Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma

Valsecchi, Matías E.; McDonald, Mph Mary; Brody, Jonathan R.; Hyslop, Terry; Freydin, Boris; Yeo, Charles J.; Solomides, Charalambos; Peiper, Stephen C.; Witkiewicz, Agnieszka K.

doi:10.1002/cncr.26661

Cited by 104 publications

(83 citation statements)

References 44 publications

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“…In a study of colorectal cancer cases with regional lymph node involvement, coexpression of the IGF-1 receptor (IGF1R) and EGFR was present in more than 75% of tumors [24]. Moreover, the EGFR and IGF1R crosstalk has been demonstrated in other cancers such as pancreatic cancer and breast cancer [25], [26], [27], [28]. Interestingly, in pancreatic cancer, cases with high membrane expression of IGF1R and cytoplasmic detection of EGFR were correlated with poor prognosis [25], [26].…”

Section: Chiefly Produced By Receptor Functionmentioning

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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Section: Chiefly Produced By Receptor Functionmentioning

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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“…IGF-I is a well-recognized stimulator of cancer cell proliferation and potent inhibitor of apoptosis [22,23]. Expression of IGF-I receptor was detected in samples of resected pancreatic cancer and was associated with higher histological grade, tumor aggressiveness and poor prognosis [24,25].…”

Section: Discussionmentioning

confidence: 99%

Serum and Bile Insulin-Like Growth Factor I, Interleukin-6 and Tumor M2- Pyruvate Kinase in Differentiation Malignant from Benign Biliary Strictures – Preliminary Report

Budzyńska¹,

Dulawa²

2016

Med chem (Los Angeles)

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Objective: To determine the value of serum and bile insulin-like growth factor I (IGF-I), interleukin-6 (Il-6) and tumor M2-pyruvate kinase (Tu M2-PK) in distinguishing pancreatobiliary cancers from benign biliary strictures.Material and methods: The study was performed prospectively on forty jaundiced patients admitted for biliary decompression due to bile duct strictures. Malignant strictures were diagnosed in 22 patients including 15 cases of CCA and 7 cases of pancreatic cancer, and benign biliary strictures in 18 cases. IGF-I, Il-6 and Tu M2-PK were measured in sera and bile by ELISA and compared to serum levels of carbohydrate antigens (CA) 19-9 and carcinoembryonic antigen (CEA).Results: Serum levels of IGF-I (74.4 vs. 117.0 ng/mL, p=0.03), Il-6 (37.1 vs. 17.0 pg/mL, p=0.04), CA19-9 (5689 vs. 38.9 U/mL, p<0.001) and CEA (27.5 vs. 1.9 ng/mL, p<0.0001) differed significantly between patients with malignant and benign biliary strictures, whereas biliary concentrations of IGF-I and Il-6 and serum and biliary levels of Tu M2-PK were comparable. Biliary IGF-I levels were significantly increased in pancreatic cancer as compared to cholangiocarcinoma and benign biliary strictures groups (966 vs. 137 ng/mL, p=0.03 and 966 vs. 90.6 ng/mL, p=0.01, respectively). The AUC-ROCs for serum IGF-I and serum Il-6 were 0.336 and 0.606, respectively, what was worse than that of CA 19-9 (0.855) and CEA (0.794).Conclusion: Measurement of serum IGF-I and Il-6 may be helpful in differentiation malignant from benign biliary strictures and biliary IGF-I seems to be a promising marker for distinguishing pancreatic cancer from cholangiocarcinoma and benign biliary occlusions.

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“…In PDAC patients, studies have reported on increased intratumoral expression of IGF1R (Hakam et al 2003) and this has been associated with higher tumor grade and poor survival (Valsecchi et al 2012). Furthermore, increased amounts of IGF1 and IGF-binding proteins have been detected in sera and tissues of PDAC patients (Korc 1998, Karna et al 2002.…”

Section: The Igf System In Pdacmentioning

confidence: 99%

“…IR and IGFR belong to the same family as EGFR and trigger similar cascades. Analysis of human PDAC samples showed existence of a potential cross talk of IGF1R with EGFR that may be relevant for progression and metastasis of cancer and to predict patient outcome (Ueda et al 2006, Valsecchi et al 2012. In this regard, the cellular localization of both receptors seems to be important, as especially the membrane-dominant IGF1R and the cytoplasmic-dominant EGFR expression was related to poor survival and higher tumor grade (Ueda et al 2006).…”

Section: How Do Igf and The Insulin Systems Cooperate And Collaboratementioning

confidence: 99%

The role of insulin and IGF system in pancreatic cancer

Trajkovic‐Arsic¹,

Kalideris²,

Siveke³

2013

Journal of Molecular Endocrinology

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The importance of the IGF system in carcinogenesis has been established for many solid cancers. It is well known that individuals with higher circulating levels of the IGF1 ligand present an increased risk of cancer. However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR), which appears to be at least equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, IGF1, and IGF2. Although the connection between insulin, diabetes, and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer is missing. In this review, we focus on the contribution of insulin and IGFs to carcinogenesis in the insulinproducing organ, the pancreas. We give a short summary on the complexity of insulin and the IGF system in the pancreas and their potential roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma. Finally, we discuss drug-targeting options of this system and the rationale of simultaneous targeting of both the insulin and the IGF systems.

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Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma

Cited by 104 publications

References 44 publications

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

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

Serum and Bile Insulin-Like Growth Factor I, Interleukin-6 and Tumor M2- Pyruvate Kinase in Differentiation Malignant from Benign Biliary Strictures – Preliminary Report

The role of insulin and IGF system in pancreatic cancer

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