Insulin-like growth factors I and II induce cell death in Wilms's tumour cells

Granerus, Marika; Johannisson, Anders; Ekblom, Peter; Engström, Wilhelm

doi:10.1136/mp.54.1.30

Cited by 8 publications

(11 citation statements)

References 26 publications

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“…Although a large number of studies have shown that IGFs induce cell proliferation and survival, only a few have suggested that IGFs may also induce apoptosis. The effect has been seen in normal rat liver hepatic stellate cells and osteoblasts [Gronowicz et al, 2004; Saile et al, 2004] as well as in osteosarcoma and Wilms' tumor cells [Granerus et al, 2001; Raile et al, 2003]. Therefore, the dogma that growth factors are survival factors is not unconditional.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that IGF‐II inhibits butyrate‐induced apoptosis in colon cancer cells [Leng et al, 2001a]. However, a few studies have suggested that IGFs induce apoptosis in some circumstances [Granerus et al, 2001; Raile et al, 2003; Gronowicz et al, 2004; Saile et al, 2004]. The precise mechanisms underlying these apparently paradoxical actions of IGFs are yet to be elucidated.…”

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confidence: 99%

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Insulin‐like growth factors induce apoptosis as well as proliferation in LIM 1215 colon cancer cells

Thompson

Leeding

et al. 2006

J of Cellular Biochemistry

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The insulin-like growth factor (IGF) system plays an important role in cell proliferation and survival. However, more recently, a small number of studies have shown that IGFs induce apoptosis in some cells. Our initial studies showed this occurred in LIM 1215 colon cancer cells but not RD rhabdomyosarcoma cells. IGFs induced both proliferation and apoptosis in LIM 1215 cells, and the induction of apoptosis was dose-dependent. [R 54 , R 55 ]IGF-II, which binds to the IGF-I receptor with normal affinity but does not bind to the IGF-II receptor, induced apoptosis to the same extent as IGF-II, whereas [L 27 ]IGF-II, which binds to the IGF-I receptor with 1000-fold reduced affinity, had no effect on apoptosis. These results suggest that the IGF-I receptor is involved in induction of apoptosis. Western blot analyses demonstrated that Akt and Erk1/2 were constitutively activated in RD cells. In contrast, phosphorylation of Akt and Erk1/2 were transient and basal expression of Akt protein was lower in LIM 1215 cells. Analysis of apoptosis-related proteins showed that IGFs decreased pro-caspase-3 levels and increased expression of pro-apoptotic Bad in LIM 1215 cells. IGFs co-activate proliferative and apoptotic pathways in LIM 1215 cells, which may contribute to increased cell turnover. Since high turnover correlates with poor prognosis in colorectal cancer, this study provides further evidence for the role of the IGF system in its progression.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Insulin‐like growth factors induce apoptosis as well as proliferation in LIM 1215 colon cancer cells

Thompson

Leeding

et al. 2006

J of Cellular Biochemistry

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“…Overexpression of IGF2 is frequently observed in cases of Wilms' tumour, and for a long time, it was thought to be a tumour promoter [4]. However, this may not be a universal rule since IGF2 was found to induce apoptosis and necrosis in Wilms' tumour cells [25]. …”

Section: Igfs In Diseasementioning

confidence: 99%

“…In most cases of BWS, this mechanism is dysfunctional, and there is a dysregulation of gene expression. In 5% of BWS patients, the molecular defects are limited to a gain of methylation at IC1 [25]. This means that IC1 is methylated on both the maternal and paternal chromosome, resulting in biallelic activation of IGF2 and biallelic silencing of H19.…”

