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Background Intestinal perfusion at the anastomotic site is thought to be one of the most influential risk factors for postoperative anastomotic leakage (AL). We evaluated the efficacy of indocyanine green (ICG) fluorescence imaging at the stump of the proximal colon in left-sided colectomy or rectal resection in terms of decreasing the incidence of AL.MethodsProspectively collected data were retrospectively evaluated. Patients who underwent left-sided colectomy or rectal resection were enrolled (ICG group; n = 197), and patients who had undergone a similar procedure before the ICG group were enrolled from the charts as historical controls (HC group; n = 187). After ICG evaluation, anastomosis was performed where fluorescence was sufficient. The incidence of AL was compared between the ICG and HC groups. Propensity score (PS)-matched data were analyzed to clarify the risk of AL.ResultsAL occurred in 6 patients (3.3%) in the ICG group and 17 (10.7%) in the HC group. ICG evaluation revealed 179 patients with good fluorescence and 18 with poor/none perfusion (9.1%). The transection line was changed in all patients with poor/none fluorescence. Three of these 18 patients developed AL (16.7%), though transection line was changed at which is thought to be good. We hope AL in poor/none fluorescence can be prevented at the same rate of cases with good fluorescence. Actually, the rate of that was significantly higher compared with good fluorescence patients (P = 0.038). 93 patients in each group were compared by PS-matched data analysis, which showed the AL rate in the ICG group was significantly lower than that in the HC group (3.2% vs 10.8%, respectively; P = 0.046).ConclusionsEven though this study has limitations of comparison of data prospectively collected and retrospectively analyzed, intraoperative ICG fluorescence imaging evaluation could significantly decrease the incidence of AL.

Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor‐κB (NF‐κB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF‐κB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF‐κB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin‐8 (IL‐8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC‐3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC‐3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki‐67 expression, CD31‐positive microvessel density, NF‐κB p65 expression, and VEGF and IL‐8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF‐κB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer. Xanthohumol significantly inhibited tumor growth in a nude mice subcutaneous xenograft model. Moreover, loss of body weight was not observed.

The cancer-stromal interaction has been demonstrated to promote tumor progression, and cancer-associated fibroblasts (CAFs), which are the main components of stromal cells, have attracted attention as novel treatment targets. Chitinase 3-like 1 (CHI3L1) is a chitinase-like protein, which affects cell proliferation and angiogenesis. However, the mechanisms through which cells secrete CHI3L1 and through which CHI3L1 mediates tumor progression in the cancer microenvironment are still unclear. Accordingly, the present study assessed the secretion of CHI3L1 in the microenvironment of colorectal cancer and evaluated how CHI3L1 affects tumor angiogenesis. CAFs and normal fibroblasts (NFs) established from colorectal cancer tissue, and human colon cancer cell lines were evaluated using immunostaining, cytokine antibody array, RNA interference, reverse transcription-quantitative PCR (RT-qPCR), ELISA, western blotting and angiogenesis assays. The expression and secretion of CHI3L1 in CAFs were stronger than those in NFs and colorectal cancer cell lines. In addition, interleukin-13 receptor α2 (IL-13Rα2), a receptor for CHI3L1, was not expressed in colorectal cancer cell lines, but was expressed in fibroblasts, particularly CAFs. Furthermore, the expression and secretion of IL-8 in CAFs was stronger than that in NFs and cancer cell lines, and recombinant CHI3L1 addition increased IL-8 expression in CAFs, whereas knockdown of CHI3L1 suppressed IL-8 expression. Furthermore, IL-13Rα2 knockdown suppressed the enhancement of IL-8 expression induced by CHI3L1 treatment in CAFs. For vascular endothelial growth factor-A (VEGFA), similar results to IL-8 were observed in an ELISA for comparison of secretion between CAFs and NFs and for changes in secretion after CHI3L1 treatment in CAFs; however, no significant differences were observed for changes in expression after CHI3L1 treatment or IL-13Rα2 knockdown in CAFs assessed using RT-qPCR assays. Angiogenesis assays revealed that tube formation in vascular endothelial cells was suppressed by conditioned medium from CAFs with the addition of human CHI3L1 neutralizing antibodies compared with control IgG, and also suppressed by conditioned medium from CAFs transfected with CHI3L1, IL-8 or VEGFA small interfering RNA compared with negative control small interfering RNA. Overall, the present findings indicated that CHI3L1 secreted from CAFs acted on CAFs to increase the secretion of IL-8, thereby affecting tumor angiogenesis in colorectal cancer.

