The Role of Insulin-Like Growth Factor 2 and Its Receptors in Human Tumors

Pavelić, Krešimir; Buković, Damir; Pavelić, Jasminka

doi:10.1007/bf03402082

Cited by 40 publications

(30 citation statements)

References 116 publications

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“…This finding corroborates previous data where IGF-II LOH (frequently associated with a duplication event; ref. 26) was found in f40% of bladder tumors, including pT a tumors, but was more common in tumors of higher grade and stage (11). Of the four IGF-II imprinting studies in bladder in the literature, LOH was only discussed in one (17) where 1 of 13 (8%) displayed IGF-II LOH.…”

Section: Discussionmentioning

confidence: 99%

Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization

Gallagher

O’Shea

Fitzpatrick

et al. 2008

Clinical Cancer Research

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Purpose: This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II. Experimental Design: Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pT a noninvasive and 44 pT 1 lamina propria invasive) using the commercially available Novocastra antibody. Results: IGF-IILOI was evident in 7 of17 (41%) UCB tumors and 4 of11 (36%) tumor-associated normal urothelial samples.Two of four pT 1 grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-IImaintenance of imprinting tumors had concomitant CDH1cytoplasmiclocalization. UCB cell lines displaying cytoplasmic CDH1immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1staining. Finally, cytoplasmic CDH1staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage. Conclusions: We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery.To date, insulin like growth factor-II (IGF-II) loss of imprinting (LOI) has been reported in most histologic types of sporadic embryonal, solid, and hematologic malignancies (reviewed in ref. 1). Moreover, identifying IGF-II LOI as a predictive marker of cancer risk has been highlighted for colorectal cancer, where IGF-II LOI in lymphocytes identified patients at risk of developing this malignancy (2) and, when detected in normal colonic mucosa, identified patients with a 5-fold increased chance of developing adenomas (3). In normal subjects, IGF-II LOI frequencies of approximately 10% have been reported in peripheral blood lymphocytes (2, 4) and range from 12% to 17% in normal tissues (3,5,6). Importantly, IGF-II LOI has been shown to result in increased IGF-II mRNA and protein expression (3, 7) as a result of the abnormal reactivation of the normally silent maternal allele.In vivo mouse studies provide compelling evidence supporting the functional significance of IGF-II overexpression in tumor development. Specifically, transgenic overexpression of IGF-II induces spontaneous lung and mammary tumors (8, 9). Furth...

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Section: Discussionmentioning

confidence: 99%

Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization

Gallagher

O’Shea

Fitzpatrick

et al. 2008

Clinical Cancer Research

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“…As their appropriate level and/or interaction regulate cell growth, it is obvious that overexpression of either of them (or both) may be involved in enhanced tumor growth [2]. The proposed mechanism of autocrine IGF 2 action on malignant proliferation came from its elevated secretion by tumors and tumor derived cell lines [3,4].…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma

Pavelić

Radaković

Pavelić

2007

Gynecologic Oncology

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“…IGF-IR activation is involved in several processes associated to oncogenic transformation, such as proliferation, migration and invasion (Coppola et al, 1994;Pavelic et al, 2002;Samani et al, 2007;Sell et al, 1994). IGF-I expression rarely occurs in tumoral cells, but can be produced by stromal cells surrounding the tumor.…”

Section: Aberrant Expression Of Igfs In Cancermentioning

confidence: 99%

“…It appears that abnormal IGF-IR activation can result in oncogene activation leading to increased cellular proliferation and malignancy. Although the IGFs are not in themselves tumorigenic factors, it has been shown that overexpression of IGF-II, as in the case of loss of imprinting (LOI) (Pavelic et al, 2002), can contribute to gynaecological malignancies like ovarian cancer (Murphy et al, 2006) and choriocarcinoma (Diaz et al, 2007).…”

Section: Introductionmentioning

confidence: 99%