Shozo Hojo

Chemokine receptors in cancer metastasis and cancer cell‐derived chemokines in host immune response

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell‐derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9‐induced infiltration of immature myeloid cells into cancer, high‐level expression of cancer cell‐derived chemokine CXCL16 increases infiltrating CD8+ and CD4+ T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell‐derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. (Cancer Sci 2007; 98: 1652–1658)

High-Level Expression of Chemokine CXCL16 by Tumor Cells Correlates with a Good Prognosis and Increased Tumor-Infiltrating Lymphocytes in Colorectal Cancer

CXCL16 is a new member of the chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4(+) T cells, CD8(+) T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL; P < 0.01) than those with low levels of CXCL16 expression (n = 15). Furthermore, the high CXCL16 expression group showed significantly better prognosis than the low CXCL16 expression group (P < 0.05). Collectively, our data suggest that the expression of CXCL16 by tumor cells enhances the recruitment of TILs, thereby bringing about a better prognosis in CRC. Thus, CXCL16 is a new prognostic biomarker and may be useful for the development of a more effective therapeutic strategy for CRC.

CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages

BackgroundInhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients.MethodsWe generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages.ResultsCXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.ConclusionsCollectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.

Glucose transporter 3 and 1 may facilitate high uptake of 18F-FDG in gastric schwannoma.

Recently, some gastric schwannomas have been reported to have high uptake of FDG. However, Glut-1 was reported to be negative in gastric schwannomas tested. A 64-year-old female patient received a laparoscopic partial gastrectomy for a FDG PET-positive submucosal tumor (SUVmax 6.61). The resected tumor was diagnosed as a benign gastric schwannoma. Glut family immunohistochemical examination revealed diffuse positive expression of Glut-3 and partial positive expression of Glut-1. On the other hand, Glut-2 and Glut-4 expression in the tumor were negative. This case suggested that Glut-3 and Glut-1 expression were facilitators of high FDG uptake in the benign gastric schwannoma.

Synchronous asymptomatic colonic metastasis from primary esophageal squamous cell carcinoma

The management of synchronous asymptomatic colonic metastases from primary esophageal squamous cell carcinoma (ESCC) has not yet been reported. A 64-year-old male patient was diagnosed with middle thoracic ESCC. The patient received chemoradiotherapy and incomplete response/stable disease was achieved. Preoperative colonoscopy revealed a 1.0-cm submucosal tumor at the splenic flexure of the colon, and biopsy results indicated possible metastasis from primary ESCC. The patient underwent subtotal esophagectomy and the colonic tumor was excised. A postoperative pathological diagnosis confirmed that the colonic tumor had metastasized from primary ESCC. Even though the patient was discharged 18 days after surgery without any complications, he died on the 72nd postoperative day due to multiple bone metastases and pleural dissemination. Our findings suggest that even with well-controlled and asymptomatic colonic metastasis from primary esophageal lesions, the prognosis of patients with primary ESCC is poor.

Prognostic significance of KLF4 expression in gastric cancer

To understand the roles of pluripotent stem cell-inducing genes in gastric cancer, the expression of Krüppel-like factor 4 (KLF4), Nanog, octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc) and sex-determining region Y-box 2 (SOX2) was examined using the newly developed gastric carcinoma tissue microarray. The associations between the immunohistochemical expression levels of the pluripotency-inducing factors and the clinicopathological data of 108 patients with gastric cancer were analyzed. No associations were identified between the expression levels of the five pluripotency-inducing factors and the tumor-node-metastasis (TNM) classification or clinicopathological characteristics of the patients. In addition, multivariate analysis revealed no association of Nanog, Oct4, SOX2 or c-Myc with the prognosis of the gastric cancer patients; however, low expression of KLF4 was determined to be an independent negative prognostic factor (P=0.0331), particularly in patients who underwent R0 resection (TNM stages 2 and 3; P=0.0048). In summary, low KLF4 expression was found to be negatively associated with overall survival, and may therefore be a useful prognostic marker in gastric cancer patients.

