Distant Metastasis Of Colorectal Cancer Research Articles

TCF19 aggravates the malignant progression of colorectal cancer by negatively regulating WWC1.

The aim of this study was to clarify the role of TCF19 in influencing the malignant progression of colorectal cancer (CRC) by negatively regulating WWC1. Relative expression levels of TCF19 and WWC1 in CRC tissues and cells were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The prognosis of CRC patients was assessed by the Kaplan-Meier method. Meanwhile, the correlation between TCF19 and pathological indexes of CRC patients was evaluated. Regulatory effects of TCF19/WWC1 on viability, colony formation ability, and migration in HT29 and HCT-8 cells were evaluated. Finally, rescue experiments were conducted to elucidate a negative feedback loop of TCF19/WWC1 in influencing the progression of CRC. TCF19 was significantly up-regulated in CRC, while WWC1 was down-regulated. High-level TCF19 or low-level WWC1 indicated worse survival of CRC patients. Besides, TCF19 expression level was positively correlated with the occurrence of distant metastasis in CRC. Silence of TCF19 significantly attenuated proliferative and migratory capacities of HT29 cells. However, overexpression of TCF19 yielded the opposite trends in HCT-8 cells. WWC1 expression was negatively regulated by TCF19 in CRC tissues. In addition, knockdown of WWC1 abolished the regulatory effect of TCF19 on CRC cells. TCF19 is closely correlated with the occurrence of distant metastasis and poor prognosis of CRC. Furthermore, it aggravates the malignant progression of CRC via negatively regulating WWC1.

Laparoscopic & robotic liver resection for colorectal cancer metastases

Distant metastasis of colorectal cancer to the liver will occur in approximately 50% of patients and surgical resection is associated with improved survival. Over the past decade minimally invasive techniques have been adopted with an increasing number of major hepatic resections performed for both benign and malignant disease, including colorectal cancer liver metastasis. This review aims to provide an overview and summary of the current data on the perioperative and oncologic outcomes of minimally invasive hepatectomy for metastatic colorectal cancer. Furthermore, the application of robotic assisted surgery and the use of minimally invasive techniques in locoregional treatment of colorectal liver metastasis (CRLM) are also examined.

1644 Isolated Metastatic Colorectal Cancer Involving the Kidney and Adrenal Gland: A Rare Occurrence

INTRODUCTION: Distant metastases in colorectal cancer (CRC) commonly involve liver, lung, brain and bone. Adrenal gland involvement is not uncommon on autopsy in the setting of diffuse metastatic disease. In most reported cases, it is seen as metachronous disease and is diagnosed during extensive work up or on follow up. Isolated synchronous disease involving the kidney and adrenal gland is extremely rare. We present a case where the diagnosis was established intraoperatively during a laparotomy performed for suspected primary adrenocortical malignancy. CASE DESCRIPTION/METHODS: A 66-year-old man presented with sudden worsening lower abdominal pain for 6 hours. The pain had started 4 weeks ago and was persistent, non-radiating. He reported a 50 pounds weight loss over the last 3 months. Physical exam was significant for tenderness over the right lower quadrant. Laboratory data showed anemia with hemoglobin of 8.3 g/dl. CT of abdomen and pelvis revealed a mass that was possibly originating from the right adrenal gland. MRI revealed a large heterogeneous, multilobulated, adrenal mass measuring 10 × 7.4 × 13.2 cm. A primary adrenocortical malignancy was suspected. Endocrine and metastatic work up was negative and a laparotomy was planned for adrenalectomy and possible nephrectomy. Intraoperatively, he was found to have an ulcerative tumor involving the terminal ileum and appendix penetrating through the serosa. Right hemicolectomy and nephrectomy with adrenalectomy were performed. Histopathology was consistent with poorly differentiated adenocarcinoma of colon with metastasis to right adrenal gland and kidney. DISCUSSION: Common primary tumors that metastasize to the adrenal gland include breast, lung and kidney. In most cases of CRC, adrenal or kidney metastases usually indicate distant hematogenous spread and are associated with poor prognosis. The mean survival is 7 to 8 months. However, CRC with isolated metastasis to adrenal gland and kidney is extremely rare. Retrospectively, an interesting feature in this case was the presumption of the metastatic lesion as the primary tumor as there was no radiologic abnormality involving the gastrointestinal tract. Surgical resection followed by chemotherapy has been shown to promote long term survival in several studies, but there is no prospective data due to the rarity of this condition. In patients with incidental finding of an isolated adrenal/renal mass, an evaluation for occult GI malignancy should be considered.

