Chenhan Zhong

BACKGROUND: Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC). METHODS: Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels. RESULTS: ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway. CONCLUSIONS: Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.

BACKGROUND: Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice. RESULTS: A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice. CONCLUSION: Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites. Video Abstract.

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.

purpose: The current study explored the risk of developing second primary cancers (SPCs) among long-term early-stage breast cancer survivors and identified risk factors to build an externally validated clinical prediction model. methods: The cumulative incidence of SPCs was calculated by Gray method among survivors of early-stage initial primary breast cancer (IPBC). Comparisons of treatment-related risk by selected organ sites were performed. A nomogram was established to estimate the individual risk of developing SPCs based on the multivariate Fine and Gray risk model. Decision curve analysis (DCA) was used to evaluate clinical usefulness of the model. results: The cumulative incidence of developing SPCs after early-stage IPBC was 7.43% at 10 years, 14.41% at 15 years, and 20.08% at 20 years. Radiotherapy was associated with elevated risks of any SPCs and with elevated risks of lung cancer (SHR: 1.109; P = 0.045), breast cancer (SHR: 1.389; P < 0.001), and AML (SHR: 1.298; P = 0.045). Chemotherapy was significantly associated with a declined risk of any SPCs, with decreased risks of lung (SHR: 0.895; P = 0.015) and breast cancers (SHR: 0.891; P < 0.001), as well as elevated risks of other leukemias (SHR: 1.408; P = 0.002). HR-positive status was associated with decreased risks of any SPCs; with decreased risks of breast (SHR: 0.842; P < 0.001) and ovarian cancers (SHR: 0.483; P < 0.001); and with elevated risks of urinary tract cancers (SHR: 1.214; P = 0.029). conclusion: We found that the cumulative incidence of developing SPCs increased over time and did not plateau. Risk factors for developing SPCs identified by our study were not consistent with those of previous studies. The prediction model can help identify individuals at higher risk of SPCs.