Potential crosstalk between insulin-like growth factor receptor type 1 and epidermal growth factor receptor in progression and metastasis of pancreatic cancer

Abstract

The insulin-like growth factor receptor type 1 (IGF1R) and epidermal growth factor receptor (EGFR) are reportedly overexpressed in pancreatic cancer. However, the correlation between activated EGFR and IGF1R and their clinicopathological implications still remain unclear. The cellular localization and overexpression of IGF1R and EGFR were investigated immunohistochemically in primary invasive ductal pancreatic carcinomas obtained from 74 patients who underwent radical surgical resection. We also compared the status of IGF1R and EGFR overexpression between primary tumors and hepatic metastatic tumors obtained from 44 autopsied patients. Among the 74 surgically resected primary tumors, cytoplasm-and membrane-dominant EGFR overexpression was detected in 22 (30%) and 7 (9%), respectively, whereas cytoplasm-and membranedominant IGF1R overexpression was detected in 8 (11%) and 28 (38%), respectively. Membrane-dominant EGFR and cytoplasm-dominant IGF1R were more frequent in lower-grade tumors and correlated with favorable prognosis, whereas cytoplasm-dominant EGFR and membrane-dominant IGF1R were more frequent in highergrade tumors and correlated with poor prognosis. In 36 autopsy specimens of pancreatic tumor with concurrent overexpression of IGF1R and EGFR, there was an inverse correlation between the IGF1R and EGFR localization patterns (P ¼ 0.001). In the hepatic metastatic tumors obtained by autopsy, the incidences of both IGF1R and EGFR overexpression were much higher than in the surgically resected primary tumors. More than half of the autopsy cases consistently showed membrane-dominant EGFR expression in both the primary tumor and hepatic metastases, whereas IGF1R expression showed considerable variation. Crosstalk between differently localized IGF1R and EGFR might play a role in determining the biological aggressiveness of pancreatic cancer, although their cellular localization may often alter during the process of metastasis.

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

“…Indeed, IGF-IR expression was identified as a useful predictor of liver metastasis in several tumor types including colorectal carcinoma (Oshima et al, 2008), uveal melanoma (All-Ericsson et al, 2002), gastrinoma (Furukawa et al, 2005) and pancreatic cancer (Ueda et al, 2006). Although numerous reports, including our own, have attributed the prometastatic effect of IGF-IR to its role in the regulation of matrix metalloproteinases, cell migration and invasion and cell survival (Samani et al, 2007), our present findings, to our knowledge, are the first to link the prometastatic function of IGF-IR to it ability to regulate the ECM composition and, in particular, type IV collagen expression levels.…”

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

“…In pancreatic cancer, a frequent overexpression of IGF-IR and its ligands has been reported [28,29]. IGF-IR can potently contribute not only to the development of tumors but also to the resistance to therapy [30,31]. In this sense, it has been recently reported that concomitant expression of MMP7 and activation of p-IGF-1R correlates with poor prognosis in colon cancer patients treated with inhibitors of EGFR [32].…”

Gene silencing of BAG-1 modulates apoptotic genes and sensitizes lung cancer cell lines to cisplatin-induced apoptosis

“…25 Furthermore, in advanced pancreatic cancer, EGFR expression tends to increase, while IGF1R expression decreases. 26 Other studies have described IGF1R-mediated activation of EGFR through induction of an autocrine TGFa loop. 27,28 Unexpectedly, in the current study, mRNA levels of TGFa were decreased, while those of IGF1R increased.…”