Association and diagnostic value of serum SPINK4 in colorectal cancer.

The role of serum serine peptidase inhibitor, Kazal type 4 (SPINK4), in colorectal cancer (CRC) is largely unknown. This study aimed to explore the association and diagnostic value of serum SPINK4 in CRC. A total of 70 preoperative CRC patients, 30 postoperative CRC patients, 30 gastric cancer patients, and 30 healthy controls were enrolled. Using enzyme-linked immunosorbent assays, we found that the serum SPINK4 level was significantly increased in preoperative CRC compared with postoperative CRC patients, gastric cancer patients, and healthy controls (p < 0.05). The serum SPINK4 level was remarkably elevated in colon cancer compared with rectal cancer and was enhanced in the M1 stage compared with the M0 stage (p < 0.05). The area under the receiver operating characteristic curve of serum SPINK4 level in the diagnosis of CRC was 0.9186, with a sensitivity and specificity of 0.886 and 0.900, respectively, and a cut-off value of 2.065. There was no significant difference between high and low expression of serum SPINK4 regarding the overall survival time and disease-free survival (p > 0.05). This study demonstrated that the serum SPINK4 level increased in CRC and was associated with the location and distant metastasis of CRC. It had a high diagnostic value in CRC but was not associated with the survival of CRC patients.

Collagen facilitates the colorectal cancer stemness and metastasis through an integrin/PI3K/AKT/Snail signaling pathway

PurposeDynamic remodeling of the extracellular matrix (ECM) around tumor cells is crucial for the tumor progressions. However, the mechanism is not well defined. Here, we aimed to reveal the underlying mechanism of ECM induced metastasis and provide innovative strategy to suppress the distant metastasis induced by ECM. Materials and MethodsIHC was used to detect the expression of target proteins. H&E staining was used to evaluate the growth of tumor in vivo. Using wound healing and transwell assay, we examined the ability of cell to metastasis. We employed IF and Western blot to detect the expression of target proteins. And qRT-PCR was used to examine the target genes in mRNA level. We also applied flow cytometry to examine the percent of CD133+ cell population. ResultsHerein, we observed elevated expression of type I collagen in colorectal cancer tissues from patients with high metastasis. Additionally, colorectal cancer cells cultured on 2D collagen reveal obviously enhanced capability of metastasis and tumorigenesis both in vitro and in vivo. We demonstrated that the activation of PI3K/AKT signal induced by integrin α2β1 resulted in the enhanced metastatic capability and stemness of colorectal cancer cells. Moreover, we found that Snail worked as the downstream of PI3K/AKT signaling, resulting in the intensive invasion and metastasis of colorectal cancer. Blocking the pathway by applying E7820 successfully reversed the type I collagen induced distant metastasis in colorectal cancer. ConclusionCombining E7820 and chemotherapeutic agents to block the integrin α2β1/PI3K/AKT/Snail signaling pathway revealed dramatic enhanced tumor suppression and provided an innovative approach for clinical colorectal cancer treatment.

Colorectal liver metastases: An update on multidisciplinary approach.

