Multiple genetic alterations in malignant metastatic insulinomas

Pavelić, Krešimir; Hrašćan, Reno; Kapitanovića, Sanja; Karapandža, Nikola; Vranes, Z; Belicza, Mladen; Krušlin, Božo; Čabrijan, Tomislav

doi:10.1002/path.1711770410

Cited by 53 publications

(48 citation statements)

References 8 publications

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“…b-Cell tumors are the most common tumor subtype which usually arise sporadically; however, a small proportion arise owing to loss of the multiple endocrine neoplasia type 1 (MEN1) gene (Wang et al, 1998). Activation of oncogenes such as c-myc and ras has also been observed during disease progression of sporadic endocrine tumors, but their role in tumor initiation remains unknown (Pavelic et al, 1995;Sato et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas

et al. 2007

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Thymidylate synthase (TS) is an essential enzyme for DNA synthesis and repair and elevated levels of TS have been identified as an important prognostic biomarker for colorectal cancer and several other common human malignancies. In addition, TS gene expression has been linked with cell-cycle regulation and cell proliferation through the ability of retinoblastoma protein to repress the transcriptional activation of E2F target genes such as TS. Therefore, overproduction of TS could participate in the progression to a neoplastic phenotype. Consistent with this model, a recent study has suggested that ectopic TS expression can induce a transformed phenotype in mammalian cells. To investigate the role of deregulated TS activity in tumor development, we generated transgenic mice that express high levels of catalytically active human TS (hTS) exclusively in the pancreas and low levels of hTS in multiple other tissues. Analyses of pancreatic tissue in TS transgenic mice revealed abnormalities within the endocrine pancreas, ranging from pancreatic islet hyperplasia to the detection of islet cell tumors. Overexpression of hTS in murine islets provides a new model to study genetic alterations associated with the progression from normal cells to hyperplasia to islet cell tumors, and suggests that this mouse model may be useful for regulating TS activity in vivo for development of cancer prevention and new therapies.

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Section: Introductionmentioning

confidence: 99%

Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas

et al. 2007

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“…Controversy exists with respect to p53 expression as a marker for malignancy in EPTs. Lee (1996) suggested no role for p53, whereas Pavelic et al (1995) identified p53 overexpression in all the three cases of malignant insulinomas. We have recently shown that in insulin-producing EPTs, chromosomal instability (CIN), identified by analysis of DNA copy number changes using comparative genomic hybridization (CGH), is an optimal predictor for malignant progression (Jonkers et al 2005).…”

Section: Introductionmentioning

confidence: 99%

DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients

Jonkers¹,

Claessen²,

Perren³

et al. 2007

Endocr Relat Cancer

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The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size R2 cm, Ki67 proliferative index R2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 noninsulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan-Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P%0.0004) and tumor-specific death (P%0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index R2% were reliable in predicting a poor tumor-free survival in noninsulinoma EPTs (P%0.0181, whereas CK19 expression was the most optimal predictor of tumorspecific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in noninsulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.

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“…Similar cellular mechanisms associated with islet neogenesis, including phenotypic dedifferentiation and increased cellular proliferation, are implicit in the transformation of cells to a cancerous state [16]. Moreover, growth factors used to stimulate islet neogenesis have also been associated with various cancers [16,[18][19][20]. It is therefore of utmost importance to determine if pharmaceutically induced beta cell mass expansion remains under homeostatic control.…”

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confidence: 99%

Evidence for the homeostatic regulation of induced beta cell mass expansion

et al. 2006

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Aims/hypothesis Diabetes results from an insufficient insulin-secreting beta cell mass. Restoration of beta cell mass through pharmaceutically induced endogenous beta cell mass expansion may revolutionise diabetes therapy. However, it remains to be determined whether the induced beta cell mass expansion is under homeostatic regulation. Methods Beta cell mass expansion rates were derived from three separate studies of continuous stimulation of islet neogenesis, including the partial duct obstruction of euglycaemic Syrian hamsters, administration of a pentadecapeptide with the same amino acid sequence as residues 104-118 of islet neogenesis-associated protein ) to euglycaemic Syrian hamsters, as well as to euglycaemic CD-1 mice. The incidence of islet neogenesis, average beta cell size, and beta cell replication and apoptotic rates were determined. Results Partial duct obstruction led to a õ2.5-fold increase in endocrine tissue at day 56 (p<0.05). From day 0 to day 7 the average rate of change of islet area was 12.7% per day, and this rate decreased to 5.3% per day from day 7 to day 42, and to 2.8% per day from day 42 to day 56. Administration of INGAP [104][105][106][107][108][109][110][111][112][113][114][115][116][117][118] to adult hamsters led to a 31% increase in total beta cell mass at day 30 (p=0.031).From day 0 to day 10 the average rate of beta cell mass expansion was 148 μg/day, whereas from day 10 to day 30 it decreased to 45 μg/day. INGAP 104-118 administration to adult CD-1 mice resulted in an approximately twofold increase in beta cell mass after 31 days (p=0.021). However, at day 90, there was no significant difference vs age-matched control mice (p=0.30), even though the neogenic beta cell mass was approximately fourfold greater (p=0.026). Beta cell replication was decreased by 56% (p<0.048), whereas beta cell apoptosis was fourfold greater (p<0.003) in 90-day INGAP 104-118 -treated mice compared with age-matched control mice. Conclusions/interpretation These data indicate that in the presence of ongoing islet neogenesis, homeostatic regulatory mechanisms intervene to regulate beta cell mass according to the prevailing metabolic requirements.

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Multiple genetic alterations in malignant metastatic insulinomas

Cited by 53 publications

References 8 publications

Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas

Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas

DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients

Evidence for the homeostatic regulation of induced beta cell mass expansion

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