Apigenin is a natural flavonoid that exhibits anti-proliferative activity and induces apoptosis in various types of cancer, including colon cancer. The aim of the present study was to determine the mechanism underlying the apoptosis-inducing effect of apigenin in colon cancer. Apigenin reduced the proliferation of colon cancer cell lines, stimulated the cleavage of PARP and induced apoptosis in a dose-dependent manner. Apigenin treatment also suppressed the expression of the anti-apoptotic proteins Bcl-xL and Mcl-1. Small interfering RNA was used to knockdown Bcl-xL and Mcl-1 expression alone and in concert, and the proliferation and apoptosis of cancer cells were subsequently measured. The knockdown of Bcl-xL and Mcl-1 expression together markedly suppressed cell proliferation and induced apoptosis. Apigenin treatment also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which targets Bcl-xL and Mcl-1. The results of the current study therefore determined that apigenin induces the apoptosis of colon cancer cells by inhibiting the phosphorylation of STAT3 and consequently downregulates the anti-apoptotic proteins Bcl-xL and Mcl-1.

Cancer-associated fibroblasts (CAFs) are one of the major components of the cancer stroma in the tumor microenvironment. The interaction between cancer cells and CAFs (cancer-stromal interaction; CSI) promotes tumor progression, including metastasis. Recently, the tissue inhibitor of metalloproteinase-1 (TIMP-1) was reported to promote cancer cell migration and metastasis, which is contrary to its anticancer role as an inhibitor of matrix metalloproteinase. Moreover, CAF-derived TIMP-1 is reported to regulate CAF activity. In the present study, we investigated the effect of TIMP-1 on colon cancer cell migration in vitro. The TIMP-1 secretion levels from the CAFs and cancer cell lines were comparatively measured to determine the main source of TIMP-1. Furthermore, the effect of CSI on TIMP-1 secretion was investigated using the Transwell co-culture system. Cancer cell migration was evaluated using the wound-healing assay. The results demonstrated that TIMP-1 promoted the migration of LoVo cells, a colon cancer cell line, whereas TIMP-1 neutralization inhibited the enhanced migration. The TIMP-1 levels secreted from the cancer cells were approximately 10 times less than those secreted from the CAFs. TIMP-1 secretion was higher in CAFs co-cultured with cancer cells than in monocultured CAFs. Furthermore, the migration of LoVo cells increased upon co-culturing with the CAFs. TIMP-1 neutralization partially inhibited this enhanced migration. These results suggest that CAFs are the primary source of TIMP-1 and that the TIMP-1 production is enhanced through CSI in the tumor microenvironment, which promotes cancer cell migration.

The repair of DNA damage caused by chemotherapy in cancer cells occurs mainly at two cell cycle checkpoints (G1 and G2) and is a factor contributing to chemoresistance. Most colorectal cancers harbor mutations in p53, the main pathway involved in the G1 checkpoint, and thus, are particularly dependent on the G2 checkpoint for DNA repair. The present study examined the effect of AZD6738, a specific inhibitor of ataxia telangiectasia mutated and rad3-related (ATR) involved in the G2 checkpoint, combined with 5-fluorouracil (5-FU), a central chemotherapeutic agent, on colorectal cancer cells. Since 5-FU has a DNA-damaging effect, its combination with AZD6738 is likely to enhance the therapeutic effect. The effects of the AZD6738/5-FU combination were evaluated in various colorectal cancer cells (HT29, SW480, HCT116 and DLD-1 cells) by flow cytometry (HT29 cells), western blotting (HT29 cells) and water-soluble tetrazolium 1 assays (HT29, SW480, HCT116 and DLD-1 cells), as well as in an experimental animal model (HT29 cells). In vitro, the AZD6738/5-FU combination increased the number of mitotic cells according to flow cytometry, decreased the checkpoint kinase 1 phosphorylation levels and increased cleaved caspase-3 and phosphorylated form of H2A.X variant histone levels according to western blotting, and decreased the proliferation rate of four colon cancer cell lines according to cell viability experiments. In vivo, xenografted colorectal cancer cells treated with the AZD6738/5-FU combination exhibited a marked decrease in proliferation compared with the 5-FU alone group. The present results suggested that AZD6738 enhanced the effect of 5-FU in p53-mutated colorectal cancer.

