Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Sun J
PROVIDER: S-EPMC8506248 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The deregulation of exosomal microRNAs (miRNAs) plays an important role in the progression of hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in liver cancer cells after induction of the epithelial-mesenchymal transition (EMT) and metastasis. Initially, we induced EMT in a hepatocellular carcinoma cell (HCC) line (Hep3B) by stimulation with transforming growth factor-? (TGF-?) and confirmed by western blot detection of EMT markers such as vimentin and E-cadherin. Exosomes were then isolated from the cells and identified by nanoparticle tracking analysis (NTA). The isolated exosomal particles from unstimulated Hep3B cells (Hep3B exo) or TGF-?-stimulated EMT Hep3B cells (EMT-Hep3B exo) contained higher levels of exosome marker proteins, CD63 and TSG101. After incubation with EMT-Hep3B exo, Hep3B cell proliferation increased. EMT-Hep3B exo promoted the migration and invasion of Hep3B and 7721 cells. High-throughput sequencing of miRNAs and mRNA within the exosomes showed 119 upregulated and 186 downregulated miRNAs and 156 upregulated and 166 downregulated mRNA sequences in the EMT-Hep3B exo compared with the control Hep3B exo. The most differentially expressed miRNAs and target mRNA sequences were validated by RT-qPCR. Based on the known miRNA targets for specific mRNA sequences, we hypothesized that GADD45A was regulated by miR-374a-5p. Inhibition of miR-374a-5p in Hep3B cells resulted in exosomes that inhibited the proliferation, migration, and invasion of HCC cells. These results enhance our understanding of metastatic progression of liver cancer and provide a foundation for the future development of potential biomarkers for diagnosis and prognosis of hepatic cancer.
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Project description:Tumor metastasis is a hallmark of cancer. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated pre-metastatic niche formation during colorectal cancer (CRC) liver metastasis remain incompletely understood. Here we identified HSPC111 was the leading upregulated gene in hepatic stellate cells (HSCs) incubated with CRC cell-derived exosomes. In xenograft mouse model, CRC cell-derived exosomal HSPC111 facilitated pre-metastatic niche formation and CRC liver metastases (CRLM). Consistently, CRC patients with liver metastasis had higher level of HSPC111 in serum exosomes, primary tumors and cancer-associated fibroblasts (CAFs) in liver metastasis than those without. Mechanistically, HSPC111 altered lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulated the level of acetyl-CoA. The accumulation of acetyl-CoA further promoted CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforced exosomal HSPC111 excretion from CRC cells and promoted liver metastasis. These results uncovered that CRC cell-derived exosomal HSPC111 promotes pre-metastatic niche formation and CRLM via reprogramming lipid metabolism in CAFs, and implicate HSPC111 may be a potential therapeutic target for preventing CRLM.
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Project description:BackgroundEndomucin (EMCN) is a type I transmembrane glycoprotein and a mucin-like component of the endothelial cell glycocalyx. The mechanism of EMCN action in colorectal cancer (CRC) remains unclear.AimsOur aim was to explore the role of EMCN in the progression of CRC.Materials & methodsWe examined EMCN expression in CRC tissues and normal para-carcinoma tissues. The function and mechanisms of EMCN were checked in CRC cell lines and in mouse xenograft. Additionally, we used co-immunoprecipitation and mass spectrometry to identify the potential EMCN-binding proteins. Functional annotation analysis showed where these genes were enriched.ResultsWe found that EMCN was overexpressed in tumor tissues compared with that in normal para-carcinoma tissues. We also found that overexpression of EMCN induced CRC proliferation and metastasis both in vitro and in vivo. EMCN knockdown prevents epithelial-mesenchymal transition in vitro. We identified 178 potential EMCN-binding partners. Furthermore, functional annotation analysis indicated that these genes were considerably enriched in carcinogenic-related functions and pathways. Collectively, the identification of EMCN-binding partners enhanced our understanding of the mechanism of EMCN-mediated malignant phenotypes, and this research may provide valuable insights into the molecular mechanisms underlying CRC.ConclusionTumor-derived endomucin promotes colorectal cancer proliferation and metastasis. We identified 178 EMCN-binding proteins and initially screened three potential EMCN-interacting proteins: NALCN, and TPM2, ANKK1. Our study provides valuable insights into the molecular mechanisms underlying CRC development.
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Project description:Metastasis, the development of secondary malignant growths at a distance from a primary tumor, is the cause of death for 90% of cancer patients, but little is known about how metastatic cancer cells adapt to and colonize new tissue environments. Here, using clinical samples, patient-derived xenograft (PDX) samples, PDX cells, and primary/metastatic cell lines, we discovered that liver metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program yet gain a liver-specific gene transcription program. We showed that this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical enhancers and super-enhancers. Further, we identified that the liver-specific transcription factors FOXA2 and HNF1A can bind to the gained enhancers and activate the liver-specific gene transcription, thereby driving CRC liver metastasis. Importantly, similar transcription reprogramming can be observed in multiple cancer types. Our data suggest that reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.