Liver metastasis is the commonest form of distant metastasis in colorectal cancer. Selection criteria for surgery and liver-directed therapies have recently been extended. However, resectability remains poorly defined. Tumour biology is increasingly recognized as an important prognostic factor; hence molecular profiling has a growing role in risk stratification and management planning. Surgical resection is the only treatment modality for curative intent. The most appropriate surgical approach is yet to be established. The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach; these two strategies have comparable long-term outcomes. For patients with a limited future liver remnant, portal vein embolization, combined ablation and resection, and associating liver partition and portal vein ligation for staged hepatectomy have been advocated, and each has their pros and cons. The role of neoadjuvant and adjuvant chemotherapy is still debated. Targeted biological agents and loco-regional therapies (thermal ablation, intra-arterial chemo- or radio-embolization, and stereotactic radiotherapy) further improve the already favourable results. The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials. Evidence-based protocols are missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.

Snail-1, ALDH1, and claudin-1 tissue proteinexpression in patients with colorectal cancer:clinicopathological and prognostic implications

BackgroundThe occurrence of distant metastases in colorectal cancer (CRC) is the most important parameter in assessment of the prognosis of patients with CRC. Epithelial–mesenchymal transition (EMT) is the process that is incriminated in the occurrence of metastatic spread in CRC. Snail-1 is a zinc-

Genetic variant of TMBIM1 is associated with the susceptibility of colorectal cancer in the Chinese population

Recent meta-analysis of genome-wide association studies (GWASs) identified a novel variant rs992157 at 2q35 that was associated with colorectal cancer (CRC) in the population of European ancestry. We aimed to replicate the association of rs992157 with CRC in the Chinese population and to further determine the real susceptible gene of CRC as indicated by this variant. 824 CRC patients and 1063 healthy controls were included. The frequency of the genotype and the allele of rs992157 were compared between the patients and the controls and between different subgroups of patients classified by status of metastasis. Expression level of TMBIM1 was compared between the tumor tissue and the adjacent normal tissues collected from 43 patients during surgery. Besides, the relationship between genotypes of rs992157 and the tissue expression of TMBIM1 was analyzed. Patients were found to have significantly higher frequency of allele G than the controls (44.2% vs. 40.0%, P = 0.009; OR = 1.18). Moreover, allele G was associated with an increased risk of lymph node metastasis (P = 0.02) and distant metastasis of CRC (P = 0.04). The mean expression level of TMBIM1 was significantly higher in tumor tissue than in the adjacent normal tissues (0.0019 ± 0.00068 vs. 0.00041 ± 0.00024, P < 0.001). In addition, patients with genotype GG were found to have remarkably higher TMBIM1 expression in the tumors than those with genotype AA (0.0024 ± 0.00052 vs. 0.0015 ± 0.00078, P = 0.005). Variant rs992157 is significantly associated with the susceptibility and progression of CRC. It can increase the risk of CRC possibly via up-regulation of TMBIM1.

Novel digital signatures of tissue phenotypes for predicting distant metastasis in colorectal cancer

Distant metastasis is the major cause of death in colorectal cancer (CRC). Patients at high risk of developing distant metastasis could benefit from appropriate adjuvant and follow-up treatments if stratified accurately at an early stage of the disease. Studies have increasingly recognized the role of diverse cellular components within the tumor microenvironment in the development and progression of CRC tumors. In this paper, we show that automated analysis of digitized images from locally advanced colorectal cancer tissue slides can provide estimate of risk of distant metastasis on the basis of novel tissue phenotypic signatures of the tumor microenvironment. Specifically, we determine what cell types are found in the vicinity of other cell types, and in what numbers, rather than concentrating exclusively on the cancerous cells. We then extract novel tissue phenotypic signatures using statistical measurements about tissue composition. Such signatures can underpin clinical decisions about the advisability of various types of adjuvant therapy.

Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach

Colorectal cancer (CRC) is a common malignant neoplasm worldwide. It is important to identify new biomarkers for the early detection of CRC. In this study, magnetic beads and the Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platform were used to analyse CRC and healthy control (HC) serum samples. The CRC diagnosis pattern was established to have a specificity of 94.7% and sensitivity of 92.3% in a blind test. The candidate biomarker serine/threonine kinase 4 (STK4, also known as MST1) was identified by Tandem mass spectrometry (MS/MS) and verified with western blotting and enzyme-linked immunosorbent assay (ELISA). The results indicated that there was a higher concentration of MST1 in HC subjects than stage I CRC patients for the early detection of CRC and a lower concentration in stage IV patients than in other CRC patients. The sensitivity and specificity of MST1 combined with carcinoembryonic antigen (CEA) and faecal occult blood test (FOBT) in diagnosis of colorectal cancer were 92.3% and 100%, respectively. Additionally, low MST1 expression was associated with the poor prognosis. These results illustrate that MST1 is a potential biomarker for early detection, prognosis and prediction of distant metastasis of CRC.

An Unusual Case of Late Metastasis to Jejunum From Previously Resected Colon Cancer Mass

Distant metastasis of colorectal cancer (CRC) to unusual sites, like small bowel, kidney, thyroid many years after resection of the primary tumor is rare but has been reported. A 71-year old female with a history of Stage IIIb CRC status post resection 2 years ago presented with worsening dyspnea, fatigue and post-prandial lower abdominal pain for 2 weeks. Her other medical conditions include coronary artery disease, pulmonary hypertension and atrial fibrillation on anticoagulation therapy. She denied any nausea, vomiting, bright red blood per rectum, NSAID's use or epigastric pain. Her abdominal exam was benign except for dark stool on rectal exam. Labs showed iron deficiency anemia and positive fecal occult blood. She underwent capsule endoscopy which showed a ulcerated area in the proximal small bowel with oozing blood and irregular mucosa. Eventually, she underwent single balloon enteroscopy which showed an ulcerated, friable mass in the mid-distal jejunum. Biopsies showed moderately differentiated adenocarcinoma and positive anti-CK 20, similar to her primary sigmoid lesion, confirming the diagnosis of metastasis from CRC. The incidence of CRC metastases to the small bowel is relatively rare, about 2.8-8.2%. The most common site is ileum, followed by jejunum. A significant lag time of 1.3-7 years, from the initial diagnosis of colorectal cancer to the onset of symptomatic small bowel metastasis, has been reported. The routes of metastasis to the small intestine include hematogenous, peritoneal or intestinal metastasis. The major route from CRC is, disseminated metastasis associated with peritonitis carcinomatosa. Patients may present with symptoms such as occult bleeding, intestinal obstruction, or perforation. The diagnosis is often made on a small bowel series or CT. However, neither can differentiate a primary from a metastatic small bowel cancer. Radical surgical resection of such late metastasis is reportedly associated with a good quality of life but postoperative complication rates are high, about 80% and survival is short (2-15 months), although survival up to 11 years has been reported. Our case highlights the late occurrence of CRC metastases at unusual sites like small bowel, several years after the resection of the primary. It should be suspected in any patient with occult GI bleeding and history of CRC. Diagnosis is based on capsule endoscopy for tumor localization and balloon-assisted enteroscopy for confirmation.

Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer.

T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ=0.287; p=0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r=0.68; p=0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r=-0.66; p=0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases.

The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer.

Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.

USP22 drives colorectal cancer invasion and metastasis via epithelial-mesenchymal transition by activating AP4.

Ubiquitin specific peptidase 22 (USP22), a putative cancer stem cell marker, is overexpressed in liver metastases of colorectal cancer (CRC). However, the mechanism by which USP22 promotes CRC metastasis remains largely unknown. Here, we report that USP22 and AP4 are simultaneously overexpressed during TGF-β1-induced CRC cell epithelial-mesenchymal transition (EMT). USP22 up-regulation enhances CRC cell migration and invasion and EMT-related marker and AP4 expression, but these effects are partly blocked by AP4 knockdown. In addition, USP22 binds to the promoter region of AP4 to activate its transcription. In vivo, elevated USP22 expression promotes CRC cell metastasis to the lungs in nude mice, as evidenced by the fact that CRC metastatic nodules stain deeply positive for USP22 and AP4. In human CRC tissues, the genes encoding USP22 and AP4 are overexpressed in metastatic liver lesions compared with primary cancer tissues, and their overexpression is significantly associated with poor CRC patient survival. These findings indicate that USP22 and AP4 may serve as prognostic markers for predicting the risk of developing distant metastases in CRC.