The acquisition of resistance to apoptosis is one of the biggest problems in colorectal cancer (CRC) treatment. This study aimed to elucidate the mechanisms of resistance to apoptosis with a focus on interleukin (IL)-6 produced by the interaction between cancer cells and cancer-associated fibroblasts (CAFs). DLD-1 and HCT116 cell lines were treated with IL-6 and furthermore co-cultured with CAFs. The expression levels of Bcl-xL, Mcl-1 and phosphorylation of STAT3 were evaluated by western blotting. We also performed immunostaining for CRC specimens and evaluated the correlation between CAFs invasion and Bcl-xL/Mcl-1 expression. Both IL-6 and co-culturing enhanced Bcl-xL, Mcl-1 and the phosphorylation of STAT3. Immunohistochemistry showed a positive correlation between CAFs and Bcl-xL/Mcl-1. These results showed that the interaction between CAFs and cancer cells enhances Bcl-xL and Mcl-1 through the IL-6/STAT3 signaling pathway. Our findings provide new potential therapeutic targets and strategies for CRC treatment.

Eicosapentaenoic acid (EPA) improves interleukin (IL)-6 hypercytokinemia in patients with advanced cancer due to its anti-inflammatory 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 cancer-associated fibroblasts (CAFs) from the colon stroma. With established human CAFs and normal fibroblasts from colon stroma (NFs), the authors evaluated IL-6 and vascular endothelial growth factor (VEGF) secretion with or without EPA treatment using ELISA. The signal inhibition of mitogen-activated protein kinase (ERK) in CAFs by EPA was evaluated using western blotting. In vitro anti-angiogenesis 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. IL-6 secretion was greater from CAFs compared with that from NFs and stimulation with lipopolysaccharide (LPS) resulted in greater IL-6 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 IL-6 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 anti-angiogenetic 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.

Background Indocyanine green (ICG) fluorescence imaging is widely used in gastrointestinal surgery and is considered useful for reducing anastomotic leakage; however, because ICG remains in the tissue for a certain amount of time, we occasionally must re-evaluate colonic blood flow over a short time period during surgery. Herein, we verify the usefulness of thermography (TG) for evaluating colonic blood flow in a patient who underwent a laparoscopic sigmoidectomy for sigmoid colon cancer. Case presentation The patient is 43-year-old man who underwent laparoscopic resection of the sigmoid colon for colon cancer. After vascular treatment of the colonic mesentery, ICG/TG identified the boundary between ischemic and non-ischemic colon tissues. An additional 2 cm of colonic mesentery was resected because of the presence of a diverticulum noted at the intended site of oral anastomosis when attaching the anvil head. After additional vascular treatment of the colonic mesentery and administration of ICG, fluorescence was observed in the colon; however, TG identified the zone of the temperature transition on the surface of the colonic mesentery, even after additional colonic mesentery resection in the same region as previously observed. This zone was used as the cut-off line. There were no complications, such as anastomotic leakage, after the surgery. Conclusion Although accumulation of similar cases is necessary, TG has the potential for use as an auxiliary diagnostic tool in clinical practice. TG can depict the presence or absence of blood flow based on surface temperature without the use of imaging agents, and is inexpensive and easy to perform.

Background In laparoscopic colorectal surgery, accurate localization of a tumor is essential for ensuring an adequate ablative margin. Therefore, a new method, near-infrared laparoscopy combined with intraoperative colonoscopy, was developed for visualizing the contour of a cecal tumor from outside of the bowel. The method was used after it was verified on a model that employed a silicone tube. Case presentation The patient was a 77-year-old man with a cecal tumor near the appendiceal orifice. Laparoscopy was used to clamp of the terminal ileum, and a colonoscope was then inserted through the anus to the cecum. The laparoscope in the normal light mode could not be used to identify the cecal tumor. However, a laparoscope in the near-infrared ray mode could clearly visualize the contour of the cecal tumor from outside of the bowel, and the tumor could be safely resected by a stapler. The histopathological diagnosis of the resected specimen was adenocarcinoma with an invasion depth of M and a clear negative margin. Conclusions This is the first report of the laparoscopic detection of the contour of a cecal tumor from outside the bowel. This technique is useful and safe for contouring tumors in laparoscopic colorectal surgery and can be used in various surgeries that combine endoscopy and laparoscopy.