The risk of metastatic recurrence after non-curative endoscopic resection with negative deep margins for early colorectal cancer: Two-center retrospective cohort study.

INTRODUCTION: Non-curative endoscopic resection of T1 colorectal cancers (CRC) carries a substantial risk of recurrence. However, previous studies have reported a significant proportion of cases in which the deep margin of endoscopic resection was positive for cancer due to the technical difficulties of colorectal endoscopic submucosal dissection (ESD). With the advancement of endoscopic technology and techniques resulting in the reduction of positive resection margins, it is important to reassess the long-term prognosis and major risk factors for recurrence in cases of negative deep margins. METHODS: We conducted a retrospective cohort study of consecutive patients with T1 CRC who underwent endoscopic resection between January 2006 and December 2021 with negative deep margins. Histological findings of the resected specimens were analyzed to determine the risk factors associated with the primary outcomes of this study, including recurrence and cancer-related deaths. RESULTS: The median age of the 190 patients was 70 years, of which 63% were male, and endoscopic treatment was performed in 64% by endoscopic mucosal resection and 36% by ESD. Eighty two patients were in the curative resection (CR) group and 108 were in the non-curative resection (NCR) group, wherein the latter comprised 79 patients who underwent additional surgery (AS) and 29 patients who did not receive AS. Five-year recurrence-free survival rates were 98.4% (95% CI 89.3-99.8) for CR, 98.3% (95% CI 88.8-99.8) for NCR with AS, and 73.7% (95% CI 46.5-88.5) for NCR without AS. Lymphatic invasion and budding grade 2/3 were the major risk factors for recurrence, with hazard ratios of 40.7 (p<0.001) and 23.1 (p=0.007), respectively. Of the patients in the NCR group without AS, the five-year recurrence-free rate was 85.6% (95% CI 52.5-96.3) if there were no major risk factors (i.e. no lymphatic invasion or budding grade 2/3) (n=21), whereas the prognosis was poor in the presence of one or more of the major risk factors, with a median recurrence-free survival and disease-specific survival of 2.5 and 3.1 years, respectively (n=8). DISCUSSION/CONCLUSION: In endoscopically resected T1 CRC with negative deep margins, lymphatic invasion or budding grade 2/3 may indicate a higher risk of recurrence when followed up without additional surgery.

Risk factors for postgastric endoscopic submucosal dissection bleeding in direct oral anticoagulant users.

OBJECTIVES: Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs. METHODS: We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding. RESULTS: The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran. CONCLUSIONS: The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD.

Dasatinib-induced colitis: clinical, endoscopic and histological findings.

BACKGROUND: Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with haematological malignancies. The main side effects of dasatinib are myelosuppression and pleural effusion; however, colitis, such as haemorrhagic colitis and cytomegalovirus (CMV) colitis, have been reported as rare side effects. There are only a few studies conducted on dasatinib-induced colitis. AIMS: This study aimed to clarify the clinical, endoscopic and pathological features of dasatinib-induced colitis. METHODS: This retrospective study included 51 consecutive patients who received dasatinib therapy between June 2009 and July 2020. Dasatinib-induced colitis was defined as the presence of colitis symptoms, exclusion of other diseases that could cause colitis, and improvement in symptoms after dasatinib withdrawal or dose reduction. CMV positivity was determined based on the positive result of CMV immunostaining. RESULTS: Dasatinib-induced colitis was diagnosed in nine of 51 patients (17.6%), and most of the symptoms were mild diarrhoea and bloody stools. The endoscopic findings were characterised by loss of vascular pattern (100%) and multiple small erosions (83.3%) which were mainly found in the transverse and descending colon. In a patient who underwent follow-up colonoscopy once a year while taking dasatinib, endoscopic findings changed from initial erythematous spots to multiple erosions, and finally to multiple small round elevations with erosion on the top that disappeared after discontinuation of dasatinib. Anti-CMV therapy was administered to one patient, but the treatment failed. All patients with dasatinib-induced colitis were cured after the discontinuation of dasatinib. CONCLUSION: Physicians should consider CMV reactivation to manage dasatinib-induced colitis.