COLORECTAL CANCER AND FEATURES OF ITS METASTASIS

The article analyzes the frequency of regional metastasis detection in patients with operative colorectal cancer as well as the frequency and patterns of the appearance of distant metastases depending on the presence or absence of regional metastases, tumor localization and the method of treatment. It was found that the frequency of distant metastases in colorectal cancer depended mainly on the presence or absence of metastases in the regional lymph nodes. Some influence on the decrease in the frequency of distant metastasis was exacerbated by the preoperative radiation exposure by radiomodifiers and on the increase - the interval between the end of the radiation treatment phase and the moment of surgery. In rectal cancer the localization of distant metastases depended on the level of tumor localization. In colon cancer the major part (81.6%) of distant metastases was located in the liver, the rest 18.4% -extrahepatic and was represented by peritoneum dissemination, metastases in the ovary and retroperitoneal lymph nodes. Among colon cancer patients after the combined treatment there were no cases of tumor dissemination through the abdominal cavity and the appearance of lymphogenous metastases.

Systematic assessment of intra- and peri-metastatic tumor budding in patients with stage IV colorectal cancer.

626 Background: Tumor budding is a strong independent prognostic factor in primary colorectal cancer (CRC). The prognosis of stage IV CRC is still poor and there is need for biomarkers to facilitate the clinical management. Data on tumor budding in colorectal cancer distant metastases (CRDM) are still missing. Therefore, the aim of this study was to analyze its role in tumor progression. Methods: 73 stage IV CRC with clinico-pathological data were retrieved from a cohort of 331 CRC patients, surgically treated between 2002 and 2013 at the University Hospital of Bern. Tumor budding was visualized immunohistochemically by pan-cytokeratin staining. Tumor budding was defined as intra- and peri-tumoral budding in the primary tumor (ITB = buds in the tumor center; PTB = buds at the tumor margin), intra- and perinodal budding (INB and PNB) and intra- and peri-metastatic tumor budding (IMB and PMB). Overall tumor budding was defined as tumor buds independent of the center and margin (OTB, ONB, OMB). The tumor bud count was assessed by calculating the mean number of tumor buds in 10 high power fields. For survival analysis a cut off of 10 tumor buds was applied to subdivide the tumors with low and high numbers of tumor buds. Results: In lymph nodes and CRDM, the tumor bud count was lower compared to primary tumors (PNB: 13; INB: 18; ONB: 21 vs PMB: 10; IMB: 21; OMB: 22 vs PTB: 23; ITB: 24; OTB: 33). For PTB/PNB and OTB/ONB, there were significant differences between primary tumor and lymph node metastasis (PTB/PNB: p &lt; 0.001; OTB/ONB: 0.008) and primary tumor and distant metastases (PTB/PMB: p &lt; 0.001; OTB/OMB: 0.007). The presence of PMB was predicted by INB, PNB and V1 (p = 0.032, p = 0.001 and p = 0.003). A trend towards a worse prognosis in patients with a high OMB number was observed. Conclusions: Tumor budding is present in lymph node and distant metastases of CRC, but its number is lower compared to the corresponding primary tumor. As tumor budding in local and distant metastases seems to be a predictor of tumor progression, these novel data should be considered as a basis for further analysis in large and multicentric clinical trials.

Diagnostic and prognostic value of preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography for colorectal cancer: comparison with conventional computed tomography.