Section: Igfs In Diseasementioning

confidence: 99%

Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review

Bergman

Halje²,

Nordin³

et al. 2012

Gerontology

227

169

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Background: Insulin-like growth factor 2 (IGF2) is a protein hormone known to regulate cell proliferation, growth, migration, differentiation and survival. The gene is parentally imprinted in the sense that transcripts are almost exclusively derived from the paternal allele. Loss of imprinting of the IGF2 gene is a recurrent observation in growth disorders that combine overgrowth with a variety of malignant tumours. Moreover, IGF2 has been proposed to play a role in the development of a variety of seemingly unrelated cancers that play an important role in geriatric medicine, e.g. breast cancer, colon cancer and lung cancer. Finally, IGF2 has been implicated in cardiovascular disease, since, for example, IGF2 has been shown to influence the size of atherosclerotic lesions. Objective: To summarize current knowledge about IGF2, its interactions with binding proteins and receptors and connections with key diseases. Methods: The contents of this paper were based on reviews of existing literature within the field. Results: There is a substantial amount of research linking IGF2 to growth disorders, cancer and to a much lesser degree cardiovascular disease. Some of the studies on IGF2 and tumour growth have yielded conflicting results, for instance regarding its effect on apoptosis. Conclusion: Today, our knowledge on how IGF2 is composed and interacts with receptors has come a long way. However, there is comparatively little information on how IGF2 affects tumour growth and cardiovascular diseases such as atherosclerosis. Thus, further research will be needed to elucidate the impact of IGF2 on key diseases.

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“…Analysis of our expression data showed no significant increases within relapse samples of IGFR1, IGFR2, or IGF2, whereas IGF-I was significantly down-regulated in association with relapse. Although high levels of IGF-I have been implicated in oncogenesis in several different cancers, exogenous IGF-I was reported to induce apoptosis in a Wilms tumor cell line (48), suggesting that IGF-I may in certain situations induce cell death. Therefore down-regulation of IGF-I in relapses, or up-regulation in nonrelapses, may affect cell survival.…”

Section: Discussionmentioning

confidence: 99%

Predicting Relapse in Favorable Histology Wilms Tumor Using Gene Expression Analysis: A Report from the Renal Tumor Committee of the Children's Oncology Group

Huang

Gadd

Breslow

et al. 2009

Clinical Cancer Research

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Purpose: The past two decades has seen significant improvement in the overall survival of patients with favorable histologyWilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse.This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis. Experimental Design: Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2-and 10-fold cross-validations were applied. Results: The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%. Conclusions: This study shows the feasibility and modest accuracy of stratifying local stage III FHWTusing a classifier of <50 genes.Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.Wilms tumor is the most common urogenital malignancy in children, with f500 new cases per year in North America. Several national and international cooperative group clinical trials have optimized the therapy resulting in an increase in the overall survival rate to f90%. The current therapeutic approach for Wilms tumor is based on histologic subtype (favorable versus unfavorable histology) and tumor stage (1). The majority of Wilms tumor has favorable histology, defined as the absence of anaplasia, and these represent the focus of the current study. Patients with anaplasia are treated differently than those with favorable histology Wilms tumor (FHWT) and are beyond the scope of this study.In recent years, the improvement in relapse-free and overall survival for FHWT at each stage has reached a plateau. Some patients are not successfully treated initially, resulting in relapse and less frequently death. Of equal importance, many patients may receive more therapy than needed; this is particularly true for patients with stage III disease (2, 3). Further improvements in outcome will rely in part on the ability to identify markers associated with relapse, with the hope of better stratifying patients. This goal represented a major focus of the National Wilms Tumor Study-5 clinical protocol, which included a largescale effort aimed ...

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Insulin-like growth factors I and II induce cell death in Wilms's tumour cells

Cited by 8 publications

References 26 publications

Insulin‐like growth factors induce apoptosis as well as proliferation in LIM 1215 colon cancer cells

Insulin‐like growth factors induce apoptosis as well as proliferation in LIM 1215 colon cancer cells

Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review

Predicting Relapse in Favorable Histology Wilms Tumor Using Gene Expression Analysis: A Report from the Renal Tumor Committee of the Children's Oncology Group

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