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Project description:PurposeThe Oct4 gene plays an important role in undifferentiated embryonic stem cells and regulates stem cell pluripotency. The aim of this study was to examine the relationship between Oct4 expression and liver metastasis of colorectal cancer (CRC) in clinical samples and investigate the role and abilities of Oct4-positive CRC cells.MethodsThe study included 158 patients who underwent surgery for CRC between 2009 and 2011. The correlations between the Oct4 gene expression and the clinical parameters were assessed, and liver metastasis-free survival (LMFS) was evaluated in these patients. Oct4-EGFP-positive cells were established to examine their subpopulation and ability. The capacity to form liver metastasis in vivo was examined using CRC cell lines and primary cultured CRC cells.ResultsLMFS was significantly poor in the Oct4 high-expression group compared with the low-expression group (P = 0.008). Multivariate analyses showed that Oct4 expression (P = 0.015) and TNM stage (P < 0.001) were significantly correlated with LMFS. Oct4-EGFP-positive cells highly expressed stem cell-associated markers and had self-renewal and differentiation abilities. Oct4-high cells actively formed liver metastasis.ConclusionThe Oct4 expression was correlated with liver metastasis in CRC patients. Oct4 expression cells have self-renewal and differentiation abilities like those of cancer stem cells. Oct4 contributed to forming liver metastasis in CRC.
| S-EPMC6525814 | biostudies-literature
Project description:MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR-221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR-221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR-221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR-221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.
| S-EPMC8409403 | biostudies-literature
Project description:Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. The mechanisms by which cancer cells regulate liver microenvironment to promote cancer liver metastasis have been extensively studied. However, how the liver influences intercellular communication to support tumor liver metastasis remains largely unknown. Here, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese NAFLD in mice, with exosome biogenesis and hence cancer liver metastasis. Plasma GP73 level and liver GP73 protein expression were significantly elevated in CRC patients with liver metastasis (CRLM) as compared with CRC patients without liver metastasis. Strikingly, mice with high liver GP73 expression induced by Ad5-GP73 injection exhibited significantly increased CRC liver metastasis in an exosome dependent manner. Notably, GP73 overlapped with endosomal compartments and promoted exosome production. Mechanistically, GP73 bound to cholesterol and modulated the cholesterol content in endosomal compartments/multivesicular bodies (MVBs). Quantitative proteomics profiling revealed that GP73 reshaped hepatocyte exosomal proteome and produces NAV2-containing exosomes. Clinically, serum GP73 levels correlated positively with serum exosome NAV2 levels in CRLM. In particular, exosomes from GP73-high livers promoted tumor cell invasiveness mainly through transferable NAV2. Knockdown liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade significantly mitigated CRC liver metastasis enhancement in obese mice resulting from high-fat diet (HFD) or high-fructose diet (HFrD) feeding. Collectively, our findings provide novel insight into the roles of GP73 in exosome biogenesis and GP73 blockade may merit exploration as a potential therapeutic strategy for mitigating CRC liver metastasis.
2023-06-13 | PXD042963 |
Project description:BackgroundHematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear.MethodsIn the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo.ResultsOur clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo.ConclusionsOur results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.
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Project description:Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.
| S-EPMC8176431 | biostudies-literature
Project description:Exosomal microRNA (miRNA) secretion has been characterized as a vital factor in intercellular communication among cancer cells. However, little is known about cancer-secreted miRNAs specifically involved in metastasis of colorectal cancer (CRC). Here, we found that exosomes derived from metastatic CRC cell line SW620 promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells. The profiling of exosome miRNAs revealed that microRNA (miR)-335-5p was highly expressed in exosomes from metastatic SW620 cells compared to those derived from primary SW480 cells. miR-335-5p was transmitted from metastatic SW620 cells to CRC cells via exosomes and promoted migration, invasion, and EMT of CRC cells. Moreover, exosome-transmitted miRNA-335-5p promotes CRC cell invasion and metastasis by facilitating EMT via targeting RAS p21 protein activator 1 (RASA1). Overexpression of RASA1 abolished the promotive effects of exosomal miR-335-5p on CRC cell migration, invasion, and EMT. Collectively, our data revealed that exosomal miR-335-5p derived from metastatic CRC cells promotes CRC cell invasion and metastasis by facilitating EMT via targeting RASA1, which may serve as a potential therapeutic target for CRC metastasis.
| S-EPMC7960496 | biostudies-literature