Characterization of membranous and cytoplasmic EGFR expression in human normal renal cortex and renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) is highly resistant to conventional systemic treatments, including chemotherapy, radiotherapy and hormonal therapies. Previous studies have shown over-expression of EGFR is associated with high grade tumors and a worse prognosis. Recent studies suggest anticancer therapies targeting the EGFR pathway have shown promising results in clinical trials of RCC patients. Therefore, characterization of the level and localization of EGFR expression in RCC is important for target-dependent therapy. In this study, we investigated the clinical significance of cellular localization of EGFR in human normal renal cortex and RCC. RCC and adjacent normal kidney tissues of 63 patients were obtained for characterization of EGFR expression. EGFR protein expression was assessed by immunohistochemistry on a scale from 0 to 300 (percentage of positive cells × staining intensity) and Western blotting. EGFR membranous staining was significantly stronger in RCC tumors than in normal tissues (P < 0.001). In contrast, EGFR cytoplasmic staining was significantly higher in normal than in tumor tissues (P < 0.001). The levels of membranous or cytoplasmic EGFR expression in RCC tissues were not correlated with sex, tumor grade, TNM stage or overall survival (P > 0.05). These results showed abundant expression of membranous EGFR in RCC, and abundant expression of cytoplasmic EGFR in normal tissues. EGFR expression in RCC was mostly located in the cell membrane, whereas the EGFR expression in normal renal tissues was chiefly seen in cytoplasm. Our results suggest different locations of EGFR expression may be associated with human renal tumorigenesis.

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Many current T cell-redirecting bsAbs in development target receptors that are ‘overexpressed’ on tumor cells, but are expressed at a relatively lower levels on certain normal tissues, e.g., CD33, CD123, EGFR. 7–9 Designing bsAbs against such receptors to selectively kill tumor cells while exhibiting limited or no cytotoxicity to non-targeted tissues with lower levels of target receptor expression remains a difficult endeavor. 10 In addition, the disposition of bsAbs at tumor sites of action, the numbers of tumor infiltrating T cells, the heterogeneous distribution of effector and target cells, and the possible immunosuppressive tumor microenvironment should all be taken into account when designing T-cell redirecting bsAbs, especially when treating solid tumors.…”

Expression of EGFR and p53 in Head and Neck Tumors among Sudanese Patients

“…The intensity of immunohistochemical staining for both markers was scored by two investigators based on subjective evaluation of color exhibited (brown) by antigen, antibody and chromogen complex. It was scored as 0 for negative (no color), 1+ for weak (light brown color), 2+ for moderate (dark brown color), and 3+ for strong staining (very dark brown color) with 0 or 1 scores defined as negative and 2 or 3 defined as positive (Pu et al, 2009).…”

The VHL-HIF Signaling in Renal Cell Carcinoma: Promises and Pitfalls

“…It has structural and functional homology to EGF (Derynck, 1986;Everitt et al, 1997). TGF- is thought to mediate its biological effects through the binding of EGFR, which is a family of four closely related cell membrane receptors, EGFR (HER1; ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Higashiyama et al, 2008;Pu et al, 2009). These receptors are transmembrane glycoproteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain (Higashiyama et al, 2008;Pu et al, 2009).…”

“…TGF- is thought to mediate its biological effects through the binding of EGFR, which is a family of four closely related cell membrane receptors, EGFR (HER1; ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Higashiyama et al, 2008;Pu et al, 2009). These receptors are transmembrane glycoproteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain (Higashiyama et al, 2008;Pu et al, 2009). Ligand-binding to the extracellular domain of EGFR activates tyrosine kinase, resulting in autophosphorylation of EGFR and subsequent signal transduction leading to cell cycle progression, inhibition of apoptosis, induction of angiogenesis, promotion of invasion and metastasis, and other oncogenic activities (Derynck, 1986;Everitt et al, 1997;Gunaratnam et al, 2003;Black&Dinney, 2008;Lee et al, 2008;Uberall et al, 2008;Pu et al, 2009).…”

“…These receptors are transmembrane glycoproteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain (Higashiyama et al, 2008;Pu et al, 2009). Ligand-binding to the extracellular domain of EGFR activates tyrosine kinase, resulting in autophosphorylation of EGFR and subsequent signal transduction leading to cell cycle progression, inhibition of apoptosis, induction of angiogenesis, promotion of invasion and metastasis, and other oncogenic activities (Derynck, 1986;Everitt et al, 1997;Gunaratnam et al, 2003;Black&Dinney, 2008;Lee et al, 2008;Uberall et al, 2008;Pu et al, 2009). TGF-/EGFR activation in RCC is either independent of, or dependent on the VHL status.…”