Colorectal carcinogenesis involves the overexpression of many immediate-early response genes associated with growth and inflammation, which significantly alters downstream protein synthesis and small-molecule metabolite production. We have performed a serum metabolic analysis to test the hypothesis that the distinct metabolite profiles of malignant tumors are reflected in biofluids. In this study, we have analyzed the serum metabolites from 64 colorectal cancer (CRC) patients and 65 healthy controls using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) and Acquity ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (Acquity UPLC-QTOFMS). Orthogonal partial least-squares discriminate analysis (OPLS-DA) models generated from GC-TOFMS and UPLC-QTOFMS metabolic profile data showed robust discrimination from CRC patients and healthy controls. A total of 33 differential metabolites were identified using these two analytical platforms, five of which were detected in both instruments. These metabolites potentially reveal perturbation of glycolysis, arginine and proline metabolism, fatty acid metabolism and oleamide metabolism, associated with CRC morbidity. These results suggest that serum metabolic profiling has great potential in detecting CRC and helping to understand its underlying mechanisms.

Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

BackgroundColorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. However, the prognostic value of PD-1/PD-L1 in CRC remains unclear.MethodsThe Cancer Genome Atlas (TCGA) database (N = 356) and Fudan University Shanghai Cancer Center (FUSCC) cohort of patients (N = 276) were adopted to analyze the prognostic value of PD-L1 in colorectal tumor cells (TCs) and of PD-1 in tumor infiltrating cells (TILs) for CRC. Subgroup analyses were conducted in FUSCC cohort according to patients’ status of mismatch repair.ResultsIn TCGA cohort, the cut-off values of PD-1 and PD-L1 expression were determined by X-tile program, which were 4.40 and 2.92, respectively. Kaplan-Meier analysis indicated that higher PD-1 and PD-L1 expressions correlated with better OS (P = 0.032 and P = 0.002, respectively). In FUSCC cohort, expressions of PD-1 on TILs and PD-L1 on TCs were analyzed separately by immunohistochemistry (IHC) staining based on a TMA sample (N = 276) and revealed that both TILs-PD-1 and TCs-PD-L1 were associated with OS (P = 0.006 and P = 0.002, respectively) and DFS (P = 0.025 and P = 0.004, respectively) of CRC patients. Multivariate Cox regression analysis indicated TILs-PD-1 was an independent prognostic factor both for OS and DFS of CRC patients (P < 0.05). Subgroup analyses showed that TILs-PD-1 was an independent prognostic factor for both OS and DFS in CRC patients in MSS-proficient subgroup (P < 0.05), while neither of them correlated with OS or DFS in MSS-deficient subgroup (P > 0.05).ConclusionsHigher expressions of PD-1 and PD-L1 correlates with better prognosis of CRC patients. TILs-PD-1 is an independent prognostic factor for OS and DFS of CRC patients, especially for MMR-proficient subgroup.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0539-x) contains supplementary material, which is available to authorized users.

After our serum metabonomic study of colorectal cancer (CRC) patients recently published in J. Proteome Res., we profiled urine metabolites from the same group of CRC patients (before and after surgical operation) and 63 age-matched healthy volunteers using gas chromatography-mass spectrometry (GC-MS) in conjunction with a multivariate statistics technique. A parallel metabonomic study on a 1,2-dimethylhydrazine (DMH)-treated Sprague-Dawley rat model was also performed to identify significantly altered metabolites associated with chemically induced precancerous colorectal lesion. The orthogonal partial least-squares-discriminant analysis (OPLS-DA) models of metabonomic results demonstrated good separations between CRC patients or DMH-induced model rats and their healthy counterparts. The significantly increased tryptophan metabolism, and disturbed tricarboxylic acid (TCA) cycle and the gut microflora metabolism were observed in both the CRC patients and the rat model. The urinary metabolite profile of postoperative CRC subjects altered significantly from that of the preoperative stage. The significantly down-regulated gut microflora metabolism and TCA cycle were observed in postoperative CRC subjects, presumably due to the colon flush involved in the surgical procedure and weakened physical conditions of the patients. The expression of 5-hydroxytryptophan significantly decreased in postsurgery samples, suggesting a recovered tryptophan metabolism toward healthy state. Abnormal histamine metabolism and glutamate metabolism were found only in the urine samples of CRC patients, and the abnormal polyamine metabolism was found only in the rat urine. This study assessed the important metabonomic variations in urine associated with CRC and, therefore, provided baseline information complementary to serum/plasma and tissue metabonomics for the complete elucidation of the underlying metabolic mechanisms of CRC.