Risk Factors for Gallstones and Cholecystectomy: A Large-Scale Population-Based Prospective Cohort Study in Japan.

INTRODUCTION: Studies investigating the risk of gallstones in the Japanese population are sparse. To our knowledge, this is the first prospective cohort study assessing risk factors of gallstones in Japan. METHODS: A nationwide population-based prospective cohort of 112,109 men and women, aged 40-69 years, self-completed questionnaires at baseline regarding exposures to potential risk factors, between 1990 and 1994. The occurrence of gallstones and cholecystectomy for gallstones were ascertained from another questionnaire after 10 years. Odds ratios and the 95% confidence intervals were calculated using the multivariate logistic regression. RESULTS: During the 10-year follow-up, 3,092 (5.0%) participants developed gallstones and 729 (1.2%) participants required cholecystectomy. Increasing age, high body mass index, and diabetes mellitus were associated with the risk of gallstones in both sexes. In men, weight gain or loss of >5 kg over the follow-up period and stress were associated with risk of gallstones, whereas alcohol intake was inversely associated with the risk. In women, weight gain of >5 kg during the follow-up period, smoking, menopause, and lipid-lowering drugs were associated with risk of gallstones, whereas late onset of menarche was inversely associated with risk of gallstones. The risk of cholecystectomy broadly reflected the risk of gallstones for both sexes respectively. CONCLUSION: Risk factors for both gallstones and cholecystectomy for gallstones are multifactorial and differ between men and women. Novel findings in this study include an inverse association between late onset of menarche and gallstones, and an association between self-reported stress in men and gallstones.

Anti-proteinase 3 antineutrophil cytoplasmic antibody reflects disease activity and predicts the response to steroid therapy in ulcerative colitis.

BACKGROUND: Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin. METHODS: This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission. RESULTS: Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5-9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54-17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023). CONCLUSIONS: PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC. TRIAL REGISTRATION: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.

Efficacy and Safety of Ramucirumab/nab-paclitaxel for Previously Treated Advanced Gastric Cancer in Community Hospitals.

As the nanoparticle albumin-bound paclitaxel (nab-PTX) is free of ethanol and premedication, the duration of administration is shorter and patients can drive themselves to and from the hospital. In the 2018 Japanese gastric cancer treatment guidelines, ramucirumab (RAM) plus weekly nab-PTX is conditionally recommended for previously treated patients with advanced gastric cancer. Here, we retrospectively analysed the efficacy and safety of RAM+nab-PTX for such patients in community hospitals. From January 2018 to December 2019, 43 patients with metastatic and recurrent gastric cancer received RAM+nab-PTX treatment. Six patients (13.9%) were older than 80 years and 9 patients (20.9%) showed ECOG-PS 2. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs) were reviewed retrospectively. Median PFS was 114 days (95% confidence interval [CI]: 84-190) and median OS was 297 days (95% CI: 180-398). ORR and DCR were 32.4% and 72.2%, respectively. The incidence rates of ≥grade 3 neutropenia and febrile neutropenia were 53.5% and 2.3%, respectively. No treatment-related deaths occurred. RAM plus nab-PTX combination therapy demonstrated manageable toxicity even patients who were elderly or had an ECOG-PS 2. This treatment is useful in community hospital settings.

Mitochondrial pyruvate carrier 1 expression controls cancer epithelial-mesenchymal transition and radioresistance.

Mitochondrial pyruvate carrier (MPC) is known to cause different expressions in normal and cancer cells. We observed a change in phenotype with the suppression of MPC expression. We knocked down MPC1 and/or MPC2 using siRNA or shRNA. We observed its cell morphology and accompanying molecular marker. Furthermore, the radioresistance of the MPC knockdown cell line was examined using a colony formation assay. MPC1-suppressed cells changed their morphology to a spindle shape. Epithelial-mesenchymal transition (EMT) was suspected, and examination of the EMT marker by PCR showed a decrease in E-cadherin and an increase in fibronectin. Focusing on glutamine metabolism as the mechanism of this phenomenon, we knocked down the glutamine-metabolizing enzyme glutaminase (GLS). EMT was also observed in GLS-suppressed cells. Furthermore, when MPC1-suppressed cells were cultured in a glutamine-deficient medium, changes in EMT markers were suppressed. In addition, MPC1-suppressed cells also increased with a significant difference in radioresistance. Decreased MPC1 expression favorably affects EMT and radioresistance of cancer.

A novel physical colonoscopy simulator based on analysis of data from computed tomography colonography.

PURPOSE: Laparoscopic surgery is now practiced widely because of its lower postoperative morbidity. As flexible endoscopy during laparoscopic surgery minimizes surgical trauma further, training in endoscopy will become more important for surgeons. Thus, we designed a physical simulator, the Noda-Kitada-Suzuki (NKS) model, which could provide the more realistic insertion of a colonoscope. METHODS: We designed a colonoscopy simulator, based on information from computed tomography colonography scans of the anatomy and kinetic properties of the colon and rectum. RESULTS: The transparent skeleton body of the NKS model provides instant visual feedback to the operator and the trainer. Our novel colonoscopy simulator replicates the realistic and reproducible insertion of a colonoscope from the rectum to cecum, providing authentic views of the Houston's valves, the flexures, and mucosal folds. This was verified through an objective questionnaire, with 14 of 16 colonoscopists preferring the NKS model over the previous CM15 model for training purposes. Moreover, the Modified Colonoscopy Simulator Realism Questionnaire analysis confirmed that the NKS model was significantly more realistic than the CM15 for 7 (21.2%) of the 33 items when assessed by 12 colonoscopists. CONCLUSION: The NKS model provides a realistic training platform and may improve the quality of training in colonoscopy.

Getting to the heart of the matter in cancer: Novel approaches to targeting cancer stem cells.

Cancer is one of the leading causes of deaths worldwide. While cancers may initially show good response to chemotherapy or radiotherapy, it is not uncommon for them to recur at a later date. This phenomenon may be explained by the existence of a small population of cancer stem cells, which are inherently resistant to anti-cancer treatment as well as being capable of self-renewal. Therefore, while most of the tumour bulk consisting of cells that are not cancer stem cells respond to treatment, the cancer stem cells remain, leading to disease recurrence. Following this logic, the effective targeting of cancer stem cells holds promise for providing long-term cure in individuals with cancer. Cancer stem cells, like normal stem cells are endowed with mechanisms to protect themselves against a wide range of insults including anti-cancer treatments, such as the enhancement of the DNA damage response and the ability to extrude drugs. It is therefore important to develop new strategies if cancer stem cells are to be eradicated. In this review, we describe the strategies that we have developed to target cancer stem cells. These strategies include the targeting of the histone demethylase jumonji, AT rich interactive domain 1B (JARID1B), which we found to be functionally significant in the maintenance of cancer stem cells. Other strategies being pursued include reprogramming of cancer stem cells and the targeting of a functional cell surface marker of liver cancer stem cells, the aminopeptidase CD13.

Cancer stem cells of the digestive system.

Stem cells of the digestive system are ideal in many ways for research, given they are abundant, highly proliferative and have a uniform structural arrangement. This in turn has enormously aided the research of cancer stem cells of the digestive system, which is now shaping our understanding of cancer stem cells. In this review, the recent advances in the understanding of cancer stem cells of the digestive system have been summarized, including aspects such as their identification, origin, cell-cycle dormancy, relationship with epithelial-mesenchymal transition, cellular metabolism and the underlying molecular mechanisms. Newly acquired knowledge concerning cancer stem cells have led to the development of novel cancer therapeutics with provisional yet encouraging results.

Glue versus suture fixation of mesh during open repair of inguinal hernias: a systematic review and meta-analysis.

