Cancer cell­induced tissue inhibitor of metalloproteinase­1 secretion by cancer­associated fibroblasts promotes cancer cell migration.

Cancer­associated fibroblasts (CAFs) are one of the major components of the cancer stroma in the tumor microenvironment. The interaction between cancer cells and CAFs (cancer­stromal interaction; CSI) promotes tumor progression, including metastasis. Recently, the tissue inhibitor of metalloproteinase­1 (TIMP­1) was reported to promote cancer cell migration and metastasis, which is contrary to its anticancer role as an inhibitor of matrix metalloproteinase. Moreover, CAF­derived TIMP­1 is reported to regulate CAF activity. In the present study, we investigated the effect of TIMP­1 on colon cancer cell migration in vitro. The TIMP­1 secretion levels from the CAFs and cancer cell lines were comparatively measured to determine the main source of TIMP­1. Furthermore, the effect of CSI on TIMP­1 secretion was investigated using the Transwell co­culture system. Cancer cell migration was evaluated using the wound­healing assay. The results demonstrated that TIMP­1 promoted the migration of LoVo cells, a colon cancer cell line, whereas TIMP­1 neutralization inhibited the enhanced migration. The TIMP­1 levels secreted from the cancer cells were approximately 10 times less than those secreted from the CAFs. TIMP­1 secretion was higher in CAFs co­cultured with cancer cells than in monocultured CAFs. Furthermore, the migration of LoVo cells increased upon co­culturing with the CAFs. TIMP­1 neutralization partially inhibited this enhanced migration. These results suggest that CAFs are the primary source of TIMP­1 and that the TIMP­1 production is enhanced through CSI in the tumor microenvironment, which promotes cancer cell migration.

The expression of carcinoembryonic antigen mRNA in the lavage of the dissected area of the lateral lymph nodes influences the lateral recurrence of lower rectal cancer.

PURPOSE: To determine whether or not migrating cancer cells are present on the surgical plane after lateral lymph node dissection (LLND) for lower rectal cancer and related to lateral recurrence (LR), we evaluated the lavage of LLND areas by reverse-transcription polymerase chain reaction (RT-PCR) to check the expression of CEA mRNA in the residual cancer cells. METHODS: Thirty patients who underwent curative LLND were enrolled. Lavage was collected after LLND and subjected to RT-PCR to detect CEA mRNA. The median follow-up to check for recurrence was 31.4 months. RESULTS: CEA mRNA was detected in 9 of the 46 dissected areas. Based on the receiver operating characteristic curves, the cut-off value of PCR was set at 0.025. This cut-off point classified five patients into the high-expression group for CEA mRNA. During follow-up, LR developed in 1 of 40 low-expression areas of CEA mRNA and 3 of 6 high-expression areas. The LR rate was higher in the high-expression group than in the low-expression group (p = 0.015). A multivariate analysis showed that the high expression of CEA mRNA was likely an independent prognostic factor of LR. CONCLUSION: The expression of CEA mRNA in the lavage of LLND areas indicates the presence of residual cancer cells that cause LR.

[Review of High-Risk Factors and Adjuvant Chemotherapy Indication in T4-pStage â ¡ Colon Cancer].

BACKGROUND: T4 is one of the high-risk factors, but the efficacy of adjuvant chemotherapy for T4-Stage Ⅱ colon cancer are unclear. METHOD: We retrospectively reviewed 211 patients with primary pStage Ⅱ colon cancer who underwent radical resection between 2004 and 2015. RESULTS: The 5-year overall survival rate(OS)of Stage ⅡA/ⅡB/ⅡC were 90.2/83.4/ 59.2%, and the 5-year recurrence-free survival rate(RFS)were 87.3/73.3/42.8%. Multivariate analysis of OS as a high-risk factor of T4 revealed male, ly2/3, no adjuvant chemotherapy, and in RFS, male, ly2/3. However, compared the cases with or without adjuvant chemotherapy, 5-year OS was no difference. There were no cases used oxaliplatin-based adjuvant chemotherapy. CONCLUSION: An adjuvant chemotherapy without oxaliplatin were not enough to improve the prognoses of T4-Stage Ⅱcolon cancer, so the oxaliplatin based regimen might be recommended.

Eicosapentaenoic acid suppresses angiogenesis via reducing secretion of IL­6 and VEGF from colon cancer­associated fibroblasts.

