Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer

Maki, Robert G.

doi:10.1200/jco.2009.27.5040

Cited by 187 publications

(146 citation statements)

References 129 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…The involvement of IGFBPs in cancer is not fully understood, but there are reports suggesting that down-regulation of these proteins correlates with cancer progression (28)(29)(30)(31). Fig.…”

Section: Validation Of Differentially Expressed Genes On the Protein mentioning

confidence: 99%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

show abstract

Section: Validation Of Differentially Expressed Genes On the Protein mentioning

confidence: 99%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…24 There is good evidence from the published literature that the IGF pathway has a significant role in the biological behavior of malignant tumors. 10,25 Specifically, increased protein expression of IGF2BP3 has been associated with enhanced tumor aggressiveness, metastatic behavior and inferior outcome of various solid cancers. [12][13][14][15][16][17][18] Recently, there has been growing interest in the IGF pathway from a therapeutic perspective, as monoclonal antibodies and small molecules targeting the IGF1 receptor have become available a few years ago and initial, small phase I and II, trials showed encouraging results in individual patients.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15][16][17][18] Recently, there has been growing interest in the IGF pathway from a therapeutic perspective, as monoclonal antibodies and small molecules targeting the IGF1 receptor have become available a few years ago and initial, small phase I and II, trials showed encouraging results in individual patients. 25 In this study, we investigated the mRNA expression levels of several molecules involved in IFG signaling in mantle cell lymphoma cell lines and primary mantle cell lymphoma cases. It became evident that the majority of mantle cell lymphoma cell lines and primary tumors show increased IGF2BP3 mRNA expression, in line with IGF2BP3 belonging to the 'mantle cell lymphoma gene expression signature' as reported in a global gene expression profiling study.…”

Section: Discussionmentioning

confidence: 99%

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

et al. 2012

View full text Add to dashboard Cite

Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma, characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high number of additional genetic alterations. Chromosomal gains of 7p are frequent in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is associated with an aggressive behavior in many malignant tumors. We here analyze selected genes related to IGF signaling in gene expression and genomic array data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas and study IGF2BP3 protein expression in 172 wellcharacterized primary mantle cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of 172 primary mantle cell lymphomas showed IGF2BP3 expression in 450% of tumor cells, and strong IGF2BP3 protein expression was highly associated with increased proliferation as measured by the Ki-67 index, but not with overall survival of mantle cell lymphoma patients. Only a subset of mantle cell lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in 7p, suggesting that additional mechanisms are involved in the upregulation of IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples, IGF2BP3 protein expression remained constant between primary diagnosis and relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling may contribute proproliferative stimuli in the evolution of mantle cell lymphoma tumor cells.

show abstract

“…Mounting evidence from cell culture experiments, animal models, and correlative studies in patients with cancer clearly show that the insulin-like growth factor (IGF)/IGF-1 receptor (IGF1R) system plays a central role in many cancer types (1,2). Interfering with this system has emerged as a promising strategy to treat a variety of human cancers (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

Zumsteg

Caviezel²,

Pisarsky³

et al. 2012

Molecular Cancer Research

View full text Add to dashboard Cite

NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic b-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared with Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-2, a high-affinity ligand for IGF1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials neither did affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, that is, the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-2 and of the IGF-2-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-2.

show abstract

Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer

Cited by 187 publications

References 129 publications

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

Contact Info

Product

Resources

About