Chromogranin A, Ki-67 index and IGF-related genes in patients with neuroendocrine tumors

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Abstract

Chromogranin A (CgA) and the Ki-67 proliferation index are considered as important biochemical and pathological markers for clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP NETs), respectively. The IGF system has been suggested as an important regulator of GEP NET proliferation and differentiation. A possible relationship between serum CgA (sCgA), Ki-67 proliferation index, and expression of IGF-related genes in patients with GEP NETs has not been demonstrated yet. This study investigates the relationship between sCgA, the Ki-67 proliferation index, and the expression of IGF-related genes in GEP NET tissues and their relation with 5-year survival. Tumor and blood samples from 22 GEP NET patients were studied. Tumoral mRNA expression of IGF-related genes (IGFs: IGF1, IGF2; IGF receptors: IGF1R, IGF2R; insulin receptors: subtype A (IR-A) and B (IR-B); IGF-binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, and IGFBP6) was measured using quantitative RT-PCR. Ki-67 proliferation index was determined using immunohistochemistry. sCgA was measured with ELISA. Five-year survival in patients with nonelevated sCgA ( n=11) was 91 vs 46% in patients with elevated sCgA ( n=11) ( P=0.006). IR-A mRNA expression was significantly higher in tumors obtained from patients with elevated sCgA than in those from patients with nonelevated sCgA (6.42±2.08 vs 2.60±0.40; P=0.04). This data suggests that sCgA correlates well with 5-year survival of GEP NET patients, and that IR-A mRNA expression correlates well with tumor mass in GEP NET patients.

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Most cited references 25

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In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Connect

Journal ID (iso-abbrev): Endocr Connect

Journal ID (publisher-id): ECC

Title: Endocrine Connections

Publisher: BioScientifica (Bristol )

ISSN (Electronic): 2049-3614

Publication date (Electronic): 18 November 2013

Publication date Collection: 01 December 2013

Volume: 2

Issue: 4

Pages: 172-177

Affiliations

[1 ]Department of Internal Medicine, Sector of Endocrinology, Erasmus MC 's Gravendijkwal 230, Room D-4303015 CE, RotterdamThe Netherlands

[2 ]Department of Surgery, Erasmus MC RotterdamThe Netherlands

[3 ]Department of Pathology, Erasmus MC Rotterdam, and Reinier de Graaf Hospital DelftThe Netherlands

Author notes

Correspondence should be addressed to W W de Herder Email: w.w.deherder@ 123456erasmusmc.nl

Article

Publisher ID: EC130052

DOI: 10.1530/EC-13-0052

PMC ID: 3847918

PubMed ID: 24042314

SO-VID: efadf190-128b-4660-bbd4-9aafc88b094e

License:

This work is licensed under a Creative Commons Attribution 3.0 Unported License

History

Date received : 11 September 2013

Date accepted : 16 September 2013

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