Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression.

Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.

PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages.

Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy.

Outcomes of Laparoscopic Surgery in Colorectal Cancer Patients With Dialysis.

BACKGROUND/AIM: To investigate the outcomes of laparoscopic surgery in colorectal cancer patients with dialysis. PATIENTS AND METHODS: Fourteen dialysis (dialysis group) and 567 non-dialysis (non-dialysis group) patients who underwent laparoscopic and open surgery for colorectal cancer between April 2008 and December 2015 were included. Short-term and long-term outcomes were compared between the groups. A 1:2 propensity score matching was performed to compare long-term outcomes. RESULTS: All the dialysis patients underwent laparoscopic surgery. There were no significant differences in operative outcomes and postoperative short-term outcomes between the two groups. In the whole cohort, overall survival of dialysis patients was shorter than that in the non-dialysis ones (p=0.020), while disease-free survival did not differ between the two groups. After matching, there was no significant difference between the groups in overall or disease-free survival. CONCLUSION: Laparoscopic colorectal cancer surgery for dialysis patients seems safe and feasible and associates with comparable short-term outcome and recurrence rate to non-dialysis patients.

ANXA10 induction by interaction with tumor-associated macrophages promotes the growth of esophageal squamous cell carcinoma.

Tumor-associated macrophages (TAMs) have important roles in the growth, angiogenesis and progression of various tumors. Although we have demonstrated the association of an increased number of infiltrating CD204+ TAMs with poor prognosis in esophageal squamous cell carcinomas (ESCCs), the roles of TAMs in ESCC remain unclear. Here, to study the effects of TAMs on the tumor microenvironment of ESCCs, we established a co-culture assay using a human ESCC cell line and TAM-like peripheral blood monocyte-derived macrophages and performed a cDNA microarray analysis between monocultured and co-cultured ESCC cell lines. Our qRT-PCR confirmed that in the co-cultured ESCC cell lines, CYP1A1, DHRS3, ANXA10, KLK6 and CYP1B1 mRNA were highly up-regulated; AMTN and IGFL1 mRNA were down-regulated. We observed that the high expression of a calcium-dependent phospholipid-binding protein ANXA10 was closely associated with the depth of invasion and high numbers of infiltrating CD68+ and CD204+ TAMs and poor disease-free survival (P = 0.0216). We also found ANXA10 promoted the cell growth of ESCC cell lines via the phosphorylation of Akt and Erk1/2 pathways in vitro. These results suggest that ANXA10 induced by the interaction with TAMs in the tumor microenvironment is associated with cell growth and poor prognosis in human ESCC tissues.

Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with frequent recurrence even after curative resection. The tumor microenvironment, which consists of non-cancer cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), was recently reported to promote several cancers, including ESCC. However, the role of CAF as a coordinator for tumor progression in ESCC remains to be elucidated. In our immunohistochemical investigation of ESCC tissues, we observed that the intensity of expression of two CAF markers-alpha smooth muscle actin (αSMA) and fibroblast activation protein (FAP)-in the tumor stroma was significantly correlated with the depth of tumor invasion, lymph node metastasis, advanced pathological stage, and poor prognosis. We co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of FAP expression in the co-cultured MSCs. These FAP-positive MSCs (which we defined as CAF-like cells) promoted the cell growth and migration of ESCC cells and peripheral blood mononuclear cell-derived macrophage-like cells. CAF-like cells induced the M2 polarization of macrophage-like cells. A cytokine array and ELISA revealed that CAF-like cells secreted significantly more CCL2, Interleukin-6, and CXCL8 than MSCs. These cytokines promoted the migration of tumor cells and macrophage-like cells. The silencing of FAP in CAF-like cells attenuated cytokine secretion. We compared cell signaling of MSCs, CAF-like cells, and FAP-silenced CAF-like cells; PTEN/Akt and MEK/Erk signaling were upregulated and their downstream targets, NF-κB and ß-catenin, were also activated with FAP expression. Silencing of FAP attenuated these effects. Cytokine secretion from CAF-like cells were attenuated by inhibitors against these signaling pathways. These findings indicate that the collaboration of CAFs with tumor cells and macrophages plays a pivotal role in tumor progression, and that FAP expression is responsible for the tumor promotive and immunosuppressive phenotypes of CAFs.

Recent updates in the surgical treatment of colorectal cancer.

