The role of transforming growth factor alpha in the enterochromaffin- like cell tumor autonomy in an African rodent mastomys

Tang, Lars Hermann; Modlin, I M; Lawton, Gary P.; Kidd, Mark; Chinery, Rebecca

doi:10.1053/gast.1996.v111.pm8898635

Cited by 36 publications

(25 citation statements)

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“…These findings confirm that of a previous small-sized study that also showed expression of CTGF-IR cells in ECL-CCs (Kidd et al 2007a,b), and also the data reported from the Mastomys model of ECL cell neoplasia, showing that CTGF transcript and CTGF protein are overexpressed in ECL tumour cells compared with normal ECL cells (Tang et al 1996, Kidd et al 2007a. Furthermore, we demonstrated that CTGF was present in tumours larger than 5 mm, and its expression was correlated with a tumour size O1 cm but only in type I ECL-CCs.…”

Section: Discussionsupporting

confidence: 90%

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Kaltsas¹,

Cunningham²,

Falkmer³

et al. 2010

Endocrine Related Cancer

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Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; nZ58) and midgut NETs (nZ38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.

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Section: Discussionsupporting

confidence: 90%

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Kaltsas¹,

Cunningham²,

Falkmer³

et al. 2010

Endocrine Related Cancer

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“…6 Western Blot Analysis KRJ-I cells (2 3 10 6 KRJ-I cells in log phase growth: n ¼ 3) were prepared as previously described. 43 Cells were snap-frozen in liquid nitrogen and homogenized using a mortar and pestle before the addition of RIPA buffer. Protein concentration was assayed using the Bio-Rad protein assay (Bio-Rad).…”

Section: Sequence Analysismentioning

confidence: 99%

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Kidd

Modlin

Pfragner

et al. 2007

Cancer

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Objective To examine whether and to what extent the intracellular trafficking features of HLA–B*2705, which is associated with the development of spondylarthritis (SpA), differ from those of HLA–B*2709 and HLA–B*0702, which are not associated with SpA. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to Renilla luciferase or yellow fluorescent protein. The subcellular distribution of properly folded and unfolded/misfolded HLA–B proteins was examined by flow cytometry and confocal microscopy of cells labeled with ME1 and HC‐10 antibodies, respectively. HLA–B/HLA–B interactions were monitored in endoplasmic reticulum (ER)– and plasma membrane–enriched subcellular fractions, by bioluminescence resonance energy transfer (BRET). Results All 3 HLA–B alleles displayed a similar distribution pattern (properly folded heavy chain at the cell surface, unfolded/misfolded proteins only in the cytoplasm). By means of BRET, we provided evidence that both HLA–B*2705 and HLA–B*2709 formed more oligomers in the ER and the plasma membrane than did HLA–B*0702. The propensity of HLA–B*2705 to form oligomers in the ER was partly attributable to residue Cys67 of the molecule. For all 3 alleles, increased expression of HLA–B proteins was associated with intracytoplasmic accumulation of unfolded/misfolded proteins and intracellular vesicles, probably corresponding to expanded ER–Golgi intermediate compartments, in which these proteins accumulated together with the stress sensor BiP. Conclusion Our results suggest that the difference in disease susceptibility conferred by HLA–B*2705 and HLA–B*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors.

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“…The identity of these agents and the mechanism(s) by which autonomous growth occurs remain unresolved. A number of pathways have been considered in this capacity and include activation of the EGF/transforming growth factor (TGF)-␣ pathway and the polyamine pathway (19,35).Of particular interest is CCN2 (also known as CTGF) since expression of this growth factor has been identified in a variety of tumors of mesenchymal, epithelial, and lymphoid origin. Levels of CCN2 transcript and/or protein are positively correlated with bone metastasis in breast cancer (13), glioblastoma growth (29), poor prognosis in esophageal adenocarcinoma (20), aggressive behavior of pancreatic cancer cells (38), and invasive melanoma (21).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Gastrin itself has no proliferative effect on ECL cells once neoplastic transformation has occurred and the ECL cells become gastrin autonomous (34). Nevertheless, proliferation continues even if the gastrin stimulus is withdrawn, indicating that an alternative proliferative agent(s) is now operative (35). The identity of these agents and the mechanism(s) by which autonomous growth occurs remain unresolved.…”

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confidence: 99%

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Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Kidd¹,

Modlin²,

Eick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 ϩ EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1-100 M) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (ϩ2.36-fold, P Ͻ 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (Ͼ98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 Ϯ 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 ϩ EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC 50 ϳ0.01 ng/ml); EGF significantly augmented (P Ͻ 0.01) CCN2-induced tumor cell proliferation (EC50 ϭ 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (Ϫ12 Ϯ 3%, P Ͻ 0.05) and ERK1/2 phosphorylation (Ϫ34 Ϯ 5%, P Ͻ 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids (P Ͻ 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.connective tissue growth factor; epithelial growth factor AGENTS involved in regulating cell proliferation during the development of carcinoids and neuroendocrine (NE) tumors remain an elusive issue. Little information in this area is available since few models and NE cell lines exist to evaluate the problem. The rodent Mastomys develops gastric carcinoids both spontaneously (12-18 mo) and very rapidly (8 -12 wk) when acid suppression and hypergastrinemia are engendered (26, 34). In the stomach, the enterochromaffin-like (ECL) cell, which regulates acid secretion under the effect of both gastrin and PACAP (31, 40), transforms into a neoplastic phenotype when exposed to hypergastrinemia (34). Gastrin itself has no proliferative effect on ECL cells once neoplastic transformation has occurred and the ECL cells become gastrin autonomous (34). Nevertheless, proliferation continues even if the gastrin stimulus is withdrawn, indicating that an alternative proliferativ...

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The role of transforming growth factor alpha in the enterochromaffin- like cell tumor autonomy in an African rodent mastomys

Cited by 36 publications

References 1 publication

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

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