title: PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target.
abstract: Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p = 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p = 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.
authors.affiliation: a Abramson Family Cancer Research Center; Department of Cancer Biology ; University of Pennsylvania School of Medicine ; Philadelphia , PA USA.
authors.forename: Buddha
authors.initials: B
authors.lastname: Gurung
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
authors.forename: Melissa
authors.initials: M
authors.lastname: Runske
authors.forename: Bonita
authors.initials: B
authors.lastname: Bennett
authors.forename: Virginia
authors.initials: V
authors.lastname: LiVolsi
authors.forename: Robert
authors.initials: R
authors.lastname: Roses
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Fraker
authors.forename: David C
authors.initials: DC
authors.lastname: Metz
mesh_terms: D000328:Adult; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009377:Multiple Endocrine Neoplasia / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface
keywords: ACTH, Adrenocorticotrophic hormone; BCNS, basal cell nevus syndrome; CgA, chromogranin A; HH, hedgehog; IHC, immunohistochemical; MEN-1; MEN-1, multiple neuroendocrine tumor syndrome type 1; NF-1, neurofibromatosis type 1; PNET, pancreatic neuroendocrine tumor; PRRT, peptide radioreceptor therapy; PTCH 1, protein patched homolog 1; SMO, smoothened; VHL, von Hippel Lan- dau; WHO, World Health Organization; hedgehog; neuroendocrine; pancreas