Cancer-Secreted Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis By Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts

2021 ◽  
Author(s):  
Chong Zhang ◽  
Xiang-Yu Wang ◽  
Peng Zhang ◽  
Tao-Chen He ◽  
Jia-Hao Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Liver Metastasis ◽  
Metabolic Reprogramming ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Cancer Associated Fibroblasts ◽  
Metastatic Niche

Abstract Background: Metastasis and metabolic deregulation are two of the major hallmarks of cancer. Recent studies have revealed the critical driving role of metabolic reprogramming of tumor cells to promote colorectal cancer (CRC) metastasis. However, little is known about the metabolic alterations of cancer-associated fibroblasts (CAFs) in the pre-metastatic niche and how these changes facilitate CRC metastasis.Methods: Liquid chromatography-mass spectrometry (LC-MS) and Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the comparative metabolites and proteins expression in CAFs treated with exosomes derived from CRC cells, respectively. Tissue Microarray (TMA) was used to evaluate the level of HSPC111 in patient’s primary CRC tissues with or without liver metastasis. Co-immunoprecipitation (Co-IP), RNA-seq, chromatin immunoprecipitation (ChIP) migration and wound healing assay and immunofluorescence staining were employed to explore the expression regulation mechanism of exosomal HSPC111 in CAFs. Xenograft models were used to determine whether exosomal HSPC111 can remolding pre-metastatic niche of CAFs to promote CRC liver metastasis (CRLM) in vivo.Results: Here, we demonstrate that CRC cell-secreted exosomal HSPC111 induces a lipid metabolism reprogramming process in CAFs. Importantly, our results indicate that CRC patients with liver metastasis had significantly high level of HSPC111 in CRC tissues than CRC patients without liver metastasis. Mechanistically, HSPC111 upregulate the level of acetyl-CoA and histone acetylation by phosphorylating of ATP-citrate lyase (ACLY) in CAFs. This lipid metabolism reprogramming in CAFs facilitates CXCL5 secretion in vitro and pre-metastatic niche formation in the liver to promote CRLM in an exosomal HSPC111-dependent manner in vivo. In addition, conditioned medium (CM) from CAFs induce EMT of CRC cells by down-regulating E-cadherin levels and up-regulating Vimentin and Snail levels, which could be abolished by CXCL5-neutralizing antibody and CXCR2 inhibitor navarixin. Moreover, the HSPC111-ACLY association in CAFs was reinforced by CXCL5-CXCR2 axis, further promoting exosomal HSPC111 secretion from CRC cells to form a feedforward regulatory loop.Conclusion: Our present study reveals a novel insight into the pro-metastatic role of lipid metabolism reprogramming in CAFs and suggests the CXCL5-CXCR2 axis may be a promising target for halting CRLM.

scholarly journals The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

2018 ◽  
Vol 19 (12) ◽  
pp. 3711 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Daniel Sur ◽  
Calin Cainap ◽  
Simona Visan ◽  
Daniel Cruceriu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Cancer Progression ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Incidence And Mortality ◽  
The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

scholarly journals The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

2018 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Daniel Sur ◽  
Calin Cainap ◽  
Simona Visan ◽  
Daniel Cruceriu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Incidence And Mortality ◽  
The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis, published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial-mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.  

scholarly journals TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Fanglong Wu ◽  
Shimeng Wang ◽  
Qingxiang Zeng ◽  
Junjiang Liu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oral Cancer ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts

AbstractCancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

scholarly journals Ibrutinib Disrupts the Metabolic Program of CLL Cells in-Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4348-4348
Author(s):  
Uri Rozovski ◽  
David M. Harris ◽  
Ping LI ◽  
Zhiming Liu ◽  
Preetesh Jain ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Metabolic Reprogramming ◽  
Short Exposure ◽  
Dependent Manner ◽  
Ffa Metabolism

