics of their neural crest origin, including secretion of neuroactive peptides and responsiveness to neurotrophic substances. Nerve growth factor (NGF), a neurotrophic protein involved in maintenance and differentiation of peripheral sympathetic and sensory neurons, regulates growth of several neural tumor cells by inducing a differentiated phenotype and subsequent inhibition of cell growth rate. We examined the actions of NGF in a functioning human pancreatic carcinoid cell line (termed BON). NGF has no effect on the cytoarchitecture or constitutive secretion of bioamines in this carcinoid cell line. NGF, however, stimulates the in vitro cellular proliferation of BON cells. BON cells possess mRNA for the NGF receptors (p75LNGFR and p140trkA) and membrane‐associated tyrosine kinase activity is increased in response to NGF. Both the mitogenic activity of NGF, as well as the receptor‐linked tyrosine kinase activity, can be abrogated in BON cells by the trkA inhibitor K‐252a and specific anti‐NGF antibody. Our studies demonstrate that NGF is a mitogen for this carcinoid cell line without effect on cellular phenotype or cytoarchitecture. NGF may play a role in the development and progression of human carcinoid tumors.

[1]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[2]  R. Jaenisch,et al.  Dependence on p75 for innervation of some sympathetic targets. , 1994, Science.

[3]  B. Haber,et al.  Characterization of a Human Pancreatic Carcinoid in Vitro: Morphology, Amine and Peptide Storage, and Secretion , 1994, Pancreas.

[4]  R. Cancedda,et al.  Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulates their growth by a novel autocrine loop. , 1993, The Journal of biological chemistry.

[5]  M. Chao,et al.  Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Dominici,et al.  Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. , 1993, Cancer research.

[7]  V. Cherington,et al.  Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  F. Hefti,et al.  K‐252 Compounds: Modulators of Neurotrophin Signal Transduction , 1992, Journal of neurochemistry.

[9]  M. Barbacid,et al.  Nerve growth factor mediates signal transduction through trk homodimer receptors , 1992, Neuron.

[10]  M. Sliwkowski,et al.  Biochemical Characterization of Recombinant Human Nerve Growth Factor , 1992, Journal of neurochemistry.

[11]  E. Shooter,et al.  The nerve growth factor family of receptors , 1992, Trends in Neurosciences.

[12]  A. Ullrich,et al.  Growth factor signaling by receptor tyrosine kinases , 1992, Neuron.

[13]  A. Saltiel,et al.  Nerve growth factor stimulates the activities of the raf-1 and the mitogen-activated protein kinases via the trk protooncogene. , 1992, The Journal of biological chemistry.

[14]  E. Shooter,et al.  The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Barbacid,et al.  K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors. , 1992, Oncogene.

[16]  D. Sternberg,et al.  K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. , 1992, The Journal of biological chemistry.

[17]  B. Evers,et al.  Expression of neurotensin messenger RNA in a human carcinoid tumor. , 1991, Annals of surgery.

[18]  J. Wrathall,et al.  Regulation of growth by a nerve growth factor-like protein which modulates paracrine interactions between a neoplastic epithelial cell line and stromal cells of the human prostate. , 1991, Cancer research.

[19]  M. Bothwell.  Keeping track of neurotrophin receptors , 1991, Cell.

[20]  M. Barbacid,et al.  The trk proto-oncogene encodes a receptor for nerve growth factor , 1991, Cell.

[21]  B. Haber,et al.  The effect of somatostatin on 5-hydroxytryptamine release from a carcinoid tumor. , 1990, Surgery.

[22]  A. Dahlström,et al.  Presence of nerve growth factor‐like immunoreactivity in carcinoid tumour cells and induction of a neuronal phenotype in long‐term culture , 1989, International journal of cancer.

[23]  M. Barbacid,et al.  Molecular and biochemical characterization of the human trk proto-oncogene , 1989, Molecular and cellular biology.

[24]  T. H. Wareing,et al.  Carcinoids and the carcinoid syndrome. , 1983, American journal of surgery.

[25]  R. Levi‐montalcini,et al.  Nerve growth factor. , 1975, Science.

[26]  A. Dahlström,et al.  Production of transferable neuronotrophic factor(s) by human midgut carcinoid tumour cells; studies using cultures of rat fetal cholinergic neurons. , 1991, Acta physiologica Scandinavica.

[27]  M. Barbacid,et al.  A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences , 1986, Nature.

[28]  R. M. Jager,et al.  Carcinoid apudomas. , 1977, Current problems in cancer.