Background:Despite the recent improvements in multimodal therapies for oesophageal squamous cell carcinoma (ESCC), the prognosis remains poor. The identification of suitable biomarkers for predicting the prognosis and chemo-sensitivity is required to develop targeted treatments and improve treatment results.Methods:Proteins highly expressed in ESCC cell lines compared with normal oesophageal cell lines were screened by isobaric tag for relative and absolute quantitation (iTRAQ). We identified glypican-1 (GPC1) as a novel molecule. The clinicopathological characteristics of GPC1 were evaluated by immunohistochemistry using ESCC specimens, and clinical parameters were assessed. The correlation between GPC1 expression levels and chemo-sensitivity were analysed in vitro.Results:In the immunohistochemical assessment of 175 ESCC patients, 98.8% expressed GPC1. These patients demonstrated significantly poorer prognosis compared with patients with low-GPC1 expression by survival assay (P<0.001). Higher chemoresistance was observed in the GPC1 high-expression group. GPC1 expression levels positively correlated with chemo-sensitivity against cis-Diammineplatinum (II) dichloride (CDDP), and are potentially associated with anti-apoptotic function based on alterations in the MAPK downstream signalling pathway and Bcl-2 family member proteins.Conclusions:GPC1 is an independent prognostic factor in ESCC and is a critical molecule for altering the threshold of chemoresistance to CDDP.

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.

BACKGROUND: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. METHODS: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. RESULTS: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. CONCLUSION: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFRmutated lung cancer.

Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC.