Abstract
Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite the development of multimodal therapy. Expression of glypican-1 (GPC1) has been reported to be elevated in a subset of patients with ESCC and associated with chemoresistance. This study aimed to determine the association of GPC1 with ESCC growth and potential usefulness of the GPC1 targeted therapy by monoclonal antibody (mAb) in ESCC. Expression of GPC1 was higher in ESCC tumor tissues than in adjacent non-tumoral tissues and normal tissues. Knockdown of GPC1 decreased growth of ESCC cells and induced apoptosis via inhibition of EGFR, AKT and p44/42-MAPK signaling pathways in vitro. Anti-GPC1 mAb strongly inhibited tumor growth via antibody-dependent cellular cytotoxicity dependent and independent manner in GPC1-positive ESCC xenograft models. Anti-GPC1 mAb also inhibited tumor growth of GPC1 positive ESCC patients derived tumor xenograft models. Furthermore, anti-GPC1 mAb showed a significant tumor growth inhibition with decreased angiogenesis compared with IgG treated controls in ESCC xenografted mice. Treatment with anti-GPC1 mAb was not toxic in mice. Anti-GPC1 mAb may have a potent anti-tumor effect and represent a novel treatment option for patients with GPC1-positive ESCC.
Highlights
Esophageal cancer is the sixth leading cause of cancer death worldwide and esophageal squamous cell carcinoma (ESCC) is the predominant histological type in Japan and Eastern countries [1]
Molecular targeted therapy can act on various molecular pathways, including those involved in growth factor receptor signaling [epidermal growth factor receptor (EGFR) and Her-2/neu], the cell cycle, apoptosis and angiogenesis
Expression of GPC1 was detected in lymph node Esophageal squamous cell carcinoma (ESCC) metastases, indicating GPC1 may represent a therapeutic target for ESCC with lymph node metastasis (Figure 1C).These data indicate GPC1 may be an attractive therapeutic target for ESCC therapy
Summary
Esophageal cancer is the sixth leading cause of cancer death worldwide and esophageal squamous cell carcinoma (ESCC) is the predominant histological type in Japan and Eastern countries [1]. Molecular targeted agents have become front-line cancer therapies. Molecular targeted therapy can act on various molecular pathways, including those involved in growth factor receptor signaling [epidermal growth factor receptor (EGFR) and Her-2/neu], the cell cycle, apoptosis and angiogenesis. In breast carcinoma, targeted therapy against HER2 using the humanized monoclonal antibody trastuzumab has become integrated into standard adjuvant treatment regimens and has led to significant improvements in disease-free and overall survival in patients with Her2-positive cancer [3]. The identification of potential cancer antigens for the www.impactjournals.com/oncotarget development of innovative cancer-targeted therapies has become essential
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