Eicosapentaenoic acid (EPA) improves interleukin (IL)­6 hypercytokinemia in patients with advanced cancer due to its anti­inflammatory effects. This EPA mechanism has been revealed to lead to several anticancer effects. While the effects of EPA on cancer cells have been investigated, particularly in terms of angiogenesis, its effects on the tumor stroma remain unclear. In the present study, the authors clarified the role of EPA in cancer angiogenesis against colon cancer­associated fibroblasts (CAFs) from the colon stroma. With established human CAFs and normal fibroblasts from colon stroma (NFs), the authors evaluated IL­6 and vascular endothelial growth factor (VEGF) secretion with or without EPA treatment using ELISA. The signal inhibition of mitogen­activated protein kinase (ERK) in CAFs by EPA was evaluated using western blotting. In vitro anti­angiogenesis effects were evaluated by the angiogenesis assay on Matrigel using human umbilical vein endothelial cells (HUVECs) cultured with the supernatant obtained from CAF cultures with or without EPA. IL­6 secretion was greater from CAFs compared with that from NFs and stimulation with lipopolysaccharide (LPS) resulted in greater IL­6 secretion from the two fibroblast types compared with that from fibroblasts without LPS stimulation. While LPS stimulation increased VEGF secretion from the two fibroblast types, EPA decreased IL­6 and VEGF secretion from CAFs. Western blotting revealed that the addition of 30 µM EPA inhibited the ERK phosphorylation signal in CAFs. Furthermore, the angiogenesis assay with Matrigel revealed that the CAF culture supernatants treated with EPA suppressed tubular formation in HUVECs. These reductions may have been caused by the inhibition of ERK phosphorylation by EPA. Thus, EPA reduces cancer angiogenesis associated with CAFs. Additional studies will be needed to clarify the continuous anti­angiogenetic effect of chemotherapy using angiogenesis inhibitors (e.g. bevacizumab and aflibercept) in conjunction with or without EPA, and the clinical usage of EPA in conjunction with chemotherapy in vivo.

Laparoscopic extraperitoneal sigmoid colostomy using the totally extraperitoneal hernia repair technique after abdominoperineal resection for rectal cancer.

Stoma creation through the extraperitoneal route reportedly reduces the risk of parastomal hernia and stomal prolapse after abdominoperineal resection (APR) for rectal cancer. We describe a new technique for laparoscopic extraperitoneal sigmoid colostomy following APR. After the rectus abdominis muscle is separated, Lap ProtectorTM and EZ AccessTM devices are placed. An extraperitoneal stoma tunnel is created laparoscopically as much as possible. Next, the peritoneum is separated from the inside of the abdominal cavity, and the extraperitoneal tunnel is opened. At the time of writing, we had performed laparoscopic extraperitoneal sigmoid colostomy in eight patients, without any complications or conversion to the conventional procedure. Thus, laparoscopic extraperitoneal sigmoid colostomy is a useful and safe technique for the laparoscopic creation of an extraperitoneal stoma tunnel after APR.

No inflammatory benefit obtained by single-incision laparoscopic surgery for right hemicolectomy compared with conventional laparoscopy.

PURPOSE: We evaluated the perioperative inflammatory mediators in a right hemicolectomy performed with single-incision laparoscopic surgery (SILS) and traditional multi-port laparoscopic surgery (MLS) to compare the postoperative inflammatory response and feasibility of SILS with that of MLS. METHODS: In this retrospective study, we enrolled 56 consecutive colorectal cancer patients who underwent right hemicolectomy prospectively. Twenty patients underwent SILS, and 36 underwent MLS. The preoperative and postoperative levels of plasma vascular endothelial growth factor (VEGF), serum interleukin-6 (IL-6), and C-reactive protein (CRP) as well as the number of platelet cells were measured in all patients. The operation duration, number of harvested lymph nodes, length of the resected bowel, blood loss, and duration of hospital stay were also compared between the two groups. RESULTS: Neither SILS nor MLS had any conversion cases. The operation duration was longer for MLS than for SILS. Blood loss tended to be lower among patients who underwent SILS than among those who underwent MLS. However, the number of harvested LNs was significantly lower with SILS than with MLS. In both pre- and postoperative blood examinations, there was no marked difference in inflammatory mediators between MLS and SILS. CONCLUSION: There was no systemic inflammatory advantage associated with SILS compared with MLS.