Role of the IGF‐I receptor in the regulation of cell–cell adhesion: Implications in cancer development and progression

Mauro, Loredana; Salerno, M; Morelli, Catia; Boterberg, Tom; Bracke, Marc; Surmacz, Eva

doi:10.1002/jcp.10207

Cited by 84 publications

(68 citation statements)

References 112 publications

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“…Surface molecules participating in cell/cell and cell/matrix interactions during breast tumor growth have been reported previously. Such examples are the Notch receptors, 43 the insulin-like growth factor I receptor 44 and the CD44 receptor, which is also an established marker for BCSC. 45 Interestingly, and although EGFR overexpression is associated with breast cancer cell proliferation and invasion, 46 Kari et al 47 reported that malignant tumor cells faced with inadequate cell-matrix contacts, critically depend on EGFR activation for survival.…”

Section: Discussionmentioning

confidence: 99%

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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Breast cancer stem cells (BCSC) have been identified in breast carcinoma as CD44 C /CD24 ¡/low cells, which display tumorigenic activity and have the ability to self-renew, differentiate and metastasize. Previous studies showed that extracellular HSP90 (eHSP90) participates in the invasion and metastatic processes of various cancers including breast cancer. Here, we show for the first time that eHSP90 is over-expressed in mammosphere cultures that are derived from the MDA-MB-231, MDA-MB-453 and MCF-7 breast cancer cell lines. These mammospheres are highly enriched in cells of the CD44 C /CD24 ¡/low BCSC phenotype and additionally show high expression of the BCSC markers CD49f and Sox2. Thus our results indicate that eHSP90 represents a potential novel BCSC marker. Moreover, we present evidence that eHSP90 is functionally involved in BCSC activity in vitro and in vivo. Selective neutralization of eHSP90, using the monoclonal antibody mAb 4C5, has the capacity to inhibit stem cell activity in vitro because the formation of mammosphere-derived colonies is dramatically reduced in its presence. In vivo, the treatment of mice with mAb4C5 using a prophylactic protocol, significantly inhibited the primary growth of MDA-MB-231 and mammosphere-derived tumors. More importantly, administration of this antibody in a therapeutic protocol caused a statistically significant regression of established tumors derived from MDA-MB-231 originating mammospheres. Tumor regression was even greater when mAb 4C5 was administered in combination with paclitaxel. Overall, our findings implicate eHSP90 as a potential novel BCSC biomarker. Moreover they show that eHSP90 participates in BCSC-derived primary tumor growth. Finally, we provide additional support for the possible therapeutic value of mAb4C5 in the treatment of breast cancer.Abbreviations: ALDH1, aldehyde dehydrogenase 1; BCSC, breast cancer stem cells; eHSP90, extracellular heat shock protein 90; ER, estrogen receptor; EGF, epidermal growth factor; FGF, fibroblast growth factor; MMP-2, matrix metalloproteinase 2

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Section: Discussionmentioning

confidence: 99%

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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“…Elevated plasma concentrations of IGF-I (10, 42) and increased activity of components of the IGF-I signaling pathway (43)(44)(45) have been implicated in tumor progression. IGF-I is well known to act on cell cycle machinery as a late G 1 progression factor (31), primarily by regulating expression of checkpoint proteins at the G 1 -to-S restriction point (20,46).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

Shen

Yin

Broussard

et al. 2004

Journal of Biological Chemistry

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Cyclin A is required for cell cycle S phase entry, and its overexpression contributes to tumorigenesis. Release of pre-existing E2Fs from inactive complexes of E2F and hypophosphorylated retinoblastoma (RB) is the prevailing dogma for E2F transcriptional activation of target genes such as cyclin A. Here we explored the hypothesis that new synthesis of E2F-1 is required for insulin-like growth factor-I (IGF-I) to induce cyclin A accumulation and RB hyperphosphorylation, events that are targeted by tumor necrosis factor ␣ (TNF␣) to arrest cell cycle progression. We first established that IGF-I increases expression of cyclin A, causes hyperphosphorylation of RB, and augments the mass of E2F-1 in a time-dependent manner. As expected, E2F-1 small interfering RNA blocks the ability of IGF-I to increase synthesis of E2F-1. Most important, this E2F-1 small interfering RNA also blocks the ability of IGF-I to increase cyclin A accumulation and to hyperphosphorylate RB. We next established that TNF␣ dose-dependently inhibits IGF-I-induced phosphorylation of both RB and histone H1 by cyclin A-dependent cyclin-dependent kinases. Cyclin-dependent kinase 2 (Cdk2) mediates this suppression because co-immunoprecipitation experiments revealed that TNF␣ reduces the amount of IGF-Iinduced cyclin A that binds Cdk2, leading to a reduction in Cdk2 enzymatic activity. TNF␣ antagonizes the ability of IGF-I to increase mass of both E2F-1 and cyclin A but not cyclin E or D1. The cytostatic property of TNF␣ is also shown by its ability to block IGF-I-stimulated luciferase activity of a cyclin A promoter reporter. Deletion of an E2F recognition site from this reporter eliminates the regulatory effects of both IGF-I and TNF␣ on cyclin A transcription, indicating the essential role of E2F-1 in mediating their cross-talk. Collectively, these results establish that TNF␣ targets IGF-I-induced E2F-1 synthesis, leading to inhibition of the subsequent accumulation in cyclin A, formation of cyclin A-Cdk2 complexes, hyperphosphorylation of RB, and cell cycle arrest.

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“…Yet, IGF1R also modulates cellsubstrate adhesion, migration, invasion and cell-cell interaction by signaling via FAK [112,113]. IGF1R has also been shown to modulate the expression and function of different junctional proteins, including cadherins, catenins, ZO-1 and the small GTPases RhoA, Rac1 and Cdc42 [114]. Notably, upon IGF-II binding, activated IGF1R associates with E-cadherin and b-catenin, thereby inducing reversible scattering [115].…”

Section: Signals Elicited By Erbb Receptorsmentioning

confidence: 99%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

210

160

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Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

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Role of the IGF‐I receptor in the regulation of cell–cell adhesion: Implications in cancer development and progression

Cited by 84 publications

References 112 publications

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

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