Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy

Abstract

HB-EGF, a member of the EGF family of growth factors, exerts its biological activity through activation of the EGFR and other ErbB receptors. HB-EGF participates in diverse biological processes, including heart development and maintenance, skin wound healing, eyelid formation, blastocyst implantation, progression of atherosclerosis and tumor formation, through the activation of signaling molecules downstream of ErbB receptors and interactions with molecules associated with HB-EGF. Recent studies have indicated that HB-EGF gene expression is significantly elevated in many human cancers and its expression level in a number of cancer-derived cell lines is much higher than those of other EGFR ligands. Several lines of evidence have indicated that HB-EGF plays a key role in the acquisition of malignant phenotypes, such as tumorigenicity, invasion, metastasis and resistance to chemotherapy. Studies in vitro and in vivo have indicated that HB-EGF expression is essential for tumor formation of cancer-derived cell lines. CRM197, a specific inhibitor of HB-EGF, and an antibody against HB-EGF are both able to inhibit tumor growth in nude mice. These results indicate that HB-EGF is a promising target for cancer therapy, and that the development of targeting tools against HB-EGF could represent a novel type of therapeutic strategy, as an alternative to targeting ErbB receptors.

Figure 1

Binding specificities of members of the ErbB receptor family to EGF ligands. (a) EGF family ligands are separated into four categories according to their specificities for members of the ErbB receptor family. ErbB2 has no ligand. ErbB3 is deficient in kinase activity (X). (b) ErbB homo‐ and heterodimer combinations activated by heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF). AR, amphiregulin; BTC, betacellulin; ECD, extracellular domain; EGF, epidermal growth factor; EPR, epiregulin; ICD, intracellular domain; NRG, neuregulin; PM, plasma membrane; TGF‐α, transforming growth factor‐α.

Figure 2

Structure of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF). The membrane‐anchored form (proHB‐EGF) possesses pro, heparin‐binding, EGF‐like, juxtamembrane, transmembrane and cytoplasmic domains. Proteolytic cleavage occurs at the positions indicated by the arrows. Cleavage at the juxtamembrane region by ‘ectodomain shedding’ results in the release of the soluble active growth factor (sHB‐EGF). TM, transmembrane.

Figure 3

Clinical significance of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) expression in ovarian cancer. Progression‐free survival of patients with ovarian cancer in relation to the tumor HB‐EGF expression status. (Reproduced from Tanaka et al.,^{( 7 )} with permission.)

Figure 4

Suppression of tumor growth following administration of CRM197. The human ovarian cancer cell lines SKOV3 (A) and RMG‐1 (B) were injected subcutaneously into nude mice, followed by intraperitoneal injection of CRM197 or control saline once a week for 10 weeks. (Reproduced from Miyamoto et al.,^{( 6 )} with permission.)