Mitophagy is a vital form of autophagy for selective removal of dysfunctional or redundant mitochondria. Accumulating evidence implicates elimination of dysfunctional mitochondria as a powerful means employed by autophagy to keep the immune system in check. The process of mitophagy may restrict inflammatory cytokine secretion and directly regulate mitochondrial antigen presentation and immune cell homeostasis. In this review, we describe distinctive pathways of mammalian mitophagy and highlight recent advances relevant to its function in immunity. In addition, we further discuss the direct and indirect evidence linking mitophagy to inflammation and autoimmunity underlying the pathogenesis of autoimmune diseases including inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC).

Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. However, the prognostic value of inflammatory biomarkers in colorectal cancer (CRC) has not been established. In this study, a retrospective analysis was conducted in patients with CRC in Fudan University Shanghai Cancer Center (FUSCC) between April 1, 2007 and April 30, 2014, and 5,336 patients were identified eligible. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) were analyzed. Kaplan-Meier analysis was used to calculate the 5-year overall survival (OS) and disease-free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict OS and DFS, and Harrell's concordance index (c-index) was adopted to evaluate prediction accuracy. As results, the 5-year OS was 79.2% and the 5-year DFS was 56.0% in the cohort. Patients were stratified into 2 groups by NLR (2.72 and >2.72), PLR (219.00 and >219.00), LMR (2.83 and >2.83) and AGR (<1.50 and 1.50). Patients with NLR > 2.72, PLR > 219.00, LMR 2.83 and AGR < 1.50 were significantly associated with decreased OS and DFS (p < 0.001). Multivariate analysis indicated that NLR, LMR and AGR were independent factors of OS (p 5 0.047, p 5 0.008 and p < 0.001, respectively) and DFS (p 5 0.009, p < 0.001 and p 5 0.008, respectively). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.765 (95% CI: 0.744-0.785) and 0.735 (95% CI: 0.721-0.749), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females.1 The estimated global 5-year prevalence rate of CRC was 68.2/100,000, and cancer death rate caused by CRC was about 8.5%. 2 Compared with developed countries, the 5-year prevalence rate of CRC is significantly lower in China (52.7/100,000), but the mortality-to-prevalence ratio (MPR) of CRC in China (14%) is a lot higher, 2 which indicates that the overall survival outcome of CRC is apparently worse in China. Surgical resection remains the only curative treatment option for colorectal cancer. However, a considerable proportion of CRC patients develop recurrence or metastasis within 5 years after surgical treatment. Thus, a better model to predict the prognosis of CRC patients after radical resection is urgently needed.

BackgroundWe have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer.MethodsTPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo.ResultsTPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity.ConclusionsThese findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease.

BackgroundHigh expression of the long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) in whole blood has been reported in colorectal cancer patients; however, its’ clinical significance and origin are unclear. We evaluated the diagnostic and prognostic value, and origin of whole blood NEAT1 in colorectal cancer.MethodsExpression of NEAT1 variants, NEAT1_v1 and NEAT1_v2 were determined using real-time quantitative PCR. The diagnostic value of whole blood NEAT1 expression was evaluated in test (n = 60) and validation (n = 200) cohorts of colorectal cancer patients and normal controls (NCs). To identify the origin of NEAT1, its expression was analyzed in blood, matched primary tumor tissues, para-tumor tissues, metastatic tissues, and also immune cells from patients or NCs. Function of NEAT1 in colorectal cell lines was also assessed. The correlation of NEAT1 expression with clinical outcomes was assessed in 191 patients.ResultsWhole blood NEAT1 expression was significantly higher in colorectal cancer patients than in NCs. NEAT1_v1 and NEAT1_v2 expression were highly accurate in distinguishing colorectal cancer patients from NCs (area under the curve: 0.787 and 0.871, respectively). Knockdown of NEAT1_v1 in vitro could inhibit cell invasion and proliferation, while knockdown of NEAT1_v2 promoted cell growth. However, whole blood expression was not correlated with matched tissues. An elevated expression was seen in neutrophils from CRC patients. Furthermore, high expression of NEAT1_v1 was correlated with worse overall survival. In contrast, high expression of NEAT1_v2 alone was correlated with better overall survival.ConclusionWhole blood NEAT1 expression is a novel diagnostic and prognostic biomarker of overall survival in colorectal cancer. Elevated NEAT1 may derive from neutrophils.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0455-5) contains supplementary material, which is available to authorized users.