Abstract
We hypothesized that epidermal growth factor (EGF) receptor (EGFR) activation and vascular endothelial growth factor (VEGF)-induced angiogenic signals are important for the progression and metastasis of human salivary adenoid cystic carcinoma (ACC). To test this hypothesis, we evaluated the therapeutic effect of AEE788, a dual inhibitor of EGF and VEGF receptor (VEGFR) tyrosine kinases, on human salivary ACC. In clinical specimens of salivary ACC, EGF and VEGF signaling proteins were expressed at markedly higher levels than in adjacent normal glandular tissues. We examined the effects of AEE788 on salivary ACC cell growth and apoptosis and on the phosphorylation of EGFR and VEGFR-2 in salivary ACC cells. Treatment of salivary ACC cells with AEE788, alone or in combination with chemotherapy, led to growth inhibition, induction of apoptosis, and dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation. To determine the in vivo antitumor effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 alone, paclitaxel alone, cisplatin alone, a combination of AEE788 plus paclitaxel, a combination of AEE788 plus cisplatin, or a placebo. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. To study the mechanism of interaction between AEE788 and chemotherapy, AEE788 was found to potentiate growth inhibition and apoptosis of ACC tumor cells mediated by chemotherapy. Tumors of mice treated with AEE788 and AEE788 plus chemotherapy exhibited down-regulation of activated EGFR and VEGFR-2, increased tumor and endothelial cell apoptosis, and decreased microvessel density, which correlated with a decrease in the level of matrix metalloproteinase-9 and matrix metalloproteinase-2 expression and a decrease in the incidence of vascular metastasis. These data show that EGFR and VEGFR can be molecular targets for therapy of salivary ACC.
Highlights
Adenoid cystic carcinoma (ACC), one of the most common subtypes of salivary gland cancers [1], has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor response to traditional chemotherapies
We first evaluated the expression of transforming growth factor-a (TGF-a), epidermal growth factor (EGF), EGFR/ pEGFR, ErbB2, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR)-2/pVEGFR-2 in 35 human salivary ACC samples
Positive TGF-a, EGF, EGFR, ErbB2, and VEGFR-2 staining was found in the ductal segments of normal salivary glands but at a significantly lower staining intensity than in ACC tumor cells (P < 0.01; data not shown)
Summary
Adenoid cystic carcinoma (ACC), one of the most common subtypes of salivary gland cancers [1], has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor response to traditional chemotherapies. Epidermal growth factor (EGF) receptor (EGFR) has been shown to be overexpressed in a variety of epithelial tumors, including salivary ACC [3], and this extensively studied tyrosine kinase receptor plays a critical role in tumor cell proliferation and survival. Several studies have shown that blockade of the EGFR signaling pathway inhibits the expression and activity of matrix metalloproteinases (MMP), including MMP-9, which plays an essential role in tumor cell invasion and metastasis [6]. These findings suggest that EGF and its receptor may play a key role in the progression and metastasis of certain types of epithelial tumors
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