Abstract Introduction: Unlike their normal resting B cell counterparts, chronic lymphocytic leukemia (CLL) cells proliferate. Approximately 1% of the total CLL cell clone expands daily. To adjust for the increase in energetic demands imposed by continuous proliferation, CLL cells undergo metabolic reprogramming and, as recently shown (Rozovski U, et al. Mol Cancer Res. 2015; 13:944-53), CLL cells utilize fat in a manner similar to that of adipocytes. The recent introduction of the oral Bruton tyrosine kinase inhibitor (BTK) ibrutinib revolutionized the treatment of CLL. Because the proliferation of CLL cells is driven by lipid metabolism and ibrutinib inhibits the B cell receptor-induced proliferation of CLL cells, we sought to determine whether ibrutinib also disrupts the metabolic program that provides CLL cells with their unique energy requirements. Methods: We prospectively studied serial peripheral blood samples from 16 patients with CLL. The patients' peripheral blood CLL cells were analyzed prior to and during treatment with ibrutinib. All patients received a daily dose of 420 mg ibrutinib. In addition, we performed in vitro studies using CLL cells from 3 ibrutinib-naïve patients. CLL cells were analyzed for free-fatty acids (FFA) consumption and for the rate of cellular apoptosis using propiduim iodide (PI) and annexin V staining analyzed by flow cytometry. Results: To study lipid metabolism of CLL cells we incubated peripheral blood CLL cells from 3 randomly selected ibrutinib-naïve patients in the presence or absence of FFA and measured the concentration of culture media-dissolved O2 (dO2). Like in our previous study (Rozovski U, et al. Mol Cancer Res. 2015; 13:944-53), we found that CLL cells metabolized FFA and, as a result, the levels of dO2 decreased. However when the cells were co-cultured with FFA and ibrutinib, the delta dO2 (dO2 with FFA minus dO2 without FFA) remained unchanged, suggesting that ibrutinib blocked FFA metabolism in CLL cells.Then, to determine whether ibrutinib also inhibited CLL-cell lipid metabolism in patients treated with ibrutinib, we collected 2 to 5 consecutive PB samples (median: 5) from 16 CLL patients prior to and during treatment with ibrutinib. Unlike the 12% reduction in delta dO2 detected in untreated patients' CLL cells incubated with FFA in vitro, a 6% reduction in delta dO2 was detected in CLL cells of patients treated with ibrutinib 4 days into treatment and after a median of 147 days of ibrutinib treatment a change in delta dO2 was no longer detected. These data suggest that ibrutinib-treated cells lost their capacity to utilize FFA or that the number of FFA consuming circulating CLL cells declined until they were no longer detected. In addition, whereas ibrutinib induced apoptosis of CLL cells in a dose-dependent manner in vitro, ibrutinib did not induce apoptosis at the same time points in vivo, suggesting that interruption of FFA metabolism does not lead to apoptotic cell death and that the metabolic and proapoptotic pathways are not linearly intertwined in CLL cells. In conclusion: Treatment with ibrutinib changes the metabolic profile CLL cells. Even after short exposure to the drug the cells were less capable of utilizing FFA, and after longer exposure, the cells could no longer utilize FFA. Whether ibrutinib induced reduction in FFA metabolism decreases the proliferation capacity of CLL cells remains to be determined. Disclosures Burger: Pharmacyclics: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jain:Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novimmune: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; BMS: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

scholarly journals The Role and Therapeutic Potential of miRNAs in Colorectal Liver Metastasis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Smiti S. Sahu ◽  
Shatovisha Dey ◽  
Sarah C. Nabinger ◽  
Guanglong Jiang ◽  
Alison Bates ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Metastatic Potential ◽  
Sequencing Project ◽  
Cancer Genome Sequencing ◽  
Novel Therapeutic Strategies

Abstract Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Liver metastasis is the major cause of CRC patient mortality, occurring in 60% patients with no effective therapies. Although studies have indicated the role of miRNAs in CRC, an in-depth miRNA expression analysis is essential to identify clinically relevant miRNAs and understand their potential in targeting liver metastasis. Here we analyzed miRNA expressions in 405 patient tumors from publicly available colorectal cancer genome sequencing project database. Our analyses showed miR-132, miR-378f, miR-605 and miR-1976 to be the most significantly downregulated miRNAs in primary and CRC liver metastatic tissues, and CRC cell lines. Observations in CRC cell lines indicated that ectopic expressions of miR-378f, -605 and -1976 suppress CRC cell proliferation, anchorage independent growth, metastatic potential, and enhance apoptosis. Consistently, CRC patients with higher miR-378f and miR-1976 levels exhibited better survival. Together, our data suggests an anti-tumorigenic role of these miRNAs in CRC and warrant future in vivo evaluation of the molecules for developing biomarkers or novel therapeutic strategies.

