Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

Abstract

Foregut Neuroendocrine Tumors[NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor(EGFR) by growth factors, gastrointestinal(GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid, BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

Neurotensin, a novel target of Wnt/β‐catenin pathway, promotes growth of neuroendocrine tumor cells

“…In contrast, we evaluated the autocrine/paracrine effect of NT by interfering with the endogenous NT in NET cells which produce and secrete NT. 15, 21, 24 Di Florio et al 25 showed that several GI hormones and neurotransmitters, including NT, have growth-inducing effects on foregut NETs and that these effects are highly dependent on transactivation of the EGF receptor by direct treatment.…”

Role of tumor microenvironment in tumorigenesis

“…In addition to targeted therapy, peptide receptor radionuclide therapy is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic NE tumors patients 241. Some studies have found that EGF receptor inhibition may disrupt some signaling cascades, which may inhibit the growth of foregut NE tumors/pancreatic NE tumors 242. Another result also proved that PRCRT is an effective treatment in patients with FDG-avid NE tumors, even in patients for whom conventional therapies have failed243.…”

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

“…These include pheochromocytomas[63, 165], gastric-cancer[166, 167•], cervical-cancer[168], choriocarcinoma-cells[169], neuroendocrine-tumors[60•, 62, 170] and renal-cancer[59, 171•, 172]. …”

“…VIP stimulates growth of many tumors including breast, lung, pancreas, prostate, in addition to various CNS tumors(gliomas, astrocytomas, etc), [38, 45•, 53, 54•, 55-57], as well as having an inhibitory-effect on the growth of other tumors(retinoblastoma, renal cell[58, 59]. PAC1-activation also stimulates growth of a number of tumors including neuroendocrine, brain, breast, prostate, pancreatic, colon and lung[45•, 60•, 61-62]; differentiation of pheochromocytoma cells(PC-12)[63], and has a growth inhibitory effect on some neoplasmas(medulloblastoma, gliomas)[64, 65]. …”