Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice

Abstract

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.

Cancer‐associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma

“…To evaluate the mechanism of interaction of CAFs and tumor cells, recent advances of imaging technology would be useful as their heterogeneous host‐tumor interactions . Therefore, further investigations should be performed including using patients‐derived xenografts . However, we suggest that cellular targeted therapy for CAFs should be investigated in the future; various types of targeted therapies for inhibiting the interaction between tumor cells and CAFs have already been investigated, but most, including FAP targeted therapies, have not resulted in positive clinical outcomes .…”

A novel therapeutic approach for esophageal squamous cell carcinoma: suppressor of cytokine signaling-1 gene therapy

“…In the present study, Sugase et al (4) found that SOCS1 overexpression using adenovirusexpressing SOCS1 (AdSOCS1) significantly inhibited the cell proliferation in ten ESCC cell lines and induced apoptosis via multiple signaling pathways including JAK/ signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). In gastric cancer, Souma et al (8) also reported that SOCS1 inhibits tumor growth by suppression the JAK/STAT-and MAPK-signaling.…”

“…Therefore, the identification of new molecules involved in the progression of ESCC is worthwhile, and for this, the elucidation of the underlying signaling pathway is important. Recently, Sugase et al (4) have suggested a novel promising approach for the treatment of ESCC: overexpression of the suppressor of cytokine signaling-1 (SOCS1).…”

“…Clinically, using primers selected from the CpG islands within exon 1 of SOCS1 gene, Sugase et al (4) found SOCS1 methylation in four human ESCC tissues, but not in normal esophageal tissue. Hussain et al (13) in Kashmir reported that compared with the level of SOCS1 expression in normal esophageal tissues, 40 (53%) of 75 of the surgically resected ESCC tissues exhibited decreased SOCS1 expression, which was significantly correlated with advanced stage or high histopathological grade.…”

“…Using AdSOCS1 or control adenovirus vector (AdLacZ) injected intratumorally in two xenograft models, Sugase et al (4) investigated the therapeutic effects of SOCS1 in vivo. In the first xenograft model, they used ICR nu/ nu mice in which ESCC cell lines, TE14 cells, were subcutaneously implanted.…”