Insulin promotes HER2 signaling activation during Barrett’s Esophagus carcinogenesis

Arcidiacono, Diletta; Antonello, Alessandro; Fassan, Matteo; Nucci, Daniele; Morbin, T.; Agostini, Marco; Nitti, Donato; Alberti, Alfredo; Battaglia, Giorgio; Realdon, Stefano

doi:10.1016/j.dld.2017.01.154

Cited by 8 publications

(13 citation statements)

References 31 publications

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“…Our study is not unique in finding lower growth factor receptor expression levels in tumor tissue; in breast and colorectal cancer; this phenomenon has also been described and it seems to be related to the advanced and poorly differentiated carcinoma [ 41 , 42 ]. We showed similar results in esophageal adenocarcinoma tissue from patients analyzed in our retrospective study published last year [ 18 ]. In the present study, we showed an important activation of p-ERK1/2 in both dysplastic and cancer MKR esophageal tissue, which is known to be a mitogenic signaling protein down-stream of IGF1R activation.…”

Section: Discussionsupporting

confidence: 82%

“…Immunohistochemistry staining of FFPE esophageal tissues showed HER2 positivity in both dysplastic and neoplastic lesions in ESCC and EASC, in WT and MKR mice, as previously described in human specimens [ 18 , 22 , 23 ]. As shown in the representative images ( Figure 7 A) all dysplastic and neoplastic lesions showed HER2 positivity.…”

Section: Resultssupporting

confidence: 59%

“…In an attempt to clarify IGF1R regulation in duodenal reflux-induced esophageal carcinogenesis we hypothesized a receptor cross-talk between IGF1R and another crucial growth factor receptor that is known to have a pivotal role in EAC carcinogenesis and disease progression, such as Human Epithermal Growth Factor receptor 2, HER2. Our group together with other studies showed HER2 over-expression on human Barrett’s tissue and esophageal adenocarcinoma [ 18 , 22 , 43 ]. In our previous study [ 18 ] in vitro experiments on OE19 human esophageal adenocarcinoma cell line were performed.…”

Section: Discussionsupporting

confidence: 60%

“…On the basis of our previous retrospective study [ 18 ], we hypothesized the involvement of other growth factor receptors and their cooperation with the insulin/insulin-like growth factor-1 axis in the evolution of these tumors. HER2 overexpression plays a critical role in the development, progression and metastasis of many malignancies such as breast cancer [ 12 , 13 , 19 ], gastric cancer [ 20 , 21 ] and esophageal cancer [ 18 , 22 ]. To evaluate whether in our carcinogenesis model (related exclusively to duodenal content chronic reflux) that HER2 could play a role, HER2 total protein expression was evaluated in esophageal tissue on both non-operated and operated mice.…”

Section: Resultsmentioning

confidence: 99%

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Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Arcidiacono

Dedja

Giacometti

et al. 2018

IJMS

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Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett’s Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side—to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

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Section: Discussionsupporting

confidence: 82%

Section: Resultssupporting

confidence: 59%

Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Arcidiacono

Dedja

Giacometti

et al. 2018

IJMS

Self Cite

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“…These signaling molecules are also activated in HER2-overexpressing tumors from other parts of the digestive system. For instance, a recent study investigated the role of hyperinsulinemia in Barrett's esophagus, dysplasia and esophageal adenocarcinoma [167]. The state of insulin resistance correlated with HER2 expression and downstream mediators AKT and mTOR in esophageal tissue.…”

Section: Tumors Of Other Organs and Her2 Expression Malignant Diseasementioning

confidence: 99%

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

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HER2 Testing in Breast and Gastric Cancer with CDH1 Germline Mutations

Ivanova

Sajjadi

Zattoni

et al. 2023

Hereditary Gastric and Breast Cancer Syndrome

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Insulin promotes HER2 signaling activation during Barrett’s Esophagus carcinogenesis

Cited by 8 publications

References 31 publications

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

HER2 Testing in Breast and Gastric Cancer with CDH1 Germline Mutations

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