BACKGROUND: Glue fixation of mesh has been explored for some time as a strategy for reducing postoperative chronic groin pain. Previous studies have come to different conclusions about the superiority of one method over another. We conducted a meta-analysis of randomized control trials comparing the performance of glue versus suture fixation of mesh in open inguinal hernioplasty. METHODS: Studies published up to November 2012 were searched using PubMed, EMBASE, MEDLINE, Cochrane Library, and the international standard randomised controlled trials number (ISRCTN) register. Mean differences (MDs) were derived from secondary continuous outcomes and pooled risk ratios (RRs) for categoric outcomes. Meta-analysis was conducted utilizing the random-effects and fixed-effects models as appropriate. RESULTS: Ten randomized controlled studies were selected, with a total of 1,623 patients. Glue fixation for open inguinal hernioplasty reduced chronic groin pain (RR 0.46, 95 % confidence interval (CI) 0.22-0.97), hematoma (RR 0.56, 95 % CI 0.34-0.90), acute postoperative pain (MD -7.92, 95 % CI, -13.17 to -2.66), and time taken to return to normal activities (MD -1.39, 95 % CI, -2.58 to -0.21). There was no evidence of an increase in adverse outcomes including recurrence with glue fixation (RR 0.83, 95 % CI 0.30-2.35). CONCLUSIONS: Glue fixation of mesh for open inguinal hernioplasty is superior in many outcomes including the reduction of chronic groin pain. Glue fixation was not associated with an increased risk of hernia recurrence.

Clinical and histopathological factors affecting failed sentinel node localization in axillary staging for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the standard of care in axillary staging of clinically node-negative breast cancer patients. AIMS: To analyze reasons for failure of SLN localization by means of a multivariate analysis of clinical and histopathological factors. METHODS: We performed a review of 164 consecutive breast cancer patients who underwent SLNB. A superficial injection technique was used. RESULTS: 9/164 patients failed to show nodes. In 7/9 patients no evidence of radioactivity or blue dye was observed. Age and nodal status were the only statistically significant factors (p < 0.05). For every unit increase in age there was a 9% reduced chance of failed SLN localization. Patients with negative nodal status have 90% reduced risk of failed sentinel node localization than patients with macro or extra capsular nodal invasion. DISCUSSION: The results suggest that altered lymphatic dynamics secondary to tumour burden may play a role in failed sentinel node localization. We showed that in all failed localizations the radiocolloid persisted around the injection site, showing limited local diffusion only. While clinical and histopathological data may provide some clues as to why sentinel node localization fails, we further hypothesize that integrity of peri-areolar lymphatics is important for successful localization.

Conversion surgery of Stage IV gastric cancer with peritoneal dissemination after nivolumab.

A 69-year-old man was clinically diagnosed as stage IV gastric cancer with peritoneal dissemination. We performed systemic chemotherapy consisting of S-1 plus oxaliplatin as a first line, and ramucirumab plus nab-paclitaxel as a second line. However, CT and EGD revealed growth of the primary tumor and the lymph nodes along the lesser curvature and adjacent to the cardia. In addition, CT revealed ascites in the rectovesical pouch. Therefore, treatment was switched to nivolumab. After 3 treatment courses, CT revealed shrinkage of lymph nodes and disappearance of ascites. After 12 courses of nivolumab, however, EGD revealed growth of the tumors in the stomach with minor hemorrhage, prompting the consideration of gastrectomy. At the time of laparotomy, the peritoneal dissemination had completely disappeared, and peritoneal cytology was negative. Therefore, total gastrectomy with D2 and paraaortic lymphadenectomy was performed, after 21 months following the initial diagnosis. To our knowledge, there are no previous reports that have demonstrated the disappearance of peritoneal dissemination and ascites in response to nivolumab, resulting in curative gastrectomy.

Enzymes of the one-carbon folate metabolism as anticancer targets predicted by survival rate analysis.

The significance of mitochondrial metabolism in cancer cells has recently been gaining attention. Among other findings, One-carbon folate metabolism has been reported to be closely associated with cellular characteristics in cancer. To study molecular targets for efficient cancer therapy, we investigated the association between the expressions of genes that code enzymes involved in one-carbon metabolism and survival rate of patients with adenocarcinomas of the colorectum and lung. Patients with high expression of genes that control the metabolic cycle of tetrahydrofolate (THF) in mitochondria, SHMT2, MTHFD2, and ALDH1L2, have a shorter overall survival rate compared with patients with low expression of these genes. Our results revealed that these genes could be novel and more promising anticancer targets than dihydrofolate reductase (DHFR), the current target of drug therapy linked with folate metabolism, suggesting the rationale of drug discovery in cancer medicine.

Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane. Although MPC is composed of two subunits, it has been reported that the MPC1 subunit is specifically associated with poor prognosis in several cancers, including colorectal and prostate cancer. However, only a few studies have assessed the clinical significance of MPC1 and the molecular mechanisms underlying its influence on cancer progression are not well understood. This study aimed to clarify the function of MPC1 that affects the malignant potential of ICC. The expression of MPC1 in ICC clinical specimens was determined by immunohistochemistry. In addition, the correlations between MPC1 expression and the survival rate, as well as various clinicopathological parameters were assessed. Low MPC1 expression correlated with poor ICC prognosis and was correlated with tumor invasion and distant metastasis. Both these phenomena are closely associated with the epithelial-mesenchymal transition (EMT). Therefore, we investigated the impact of altering the MPC1 gene expression on the malignant potential of cancer cells using biliary tract cancer cell lines in vitro. The expression of MPC1 was downregulated in the cells induced to undergo EMT following treatment with TGF-ß. Furthermore, the inhibition of MPC1 expression induced EMT in cancer cells, and the overexpression of MPC1 suppressed the migration of tumor cells. These results indicated that MPC1 could be a novel therapeutic target in some cancers.

Gastroenterological surgery in Japan: The past, the present and the future.

In the last two centuries, there has been remarkable progress in the field of gastroenterological surgery, including the curative resection of cancers, replacement of failed organs through transplantation, increased safety of undergoing major surgeries and decreased operative morbidity through developments in minimal access surgery. Japan has very much been at the forefront of these advances, as is evident from the present review, from advancing the surgical management of gastric cancer to the pioneering work in live-donor transplantation. This review also highlights many instances where surgical management of the same pathologies has evolved differently between Japan and the West. It is encouraging that many procedures established in Japan are eventually taken up by the West, often after rigorous assessment affirming the quality and applicability of such techniques. In Japan, many of the crucial issues in gastroenterological surgery are increasingly addressed through large multi-institutional prospective control trials, ensuring that Japanese surgeons continue to contribute to the advances in gastroenterological surgery.

The importance of mitochondrial folate enzymes in human colorectal cancer.

Folate plays a pivotal role in the one-carbon metabolism needed for methylation reactions, nucleotide synthesis, and DNA repair. Although folate metabolism was recently shown to be associated with carcinogenesis in some solid tumors, the importance of folate metabolism in colorectal cancer remains unclear. In the present investigation we found that expression of three mitochondrial folate metabolic enzymes, serine hydroxymethyl transferase (SHMT2), methylenetetrahydrofolate dehydrogenase (MTHFD2) and aldehyde dehydrogenase 1 family member L2 (ALDH1L2), were upregulated in human colorectal tumor tissues compared to normal tissues. Colorectal cancer tissue samples were obtained from 117 consecutive patients. We evaluated the expression of the enzymes with immunohistochemical analysis and determined their relevance to clinicopathological characteristics and prognosis. Rates of recurrence-free survival (RFS) and overall survival (OS) in patients with high expression of SHMT2, MTHFD2 and ALDH1L2 tended to be lower than in patients with low expression of SHMT2, MTHFD2 and ALDH1L2 (P=0.446 and P=0.337, P=0.099 and P=0.064, P=0.178 and P=0.257, respectively). Notably, the combined high expression of SHMT2, MTHFD2 and ALDH1L2 (triple high) was more highly associated with poor prognosis than the individual expression levels (RFS; P=0.004 and OS; P=0.037). A multivariate analysis showed that triple high expression was independently associated with RFS (P=0.017). These findings suggested that mitochondrial folate metabolic enzymes could provide a potential therapeutic strategy for treating colorectal cancer.

BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells.

Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells.

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer.

Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer.

Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. Furthermore, we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress. GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer. In conclusion, GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments.