Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc^−/− mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.

Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1−/− mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-β signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC−/− mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Accumulating evidence from clinical and epidemiological studies has highlighted the close correlation between the individual risk of cancer and nervous system diseases. The expression of neuronal pentraxin 2 (NPTX2) is absent in Alzheimer’s disease, anxiety, and depression. Herein, we found that NPTX2 mRNA and protein expression was significantly upregulated in colorectal carcinoma (CRC). NPTX2 expression level gradually increased with CRC progression and was closely associated with poor prognosis. In vitro and in vivo studies demonstrated that NPTX2 promoted CRC proliferation and metastasis through the activation of the Wnt/β-catenin signaling pathway. As NPTX2 receptors are absent on CRC cells, NPTX2 was shown to physically interact with frizzled class receptor 6 (FZD6) to promote β-catenin translocation into the cell nucleus, resulting in an increase in the expression of MYC, cyclin D1, snail, and N-cadherin along with a decrease in the expression of E-cadherin. Knockdown of FZD6 expression with a small-interfering RNA almost completely reversed the proliferative effects of NPTX2 on CRC development. In conclusion, NPTX2, a molecule related to nervous system diseases, promotes CRC cell proliferation and metastasis through the activation of the Wnt/β-catenin pathway via direct interaction with FZD6.

Colorectal cancer (CRC) is the third most common malignancy globally and the second leading cause of cancer-related mortality. Its development is a multifactorial and multistage process influenced by a dynamic interplay between gut microbiota, environmental factors, and fatty acid metabolism. Dysbiosis of intestinal microbiota and abnormalities in microbiota-associated metabolites have been implicated in colorectal carcinogenesis, highlighting the pivotal role of microbial and metabolic interactions. Fatty acid metabolism serves as a critical nexus linking dietary patterns with gut microbial activity, significantly impacting intestinal health. In CRC patients, reduced levels of short-chain fatty acids (SCFAs) and SCFA-producing bacteria have been consistently observed. Supplementation with SCFA-producing probiotics has demonstrated tumor-suppressive effects, while therapeutic strategies aimed at modulating SCFA levels have shown potential in enhancing the efficacy of radiation therapy and immunotherapy in both preclinical and clinical settings. This review explores the intricate relationship between gut microbiota, fatty acid metabolism, and CRC, offering insights into the underlying mechanisms and their potential translational applications. Understanding this interplay could pave the way for novel diagnostic, therapeutic, and preventive strategies in the management of CRC.

Background: Aerobic glycolysis is a typical metabolic reprogramming in tumor cells, which contributes to the survival and proliferation of tumor cells. The underlying mechanisms controlling this metabolic switch in colorectal cancer (CRC), however, remain only partially understood. Methods: The Cancer Genome Atlas (TCGA) dataset and Gene Expression Omnibus (GEO) (GDS4382, GSE6988, GSE35834) were used to analyzed the mRNA expression of THBS2. 392 paired samples of CRC and adjacent non-cancerous tissues were collected to detect the expression of THBS2 by IHC. The correlation of THBS2 expression with categorical clinical variables in patients with CRC was evaluated using chi-square analysis or Student’s t-test. CCK-8, colony formation, and animal CT scan were used to functional analysis of THBS2 in CRC. Results: Thrombospondin 2 (THBS2) is aberrantly upregulated and linked to a poor prognosis in CRC. Subsequent experiments also showed that THBS2 promotes the proliferation of CRC cells. In terms of mechanism, THBS2 interacted with Toll-like receptor 4 (TLR4), but not with the other toll-like receptors (TLRs), which upregulated the mRNA expression of GLUT1, HK2, ALDOA, PKM2, and LDHA and enhanced glycolytic capacity in CRC cells. Moreover, THBS2/TLR4 axis significantly increased the protein level of HIF-1α and blocking HIF-1α by siRNA reversed the enhanced glycolytic capacity and the upregulated expression of glycolytic enzymes in CRC cells. Conclusion: Our findings revealed that the THBS2/TLR4 axis contributes to HIF-1α derived glycolysis and eventually promotes CRC progress.

The microenvironment of distant organ plays vital roles in regulating tumor metastases. However, little is known about the crosstalk between metastasized tumor cells and target organs. Herein, we found that EFNB2 expression was upregulated in liver metastases (LM) of colorectal cancer (CRC), but not in pulmonary metastases (PM) or primary CRC tumors. EFNB2 played a tumor-promoting role in CRC LM in vitro and in vivo. Through forward signaling, EFNB2-promoted CRC LM by interacting with the EPHB4 receptor. EFNB2/EPHB4 axis enhances LDLR-mediated cholesterol uptake in CRC LM. Subsequently, EFNB2/EPHB4 axis promotes LDLR transcription by regulating STAT3 phosphorylation. Blocking LDLR reversed the role of the EFNB2/EPHB4 axis in promoting CRC LM. Using clinical data, survival analysis revealed that the survival time of patients with CRC LM was decreased in patients with high EFNB2 expression, compared with low EFNB2 expression. Inhibition of the EFNB2/EPHB4 axis markedly prolonged the survival time of BALB/c nude mice with CRC LM with a high cholesterol diet. These findings revealed a key step in the regulation of cholesterol uptake by EFNB2/EPHB4 axis and its tumor-promoting role in CRC LM.