Ursolic acid from Trailliaedoxa gracilis induces apoptosis in medullary thyroid carcinoma cells.

Medullary thyroid carcinoma (MTC) originates from the C‑cells of the thyroid and is not sensitive to radiation or chemotherapy. Therefore, surgical removal of the tumor tissue in its entirety is the only curative treatment for MTC. The present study aimed to examine the potential mechanisms of action of extracts of Trailliaedoxa gracilis (TG; WW Smith & Forrest), a plant from the province of Sichuan, China, and of ursolic acid (UA), a pentacyclic triterpen present in TG, on the MTC‑SK MTC cell line.

Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation.

Introduction: Chromogranin A is a neuroendocrine secretory product and its loss is a feature of malignant NEN de-differentiation. We hypothesized that chromogranin A fragments were differentially expressed during NEN metastasis and played a role in the regulation of NEN proliferation.

Methods: Chromogranin A mRNA (PCR) and protein (ELISA/western blot) were studied in 10 normal human mucosa, 5 enterochromaffin cell preparations, 26 small intestinal NEN primaries and 9 liver metastases.

The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.

Objective: We recently demonstrated that hypoxia, a key feature of IBD, increases enterochromaffin (EC) cell 5-HT secretion, which is also physiologically regulated by the ADORA2B mechanoreceptor. Since hypoxia is associated with increased extracellular adenosine, we wanted to examine whether this nucleotide amplifies HIF-1α-mediated 5-HT secretion.

Design: The effects of hypoxia were studied on IBD mucosa, isolated IBD-EC cells, isolated normal EC cells and the EC cell tumor derived cell line KRJ-1.

Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors.

Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT₇ receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion.

Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors.

The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O(2). Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O(2) would reduce 5-HT production and secretion.

Comparison of PCR-based detection of chromogranin A mRNA with traditional histological lymph node staging of small intestinal neuroendocrine neoplasia.

Background: Accurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining.

Microencapsulation of small intestinal neuroendocrine neoplasm cells for tumor model studies.

Basic cancer research is dependent on reliable in vitro and in vivo tumor models. The serotonin (5-HT) producing small intestinal neuroendocrine tumor cell line KRJ-1 has been used in in vitro proliferation and secretion studies, but its use in in vivo models has been hampered by problems related to the xeno-barrier and tumor formation. This may be overcome by the encapsulation of tumor cells into alginate microspheres, which can function as bioreactors and protect against the host immune system.

A water soluble tri-cationic porphyrin-EDTA conjugate induces apoptosis in human neuroendocrine tumor cell lines.

In this study, a completely water soluble tri-cationic porphyrin-EDTA conjugate was synthesized. We present data demonstrating the tumoristatic effects of the novel fully water soluble cationic porphyrin TMPy(3)PhenEDTA-P-Cl(4) in the dark, in the medullary thyroid carcinoma cell lines MTC-SK and SHER-I and weaker effects in the small intestinal neuroendocrine tumor cell line KRJ-I. In addition, cytotoxic effects were also studied in normal human fibroblasts that represent normal tissue and the results are compared to the tumor cell lines.

The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms.

Background: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) exhibit widely divergent behavior, limited biologic information (apart from Ki-67) is available to characterize malignancy. Therefore, the identification of alternative biomarkers is a key unmet need. Given the role of internexin alpha (INA) in neuronal development, the authors assessed its function in neuroendocrine cell systems and the clinical implications of its expression as a GEP-NEN biomarker.

Gene network inference and biochemical assessment delineates GPCR pathways and CREB targets in small intestinal neuroendocrine neoplasia.

Small intestinal (SI) neuroendocrine tumors (NET) are increasing in incidence, however little is known about their biology. High throughput techniques such as inference of gene regulatory networks from microarray experiments can objectively define signaling machinery in this disease. Genome-wide co-expression analysis was used to infer gene relevance network in SI-NETs.

Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT.

Background: Treatment of small intestinal neuroendocrine tumors (SINETs) with mammalian target of rapamycin (mTOR) inhibitors alone or with somatostatin analogs has been proposed as effective therapy, because both agents have been reported to exhibit antiproliferative activity. Because adenocarcinomas escape mTOR inhibition, we examined whether the escape phenomenon occurred in SINETs and whether usage of somatostatin analogs with mTOR inhibitors surmounted loss of inhibition.

Methods: The effects of the somatostatin analog octreotide (OCT), the mTOR inhibitor RAD001 (RAD), or the combination were evaluated in SINET cell lines (KRJ-I, H-STS) using cell viability assays, western blotting, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction to assess antiproliferative signaling pathways and feedback regulation.

The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors.