The expression of microRNA 574-3p as a predictor of postoperative outcome in patients with esophageal squamous cell carcinoma.

BackgroundDespite advances in radical esophagectomies and adjuvant therapy, the postoperative prognosis in esophageal squamous cell carcinoma (ESCC) patients remains poor. The aim of this study was to identify a molecular signature to predict postoperative favorable outcomes in patients with ESCC.MethodsAs a training data set, total RNA was extracted from formalin-fixed paraffin-embedded samples of surgically removed specimens from 19 ESCC patients who underwent curative esophagectomy. The expression of microRNA (miRNA) was detected using a miRNA oligo chip on which 885 genes were mounted. As a validation data set, we obtained frozen samples of surgically resected tumors from 12 independent ESCC patients and the expression of miR-574-3p was detected by quantitative real-time PCR.ResultsOur microarray analysis in the training set patients identified three miRNAs (miR-574-3p, miR-106b, and miR-1303) and five miRNAs (miR-1203, miR-1909, miR-204, miR-371-3p, miR-886-3p) which were differentially expressed between the patients with (n = 14) and without (n = 5) postoperative tumor relapse (p < 0.01 and p < 0.05, respectively). Higher expression of miR-574-3p, which showed the most significant association with non-relapse (p = 0.001), was associated with favorable overall survival (p = 0.016). Real-time PCR experiments on the validation set patients confirmed that higher expression of miR-574-3p was associated with non-tumor relapse (p = 0.029) and better overall survival (p = 0.004).ConclusionsOur results suggest that the aberrant expression of the miRNAs identified in this study plays key roles in the progression of ESCC. miR-574-3p was suggested to have a tumor suppressor effect, and thus, to be a predictor of postoperative outcome in patients with ESCC.

Clinicopathological significance of deoxycytidine kinase expression in esophageal squamous cell carcinoma

Deoxycytidine kinase (dCK) mediates the rate-limiting catabolic step in the activation of gemcitabine. Gemcitabine is a key drug for pancreatic and biliary tract cancer. However, gemcitabine is not widely used for esophageal squamous cell carcinoma (ESCC). In this study, we analyzed the expression of dCK in ESCC and evaluated the possibility of gemcitabine treatment for ESCC. In total, 76 ESCC patients who underwent esophagectomy between 1990 and 2008 were analyzed. dCK expression was analyzed immunohistochemically using tissue microarray and compared to the clinocopathological characteristics of the patients. Results identified 41 patients positive for dCK and 35 patients negative for dCK. A significant association was observed between dCK expression and gender (P=0.01), whereas the remaining factors were not associated with dCK expression. Prognosis of the patients with a high dCK expression was significantly worse than that of the patients with a low dCK expression (P=0.022). Furthermore, dCK expression was an independent prognostic factor regarding cause-specific prognosis (risk ratio, 2.2; P=0.031). In conclustion, the results of the present study suggested that dCK expression is a prognostic factor of the ESCC patients.

Multiple Synchronous Sporadic Gastrointestinal Stromal Tumors in the Stomach and Jejunum

A 77-year-old patient was admitted to our hospital for the further examination of melena. A computed tomography scan detected two submucosal tumors (SMTs) in the stomach and jejunum. Double-balloon endoscopy revealed the presence of a delle on the jejunal SMT, suggesting that the SMT was the origin of the gastrointestinal bleeding. Both tumors were surgically resected and subsequently diagnosed via histology as gastrointestinal stromal tumors (GISTs). Furthermore, the two GISTs had different mutations in the c-kit gene, suggesting that they were derived from different clonal origins. This report depicts an extremely rare case of multiple synchronous sporadic GISTs in the stomach and jejunum.

The efficacy of steroids for postoperative persistent inflammatory reaction in a patient with barium peritonitis: A case report

Highlights • Residual barium in intraperitoneal cavity causes persistent inflammatory reaction.• Steroids are effective for persistent inflammation caused by residual barium.• If infectious or other inflammation origins exist, steroids should be avoided.