Absence or low IGF‐1R‐expression in esophageal adenocarcinoma is associated with tumor invasiveness and radicality of surgical resection

Bruijn, Kirstin De; Biermann, Katharina; Shapiro, Joël; Dogan, Fadime; Spaander, Manon; Janssen, Joseph A M J L; Wijnhoven, Bas P. L.; Borsboom, Gerard; Hofland, Leo J.; Eijck, Casper van

doi:10.1002/jso.23923

Cited by 4 publications

(3 citation statements)

References 35 publications

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“…This finding is furthermore reflected in the lower levels of these IGF pathway proteins and their mRNAs in association with shorter 10-year disease-free survival and overall rates. A decrease in both IGF1R protein and gene expression levels has been described before in esophageal adenocarcinoma, colorectal and breast cancer (Schnarr et al 2000, Allison et al 2007, Kuklinski et al 2011, De Bruijn et al 2015 and might reflect a dedifferentiation process. Indeed, two recent genomic studies have identified distinctive m(i) RNA expression profiles, separating PanNET with liver metastases (metastasis like primary tumor subtype) from well-differentiated PanNETs (well-differentiated islet/insulinoma tumor subtype), further underscoring dedifferentiation to be reflected in gene expression signatures (Sadanandam et al 2015, Scarpa et al 2017.…”

Section: Discussionsupporting

confidence: 54%

The IGF pathway is activated in insulinomas but downregulated in metastatic disease

Henfling¹,

Perren²,

Schmitt³

et al. 2018

Endocrine-Related Cancer

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Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

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Section: Discussionsupporting

confidence: 54%

The IGF pathway is activated in insulinomas but downregulated in metastatic disease

Henfling¹,

Perren²,

Schmitt³

et al. 2018

Endocrine-Related Cancer

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“…For the construction of a tissue microarray (TMA), formalin‐fixed paraffin‐embedded tissue from the resection specimens was retrieved from the archives at the Departments of Pathology of the participating institutions. For each tumour, three to six cores from multiple representative areas of OAC, as identified by a pathologist on haematoxylin and eosin‐stained slides, were taken from the original paraffin blocks, including the central part and invasive front of the tumour.…”

Section: Methodsmentioning

confidence: 99%

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma

Kate

Olphen

Bruno

et al. 2017

British Journal of Surgery

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BackgroundOesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)‐box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC.Methods SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort).ResultsLoss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1–2 tumours (P = 0·010) and node‐negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022).Conclusion SOX2 is an independent prognostic factor for long‐term survival in OAC, especially in patients with stage I OAC.

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“…Reports on the association between tissue expression of IGF-1R and survival in OAC have been mixed. De Bruijn et al [29] found that absence or low expression of IGF-1R was associated with high grade and advanced tumours, less radical resections and decreased OS but not decreased DFS on univariate analysis. Doyle et al [120] found no association between IGF-1R expression in tissue samples and obesity status, tumour stage, nodal status, or survival, however, they noted that in both OAC and SCC sections, increased levels of IGF-1R expression were observed in tumour cells within islets and at the invasive edge compared with tumour-associated stromal cells, this coincided with increased levels of CD68+ macrophages which are a known source of IGF-1 secretion and likely aid the growth of IGF-1R+ positive tumours.…”

Section: Igf-1rmentioning

confidence: 99%

Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma

McShane

Arya

Stewart

et al. 2021

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Absence or low IGF‐1R‐expression in esophageal adenocarcinoma is associated with tumor invasiveness and radicality of surgical resection

Abstract: Absence or low expression of IGF-1R was associated with high grade- and advanced tumors and less radical resections. IGF-1R might be a tumor marker in Barrett's esophagus since a change in expression patterns was found in the course from normal esophageal tissue to adenocarcinoma.

Cited by 4 publications

References 35 publications

The IGF pathway is activated in insulinomas but downregulated in metastatic disease

The IGF pathway is activated in insulinomas but downregulated in metastatic disease

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma

Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma

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