Chromogranin A, although it exhibits limitations, is currently the most useful general tumor biomarker available for use in the diagnosis and management of gastroenteropancreatic neuroendocrine tumors (NETs). The value of the chromogranin A lies in its universal cosecretion by the majority of neuroendocrine cells that persists after malignant transformation. Clinicians aware of the physiologic role of chromogranin A and its secretion in a variety of non-NET-related pathologic conditions can use this protein as a moderately effective tumor biomarker in the management of GEP-NETs.

The epidemiology of gastroenteropancreatic neuroendocrine tumors.

In this article, updated analyses of the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registry (1973-2007) are presented and compared with epidemiologic GEP-NET data from Europe and Asia. Several studies have demonstrated a steadily increasing incidence of GEP-NETs, and this escalation is still ongoing (SEER data 2004-2007). The common primary GEP-NET sites exhibit unique epidemiologic profiles with distinct patterns of incidence, age at diagnosis, stage, and survival.

The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors.

Background: Recent data demonstrate that the incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased exponentially (overall ~500%) over the last three decades, thus refuting the erroneous concept of rarity. GEP-NETs comprise 2% of all malignancies and in terms of prevalence, are the second commonest gastrointestinal malignancy after colorectal cancer. Diagnosis is usually late since there is no biochemical screening test and symptoms are protean and overlooked.

A clinical perspective on gastric neuroendocrine neoplasia.

The incidence of gastric neuroendocrine tumors (NETs) has increased exponentially based on widespread use of endoscopy and a greater pathological awareness of the condition. A key concern is the potential association with hypergastrinemia induced by proton pump inhibitor administration. Previous confusion regarding diagnosis and therapy has been diminished by a series of international consensus statements defining the biology and management strategies for the disease.

A nomogram to assess small-intestinal neuroendocrine tumor ('carcinoid') survival.

Neuroendocrine tumors (NETs) are a heterogeneous group of cancers of which the commonest site is the small intestine (SI). Most information available to determine tumor behavior reflects univariate assessment of factors or is anecdotal or experience based. There currently exists no objective multivariate analysis of indices that defines SI NET prognosis.

The 5-HT(2B) receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment.

Background: Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI-NETs) both in local peritumoral tissue and systemic sites (cardiac). 5-HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the tumor microenvironment are unclear. We hypothesized that targeting 5-HT(2B) receptors on tumor cells would inhibit SI-NET 5-HT release and, thereby, fibroblast activation in the tumor microenvironment.

Anticancer activity of novel plant extracts from Trailliaedoxa gracilis (W. W. Smith & Forrest) in human carcinoid KRJ-I Cells.

Background: Small intestinal (SI) neuroendocrine tumors (NETs) are rare neoplasms derived from neuroendocrine cells presenting distinct clinical symptoms according to the ability to secrete neuroamines. Nevertheless, many are asymptomatic and misdiagnosed. As response rates to chemotherapy are low, surgery remains the only effective treatment.

Asymmetrically substituted cationic indole- and fluorene porphyrins inhibit tumor proliferation in small intestinal neuroendocrine tumors and medullary thyroid carcinomas.

In this study we demonstrate anticancer activity of novel fully water soluble cationic porphyrins. The two cationic porphyrins 5,10,15-tris(N-methylpyridinium-4-yl)-20-[1-phenyl-4-(3-N-phenylsulfonylindolyl)]-21H,23H-porphyrin chloride (TMPy(3)PhenIndolprot(1)P-Cl(3)) and 5-{5-[2-(9,9-Dimethyl)fluorenyl]-N-methylpyridinium-3-yl}-10,15,20-tris(N-methyl-pyridinium-4-yl)-21H,23H-porphyrin chloride (TMPy(3)PyFluorenyl(1)P-Cl(4)) were prepared and their antiproliferative effects were studied in two human tumor cell lines and a normal human fibroblast cell line. Effects of the novel porphyrin compounds were evaluated in the small intestinal neuroendocrine tumor cell line KRJ-I, the medullary thyroid carcinoma cell line MTC-SK and the normal human fibroblast cell line HF-SAR by cell counting, cell proliferation assays and cell cytotoxicity analyses.

Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines.

Background: : Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not altered significantly (5-year survival rate: GI NETs, 64.1%; BP NETs, 87%-89%) in 30 years (from 1973 to 2004). No effective or specific antineoplastic agents are available to date, although somatostatin analogs inhibit NET 5-hydroxytryptophan (5-HT) secretion.

Anticancer activity of novel extracts from Cautleya gracilis (Smith) Dandy: apoptosis in human medullary thyroid carcinoma cells.

Background: Medullary thyroid carcinoma (MTC) is a calcitonin-producing tumor of the thyroid arising from the parafollicular C-cells. MTC is poorly responsive to chemotherapy and radiotherapy, hence the only effective therapy is surgery. Based on this fact, alternative strategies have been sought.