Because of recent advances in medical technology and new findings of clinical trials, treatment options for colorectal cancer are evolutionally changing, even in the last few years. Therefore, we need to update the treatment options and strategies so that patients can receive optimal and tailored treatment. The present review aimed to elucidate the recent global trends and update the surgical treatment strategies in colorectal cancer by citing the literature published in the last 2 years, namely 2016 and 2017. Although laparoscopic surgery is still considered the most common approach for the treatment of colorectal cancer, new surgical technologies such as transanal total mesorectal excision, robotic surgery, and laparoscopic lateral pelvic lymph node dissection are emerging. However, with the recent evidence, superiority of the laparoscopic approach to the open approach for rectal cancer seems to be controversial. Surgeons should notice the risk of adverse outcomes associated with unfounded and uncontrolled use of these novel techniques. Many promising results are accumulating in preoperative and postoperative treatment including chemotherapy, chemoradiotherapy, and targeted therapy. Development of new biomarkers seems to be essential for further improvement in the treatment outcomes of colorectal cancer patients.

CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells.

Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 (CXCL8) was up-regulated in the TAM-like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines' migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells' migration and invasion.

[Transnasal and transanal tube decompression versus self-expanding metallic stent as a bridge to surgery for obstructive colorectal cancer].

PURPOSE: The aim of this study was to compare the efficacy between the use of transnasal and transanal tube decompression and self-expanding metallic stents (SEMS) as a bridge to surgery for obstructive colorectal cancer. MATERIALS: Of a total of 42 patients with obstructive colorectal cancer, 29 were managed with transnasal or transanal tubes and 13 were managed by SEMS. RESULTS: The management duration to surgery in the stent group was longer than that in the tube group (18 vs 11 days; p<.05). More patients in the stent group could be discharged and take food or liquid normally. There was no difference in overall complications including anastomotic leakage, surgical side effects, or primary anastomosis. Perforation occurred in 2 patients in the tube group, while stent migration occurred in 1 patient in the stent group. There was no difference in complications between 2 groups. CONCLUSIONS: SEMS as a bridge to surgery for obstructive colorectal cancer could improve patients' quality of life during the preoperative period. Evaluations of the complications during decompression are needed for both methods.

[Therapeutic strategy for perforated colorectal cancer].

A total of 37 patients were surgically treated for a colorectal perforation between May 2006 and December 2013. The patients were divided into 2 groups: those with perforation due to colorectal cancer(colorectal cancer group, n=12) and those with perforation due to benign colorectal disease(non-colorectal cancer group, n=25). We examined the influence that onset near the perforation had on colorectal cancer clinical outcome. There was no significant difference in patient backgrounds between the two groups. In the colorectal cancer group, curative resections were performed in eight of the cases (67%), while there were 7 cases (58%) of regional lymph node dissection and all patients received a stoma without bowel anastomosis. In the colorectal cancer group, 1 patient (8%) died of a pulmonary embolism after surgery, whereas 2 patients (8.3%) in the non-colorectal cancer group died of sepsis after surgery. Nine of those patients (75%) received adjuvant chemotherapy. Four patients survived without recurrence. Prompt judgment of the disease severity and selection of optical surgical procedures including tumor resection and regional lymph node dissection is important for colorectal cancer perforation, and an adjuvant setting for the purpose of the long-term survival is necessary.

[Long-term survival of a patient with extrahepatic cholangiocarcinoma treated with adjuvant radiotherapy for positive ductal margins after surgical resection].

A 57-year-old man with abdominal discomfort visited our hospital. Abdominal computed tomography (CT) revealed no tumorous lesions. Endoscopic retrograde cholangiography (ERC) revealed a tumorous lesion in the middle bile duct. Peroral cholangioscopy-assisted biopsy was performed, and the lesion was diagnosed as a papillary adenocarcinoma. Extra bile duct resection and regional lymph node dissection were performed; however, residual carcinoma in situ was detected at the ductal margins by intraoperative frozen section analysis. Therefore, external radiation therapy at a dose 50.4 Gy/28 Fr was administered after the operation. No complication due to radiotherapy occurred. The patient remains alive and recurrence -free for more than 7 years after the operation. We report the long-term disease-free survival of a patient with extrahepatic cholangiocarcinoma who was treated with external radiation therapy for positive ductal margins after surgical resection.