Growth Characteristics of Rectal Carcinoid Tumors

Shimizu, Toshihiko; Tanaka, Shinji; Haruma, Ken; Kitadai, Yasuhiko; Yoshihara, Masaharu; Sumii, Koji; Kajiyama, Goro; Shimamoto, Fumio

doi:10.1159/000012166

Cited by 63 publications

(39 citation statements)

References 21 publications

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“…Rectal NETs that are > 5 mm in size have been reported to express TGFα more frequently, and the epidermal growth factor (EGF) receptor was expressed in all lesions (Shimizu et al 2000). It has therefore been proposed that TGFα and the EGF receptor may participate in an autocrine mechanism that regulates the growth of hindgut NETs, and hence these hindgut tumours are likely to develop via different molecular pathways from those of the foregut and midgut NETs (Shimizu et al 2000).…”

Section: Hindgut Netsmentioning

confidence: 99%

Genetics of neuroendocrine and carcinoid tumours.

Leotlela

Jauch²,

Holtgreve-Grez³

et al. 2003

Endocrine-Related Cancer

150

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Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-α and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-β, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.

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Section: Hindgut Netsmentioning

confidence: 99%

Genetics of neuroendocrine and carcinoid tumours.

Leotlela

Jauch²,

Holtgreve-Grez³

et al. 2003

Endocrine-Related Cancer

150

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“…Moreover, EGFR (over-) expression has been correlated with disease stage, reduced survival, development of tumour metastases and tumour differentiation in various cancers (Baselga, 2002;Di Lorenzo et al, 2002;Peghini et al, 2002). Several reports indicate that EGFR are expressed frequently in NE tumours in general (Wang et al, 1997;Ezzat, 2001), and in gastrointestinal NE tumours in particular (Nilsson et al, 1993(Nilsson et al, , 1995Ö berg, 1994;Shimizu et al, 2000;Peghini et al, 2002). In addition, EGFR contributes to the growth characteristics of NE tumours (Nilsson et al, 1995;Wulbrand et al, 1998;Peghini et al, 2002).…”

mentioning

confidence: 99%

A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839)

et al. 2003

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Therapeutic options to inhibit the growth and spread of neuroendocrine (NE) gastrointestinal tumours are still limited. Since gefitinib (4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline), an inhibitor of epidermal growth factor receptorsensitive tyrosine kinase (EGFR-TK), had been shown to suppress potently the growth of various non-NE tumour entities, we studied the antineoplastic potency of gefitinib in NE gastrointestinal tumour cells. In human insulinoma (CM) cells, in human pancreatic carcinoid (BON) cells and in NE tumour cells of the gut (STC-1), gefitinib induced a time-and dose-dependent growth inhibition by almost 100%. The antiproliferative potency of gefitinib correlated with the proliferation rate of the tumour cells. So the IC 50 value of gefitinib was 4.770.6 mM in the fast-growing CM cells, still 16.870.4 mM in the moderate-growing BON cells, and up to 31.572.5 mM in the slow-growing STC-1 cells. Similarly, the induction of apoptosis and cell-cycle arrest by gefitinib differed according to growth characteristics: fast-growing CM cells displayed a strong G0/G1 arrest in response to gefitinib, while no significant cell-cycle alterations were seen in the slow-growing STC-1. Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells. Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib. Among them, an upregulation of the growth arrest and DNA damage-inducible gene GADD153 was observed. Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner. However, no gefitinib-induced activation of the GADD153-inducing p38 mitogen-activated protein kinase was detected. Our data demonstrate that the inhibition of EGFR-TK by gefitinib induces growth inhibition, apoptosis and cell-cycle arrest in NE gastrointestinal tumour cells. Thus, EGFR-TK inhibition appears to be a promising novel approach for the treatment of NE tumour disease.

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“…[133] In rectal NENs TGF-α expression seemed to be increased in lesions larger than 5 mm and tumors with higher Ki67 index. [135] Despite the heterogeneity of these results, EGFR and its signal transduction pathways (RAS-RAF-MAPK) might represent an interesting target for the treatment of NETs.…”

Section: Vegf and Its Receptor Inhibitorsmentioning

confidence: 99%

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

Torniai¹,

Rinaldi²,

Morgese³

et al. 2016

JCMT

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Neuroendocrine tumors (NETs) represent a spectrum of rare neoplasms arising in different organism sites. Depending on the site of onset, they also can be distinguished using lab exams (secreting vs. nonsecreting), clinical symptoms (functioning vs. nonfunctioning), behavioral, morphological characteristics (tumor cells' architectural growth patterns, mitotic and Ki-67 index, presence of necrosis), and grade of cellular differentiation. The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) neuroendocrine neoplasms. The scientific literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases, selecting principal and more recent research articles, clinical trials, and updated guidelines. Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs. The pathogenesis of NETs has been the subject of increased interest in recent years. Many driver mutations pathway genes have been identified as important factors in the carcinogenesis process and, therefore, as potential targets for new anticancer therapies. Activating mutations have been shown in epidermal growth factor receptor, stem cell factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, basic-fibroblastic growth factor, transforming growth factor, insulin-like growth factor-1, and their receptors. Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this field such as everolimus. New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.

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Growth Characteristics of Rectal Carcinoid Tumors

Cited by 63 publications

References 21 publications

Genetics of neuroendocrine and carcinoid tumours.

Genetics of neuroendocrine and carcinoid tumours.

A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839)

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

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