scholarly journals Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wunan Mi ◽  
Chuyue Wang ◽  
Guang Luo ◽  
Jiehan Li ◽  
Yizheng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Vital Role ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Treatment Groups ◽  
Combinational Treatment

AbstractIn recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.

scholarly journals CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xin Liu ◽  
Yunze Liu ◽  
Zhao Liu ◽  
Changwei Lin ◽  
Fanchao Meng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Redox Homeostasis ◽  
Circular Rnas ◽  
Dependent Manner ◽  
Metabolism Regulation ◽  
Chemically Induced ◽  
Glycine Metabolism

Abstract Background Circular RNAs (circRNAs) play important roles in cancer progression and metabolism regulation. Serine/glycine metabolism supports the growth of cancer cells by contributing to their anabolic demands and epigenome as well as by regulating their redox state. However, the role of circRNA in the regulation of serine/glycine metabolism has not been well elucidated. Methods Microarray analysis was used to screen differentially expressed novel circRNAs. qRT-PCR and FISH were utilized to analyzed the expression of circMYH9. CCK8, colony formation and FACS were used to analyze proliferation of colorectal cancer (CRC) cells. Xenograft experiments were used to analyze tumor growth in vivo. RNA-sequencing, immunoblot and LC–MS were used to identify the downstream metabolic pathway of circMYH9. ChIRP, Mass Spectrometry, RIP and RNA pulldown were utilized to test the interaction between circMYH9, hnRNPA2B1 and p53 pre-mRNA. ChIP-qPCR was used to analyze the binding sites of HIF-1α. Chemically-induced CRC mice were generated to evaluate the role of circMYH9 in tumorigenesis. Results We identified an intron-derived circRNA, circMYH9, which was significantly upregulated in CRC tissues. A higher circMYH9 level correlated with shorter relapse-free survival and overall survival of CRC patients. CircMYH9 promoted serine/glycine metabolism, the NAD + /NADH ratio, and glutathione recycling and inhibited reactive oxygen species (ROS) in a p53-dependent manner, impacting tumour growth. Mechanistically, circMYH9 destabilized the pre-mRNA of p53 by recruiting hnRNPA2B1 in the nucleus. hnRNPA2B1 bound to N6-methyladenosine sites on the 3' untranslated region of p53 pre-mRNA and maintained its stability. Moreover, a lack of amino acids led to an elevated level of ROS, resulting in increased HIF1α, which promoted circMYH9 expression by binding to the promoter region. Furthermore, in vivo AAV9-mediated transfection of circMYH9 could drive chemically-induced carcinogenesis by suppressing p53 in mice. Conclusions The overexpression of circMYH9 promotes CRC proliferation though modulating serine/glycine metabolism and redox homeostasis in a p53-dependent manner, and targeting circMYH9 and its pathway may be an effective strategy for the treatment of CRC.

scholarly journals Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Cao ◽  
Huan Deng ◽  
Hao Cui ◽  
Ruiyang Zhao ◽  
Hanghang Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lipid Metabolism ◽  
Cell Viability ◽  
Glucose Deprivation ◽  
Metabolic Reprogramming ◽  
Cell Counting ◽  
Tumor Node Metastasis Stage

Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Methods Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. Results Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. Conclusions Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

scholarly journals UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Congcong Zhu ◽  
Long Zhang ◽  
Senlin Zhao ◽  
Weixing Dai ◽  
Yun Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dependent Manner ◽  
Poor Overall Survival ◽  
Free Survival ◽  
Protein Levels ◽  
Therapy Strategy ◽  
Risk Factor For Recurrence

AbstractUPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 in oxaliplatin resistance in colorectal cancer (CRC) remains unknown. In our study, UPF1 is upregulated in CRC in mRNA and protein levels and overexpression of UPF1 predicts a poor overall survival (OS) and recurrence-free survival (RFS) in CRC patients and is an independent risk factor for recurrence. UPF1 promotes chemoresistance to oxaliplatin in vitro and in vivo. UPF1-induced oxaliplatin resistance can be associated with interaction between zinc finger of UPF1 and Toprim of TOP2A and increasing phosphorylated TOP2A in a SMG1-dependent manner. Moreover, UPF1 maintains stemness in a TOP2A-dependent manner in CRC. Taken together, UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced chemoresistance to oxaliplatin in CRC, which may result from regulation of TOP2A activity and maintenance of stemness. Our findings could provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

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