Background/Aims18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been used for preoperative staging of colorectal cancer (CRC). However, the diagnostic accuracy of FDG-PET/CT for detection of lymph node or distant metastasis and its prognostic role have not been well established. We therefore evaluated the diagnostic and prognostic value of FDG-PET/CT in comparison with conventional CT for CRC.MethodsWe investigated 220 patients who underwent preoperative FDG-PET/CT and CT, followed by curative surgery for CRC. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG-PET/CT and CT for detection of lymph node metastasis and distant metastasis were evaluated. In addition, we assessed the findings of FDG-PET/CT and CT according to outcomes, including cancer recurrence and cancer-related death, for evaluation of prognostic value.ResultsFor detection of lymph node metastasis, FDG-PET/CT had a sensitivity of 44%, a specificity of 84%, and an accuracy of 67%, compared with 59%, 65%, and 62%, respectively, for CT (P=0.029, P=0.000, and P=0.022). For distant metastasis, FDG-PET/CT had a sensitivity of 79%, a specificity of 94%, and an accuracy of 93%, compared with 79%, 87%, and 86%, respectively, for CT (P=1.000, P=0.004, and P=0.037). In addition, positive findings of lymph node metastasis and distant metastasis on FDG-PET/CT were associated significantly with cancer recurrence or cancer-related death (P=0.009, P=0.001, respectively).ConclusionsPreoperative FDG-PET/CT had a higher specificity and accuracy compared to CT for detection of lymph node metastasis and distant metastasis of CRC. In addition, FDG-PET/CT could be a valuable prognostic tool for CRC.

Meta-analysis of clinical trials on concordance of mutational stauts of primary tumour and distant metastases of colorectal cancer

Background . During the last years several trials emerged demonstrating high tumour heterogeneity, including those on colorectal cancer. Objective. These findings made us initiate a meta-analysis of trials dedicated to this question. Materials and methods. We searched PubMed database, ASCO and ESMO abstracts for publications presented until August 2016. Studies which compared concordance of KRAS, NRAS, BRAF and PIK3CA mutations between primary tumour and metastases of colorectal cancer and which included more than 10 patients were included in meta-analysis. Meta-analysis was performed using Review Manager (RevMan), version 5.3. Results. Statistically significant differences were observed in KRAS (5 %; RR 0.95; 95 % CI 0.92–0.98; р = 0.003), PIK3CA (7 %; RR 0.93; 95 % CI 0.86–0.99; р = 0.04) mutational status, but not BRAF and NRAS. We observed no significant publication-associated systematic errors. KRAS discordance was significantly higher between primary tumour and lymph node metastases – 13.2 % (р = 0.036). Conclusions. A possibility of KRAS discordance between primary tumour and colorectal cancer metastases was demonstrated. Considering a small number of patients with discordance it is necessary to distinguish a high-risk discordance group, which will require an additional mutational analysis of metastatic nodes tissue.

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.

MiR-384 inhibits human colorectal cancer metastasis by targeting KRAS and CDC42

Colorectal cancer (CRC) is the third most common cancer worldwide. Metastatic progression is a primary factor contributing to lethality of CRC patients. However, the molecular mechanisms forming early local invasion and distant metastatic colonies are still unclear and the present therapeutic approaches for CRC are unsatisfactory. Therefore, novel therapies targeting metastatic invasion that could prevent tumor spreading and recurrence are urgently needed. Our study showed that the decrease of miR-384 was found in 83.0% (83/100) CRC patients. And low-leveled expression of miR-384 was closely correlated with the invasive depth, lymph node and distant metastasis of CRC. Overexpression of miR-384 could inhibit the invasive and migrating abilities of CRC cells in vitro and the metastatic potential in vivo. Luciferase assays showed that miR-384 repressed the expression of Kirsten Ras (KRAS) and Cell division cycle 42 (CDC42) by directly targeting their 3’-untranslated regions. There is functional and mechanistic relationship between miRNA-384 and KRAS, CDC42 in the invasion and metastasis of CRC. And our findings suggest that miR-384could be a potent therapeutic target for CRC. Restoration of miR-384 expression might provide novel therapeutic approach to the reduction of CRC metastasis.