Abstract
The epidermal growth factor receptor (EGFR) family comprehends four different tyrosine kinases (EGFR, ErbBโ2, ErbBโ3, and ErbBโ4) that are activated following binding to epidermal growth factor (EGF)โlike growth factors. It has been long established that the EGFR system is involved in tumorigenesis. These proteins are frequently expressed in human carcinomas and support proliferation and survival of cancer cells. However, activation of the EGFR in nonโmalignant cell populations of the neoplastic microenvironment might also play an important role in cancer progression. EGFR signaling regulates in tumor cells the synthesis and secretion of several different angiogenic growth factors, including vascular endothelial growth factor (VEGF), interleukinโ8 (ILโ8), and basic fibroblast growth factor (bFGF). Overexpression of ErbBโ2 also leads to increased expression of angiogenic growth factors, whereas treatment with antiโEGFR or antiโErbBโ2 agents produces a significant reduction of the synthesis of these proteins by cancer cells. EGFR expression and function in tumorโassociated endothelial cells has also been described. Therefore, EGFR signaling might regulate angiogenesis both directly and indirectly. In addition, activation of EGFR is involved in the pathogenesis of bone metastases. Within the bone marrow microenvironment, cancer cells stimulate the synthesis of osteoclastogenic factors by residing stromal cells, a phenomenon that leads to bone destruction. It has been shown that EGFR signaling regulates the ability of bone marrow stromal cells to produce osteoclastogenic factors and to sustain osteoclast activation. Taken together, these findings suggest that the EGFR system is an important mediator, within the tumor microenvironment, of autocrine and paracrine circuits that result in enhanced tumor growth. J. Cell. Physiol. 214: 559โ567, 2008. ยฉ 2007 WileyโLiss, Inc.