Novel role for insulin as an autocrine growth factor for malignant brain tumour cells

Arcaro, Alexandre; Doepfner, Kathrin T.; Boller, Danielle; Guerreiro, Ana S.; Shalaby, Tarek; Jackson, Shaun P.; Schoenwaelder, Simone M.; Delattre, Olivier; Grotzer, Michael A.; Fischer, Barbara

doi:10.1042/bj20070309

Cited by 46 publications

(31 citation statements)

References 61 publications

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“…The potential of NVP-ADW742 and NVP-AEW541 as single agents or in combination with chemotherapeutic drugs human was investigated in acute myeloid leukemia, Ewing’s sarcoma, medulloblastoma, neuroblastoma, and small cell lung cancer (Scotlandi et al, 2005; Warshamana-Greene et al, 2005; Guerreiro et al, 2006b; Tanno et al, 2006; Doepfner et al, 2007; Tazzari et al, 2007; Urbanska et al, 2007). In atypical teratoid/rhabdoid tumor cells of the central nervous system, NVP-AEW541 was shown to inhibit cell proliferation and survival by blocking IGF-1R and IR activation by autocrine loops involving IGFs and insulin (Arcaro et al, 2007). In colorectal cancer, studies with NVP-AEW541 suggested that a combination therapy targeting both EGFR and IGF-1R could be a promising approach (Kaulfuss et al, 2009).…”

Section: Small Molecule Inhibitors Of the Igf-1r Tyrosine Kinase Actimentioning

confidence: 99%

Targeting the insulin-like growth factor-1 receptor in human cancer

Arcaro¹

2013

Front. Pharmacol.

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105

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The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or IGF-2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon, and prostate cancer. Anti-cancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this mini review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.

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Section: Small Molecule Inhibitors Of the Igf-1r Tyrosine Kinase Actimentioning

confidence: 99%

Targeting the insulin-like growth factor-1 receptor in human cancer

Arcaro¹

2013

Front. Pharmacol.

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105

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“…Further genetic factors, such as IGF-1 microsatellites, may account for possible effects on melanoma risk or its aggressiveness. A strong association between melanoma severity (expressed as Breslow index) and the IGF-1(CA) 19 repeat frequency was previously found. 50 Concomitantly, serum IGF-1 concentrations were mainly reduced in indi- 19 melanoma.…”

Section: Melanoma and Cell Proliferation Effects By Igf-1mentioning

confidence: 99%

“…A strong association between melanoma severity (expressed as Breslow index) and the IGF-1(CA) 19 repeat frequency was previously found. 50 Concomitantly, serum IGF-1 concentrations were mainly reduced in indi- 19 melanoma. Therefore, these results may have been obtained at diagnosis when melanoma was already present, suggesting that these concentrations could be a consequence of the cancer and its inflammatory component (generally decreased levels) 50 rather than a predisposition marker of tumor development (increased levels).…”

Section: Melanoma and Cell Proliferation Effects By Igf-1mentioning

confidence: 99%

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Insulin-Like Growth Factor System and Sporadic Malignant Melanoma

Capoluongo¹

2011

The American Journal of Pathology

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Insulin and insulin-like growth factors (IGFsMelanoma is a malignant tumor originating from melanocytes, the melanin-producing cells.1,2 During fetal development, melanocytes migrate to different body areas, such as the skin, uvea, leptomeninges, and mucous membranes (eg, upper esophagus, vulva, and anus).2 Although melanoma may arise in all these sites, cutaneous melanoma is by far the most frequent type of melanoma, representing approximately 5% to 7% of all skin malignancies and the most lethal skin cancer (approximately 75% of all deaths from skin tumors).2,3 The following melanoma risk factors have been extensively described: i) sun exposure, ii) presence of dysplastic nevi, iii) age, iv) ethnicity, v) personal or family history of melanoma, vi) phototype, vii) presence of xeroderma pigmentosum, viii) Li-Fraumeni syndrome, ix) hereditary retinoblastoma history, and x) immunosuppressive conditions. 4 In addition to environmental and individual risk factors, the genetic pedigree may also represent a further risk factor for melanoma development; indeed, multiple differences between melanoma cell genomes and those of normal melanocytes were identified in genomewide analysis studies. In particular, point mutations, deletions, gene amplifications and translocations, and/or epigenetic modifications (eg, promoter hypermethylation) appear to be associated with a significant growth advantage, as opposed to normal skin cells. 5 Furthermore, many molecular changes have been reported in advanced stages of melanoma, as opposed to normal melanocytes. The most common mutations are as follows: i) protoncogene serine/threonine kinase B-Raf-activating mutations, 6 ii) E-cadherin expression silencing, 7 and iii) telomerase activity acquisition, 8 followed by hundreds more, identified by comparative gene expression profiling of melanomas with various American Joint Committee on Cancer stages. 1,9,10 A recent article by Bennet 1 provided a detailed list of possible genes involved in melanoma spreading and development.Along with all pathways and molecules studied in different cancers, including melanoma itself, the study of the insulin-like growth factor (IGF) network of ligands, cell surface receptors, and IGF-binding proteins (IGFBPs; eg, the IGF-1 system) have attracted considerable interest because these pathways play important roles at multiple levels, from cellular and organ to organism.11-13 The IGF system mediates growth, differentiation, and developmental processes; it is involved in a variety of metabolic activities.13 Deregulation of IGF system expression and action is linked to several pathological features, ranging from growth deficits to cancer development. TarSupported by the Italian Health Ministry (code ONC_ORD3207) and Programma strategico 3: Diagnostica ad elevata complessità e tecnologie per il monitoraggio di pazienti con patologie croniche-PROGETTO 4_ISS.Accepted for publication August 10, 2010. CME Disclosure: The author did not disclose any relevant financial relationships.Address reprint requests to Ettor...

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“…Protein expression was analyzed by immunoblotting as previously described (11,20) using antibodies specific for PI3K p110g, LYK5 (STRAD N-13), LKB1, MPP2 (Santa Cruz Biotechnology), AMPKa, phospho-Akt (Ser473; Thr308), ATR, phospho-S6 (Ser 235/236 and Ser 240/ 244), phospho-4E-BP1 (Cell Signaling Technology), and b-Actin (Sigma). The blots were quantified by densitometry using the software TotalLab Quant (TotalLab Limited).…”

Section: Western Blottingmentioning

confidence: 99%

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Guerreiro

Fattet

Kulesza

et al. 2011

Molecular Cancer Research

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Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110g (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110g phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. Mol Cancer Res; 9(7); 925-35. '2011 AACR.

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Novel role for insulin as an autocrine growth factor for malignant brain tumour cells

Cited by 46 publications

References 61 publications

Targeting the insulin-like growth factor-1 receptor in human cancer

Targeting the insulin-like growth factor-1 receptor in human cancer

Insulin-Like Growth Factor System and Sporadic Malignant Melanoma

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

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