Molecular Signatures of the Insulin-like Growth Factor 1-mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers

Cevenini, Armando; Orrú, Stefania; Mancini, Annamaria; Alfieri, Andreina; Buono, Pasqualina; Imperlini, Esther

doi:10.3390/ijms19082411

Cited by 69 publications

(57 citation statements)

References 220 publications

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“…Bioinformatics analysis, followed by experimental approaches confirmed high expression of IGFs in pericytes, contributing to breast cancer cell proliferation in vitro and in vivo. Indeed, in addition to regulating cell division, the IGF system has also been shown to promote induction of the EMT phenotype in epithelial tumors [38,39] and to play an important role in the maintenance of cancer stem cells in breast cancer [40].…”

Section: Discussionmentioning

confidence: 99%

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

et al. 2020

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Brain metastases are life‐threatening complications of triple‐negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple‐negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin‐like growth factor 2 (IGF2), which had a very significant pro‐proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation‐increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood–brain barrier‐permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple‐negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro‐metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.

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Section: Discussionmentioning

confidence: 99%

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

et al. 2020

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“…Therefore, there is a pressing need for optimal therapies [20,21]. Mounting evidence has demonstrated involvement of IGF-1-induced EMT in the metastasis and drug resistance, thus contributing to the gloomy prognosis of NSCLC patients [3][4][5][6]. This scenario promotes the efforts to develop the potential antitumor agents for NSCLC that target IGF-1 pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Worldwide, lung cancer remains the leading cause of cancer-related mortality, and approximately 85% of lung cancers are Non-small cell lung cancer (NSCLC) [1,2]. The major causes of mortality in NSCLC patients are metastasis and drug resistance, which are closely associated with Epithelial-mesenchymal transition (EMT) [3][4][5][6]. EMT is a process during which the epithelial cells lose their phenotype and acquire the characteristics of mesenchymal cells [5].…”

Section: Introductionmentioning

confidence: 99%

SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: A preliminary in vitro study

Wu¹,

Wu²,

Zhou³

et al. 2019

J. Cancer

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Insulin-like growth factor-1 (IGF-1)-induced epithelial-mesenchymal transition (EMT) plays a key role in the metastasis and drug resistance of non-small cell lung cancer (NSCLC). Sphingosine kinase-1 (SphK1) is also involved in EMT of NSCLC. However, the interaction between SphK1 and IGF-1 in the EMT of NSCLC is largely unknown. To clarify this issue, we examined the involvement of SphK1 in IGF-1-induced EMT using human lung cancer cell line A549, and its paclitaxel-resistant subline. Cell viability was evaluated by cell counting kit-8 assay; Migratory ability was examined using scratch wound healing test; Protein expression levels of SphK1, vimentin, fibronectin, N-cadherin and E-cadherin were detected by western blot analysis, respectively. The results showed that, IGF-1 treatment of A549 cells stimulated the expression of SphK1, the activation of ERK and AKT, the cell migration, and the expression of EMT hallmark proteins, while inhibition of SphK1 by its specific inhibitor SKI-II suppressed all the above changes and increased the sensitivity of A549 cells to paclitaxel. Our data demonstrate that SphK1 acts as a downstream effector of IGF-1 and plays a critical role in IGF-1-induced EMT, cell migration and paclitaxel resistance of A549 cells, suggesting that SphK1 might be a potential therapeutic target for NSCLC.

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“…The IGF system consists of two peptidic hormones (IGF-1 and IGF-2), two cell surface receptors (IGF-1R and IGF-2R), and at least six IGF-binding proteins [IGFBP [1][2][3][4][5][6]] that control normal growth and differentiation in most tissues [9,10]. The effects of free IGF-1 protein, which represent about 1% of the circulating proteins, are mediated by IGF-1R [11].…”

Section: Introductionmentioning

confidence: 99%

Influence of Insulin-Like Growth Factor 1 Gene Expression in Women with Breast Cancer: A Systematic Review

Costa‐Silva

Alves-Ribeiro

Barros-Oliveira

et al. 2020

Preprint

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Background: Breast cancer, the leading cause of cancer death among women worldwide, one of the major risk factors for breast cancer is genetic changes. Changes in the expression levels of the insulin-like growth factor 1 (IGF-1) gene have been associated with increased risk and aggressiveness of breast cancer. The IGF-1 gene encodes the IGF-1 peptide that is present in most human tissues, as in the normal and neoplastic mammary gland. Here, we conducted a systematic review to investigate the influence of IGF-1 gene expression levels in women with breast cancer.Methods: PubMed, Scopus, and Web of Science databases were searched for relevant studies published between February 2 and May 15, 2019, using inclusion and exclusion criteria in accordance with PRISMA guidelines. We analyzed the studies to find association between IGF-1gene expression and breast cancer.Results: A growing number of studies in women with breast cancer support, with controversial results, the influence of IGF-1 gene expression levels on clinical-pathological factors, disease-free survival, overall survival, and resistance to tamoxifen.Conclusions: Therefore, the elucidation of IGF-1 gene expression patterns through further studies may enable the characterization of women at high risk for breast cancer, as well as the development of effective prognostic and therapeutic strategies.

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Molecular Signatures of the Insulin-like Growth Factor 1-mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers

Cited by 69 publications

References 220 publications

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: A preliminary in vitro study

Influence of Insulin-Like Growth Factor 1 Gene Expression in Women with Breast Cancer: A Systematic Review

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