Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistan...Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg's discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.展开更多
Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor.FBXW7 is a highly mutated gene in CRC,but its biological functions in cancer are not fully characterized.Here,we report that FB...Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor.FBXW7 is a highly mutated gene in CRC,but its biological functions in cancer are not fully characterized.Here,we report that FBXW7β,a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC,is an E3 ligase of fatty acid synthase(FASN).Cancer-specific FBXW7βmutations that could not degrade FASN can lead to sustained lipogenesis in CRC.COP9 signalosome subunit 6(CSN6),an oncogenic marker of CRC,increases lipogenesis via interacting with and stabilizing FASN.Mechanistic studies show that CSN6 associates with both FBXW7βand FASN,and antagonizes FBXW7β’s activity by enhancing FBXW7βautoubiquitination and degradation,which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation,thereby regulating lipogenesis positively.Both CSN6 and FASN are positively correlated in CRC,and CSN6-FASN axis,regulated by EGF,is responsible for poor prognosis of CRC.The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab.Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC.Thus,CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.展开更多
It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the conte...It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the context of the microbiome.Owing to the availability of metagenome sequencing and multiomics studies,analyses of species characterization,host genetic changes,and metabolic profile of gut microbiota have become feasible,which has facilitated an exponential knowledge gain about microbiota composition,taxonomic alterations,and host interactions during tumorigenesis.However,the complexity of the gut microbiota,with a plethora of uncharacterized host-microbe,microbemicrobe,and environmental interactions,still contributes to the challenge of advancing our knowledge of the microbiota-cancer interactions.These interactions manifest in signaling relay,metabolism,immunity,tumor development,genetic instability,sensitivity to cancer chemotherapy and immunotherapy.This review summarizes current studies/molecular mechanisms regarding the association between the gut microbiota and the development of cancers,which provides insights into the therapeutic strategies that could be harnessed for cancer diagnosis,treatment,or prevention.展开更多
Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additi...Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor progression.Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate reaction.The tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.展开更多
Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbia...Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbial genome encodes 500 times more genes than the human genome,and so it is tempting to consider human genes as noise in the storm of microbial signals[1].Recent data suggest that,while microbial signals modulate crucial functions of the healthy human body,there are also accumulating data suggesting that many human diseases have their origin in distorted gut microbiota composition[2].展开更多
Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacte...Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacteria,which makes it easier to underestimate their potential threat to health.However,fungal infections indeed participate in the onset and progression of many intestinal diseases,so they are crucially affecting our health[1,2].Recently,Li et al.described that C-type lectin receptors(CLRs)on myeloid cells,including Dectin-1,Dectin-2,Dectin-3,and Mincle,play an important role in the immune function induced by fungal pathogens of the intestinal microbiota[3].展开更多
基金supported by the National Institutes of Health through The University of Texas MD Anderson Cancer Center’s Support Grant CA016672National Cancer Institute grant RO1CA 089266 (MHL)+3 种基金Directed Medical Research Programs Department of Defense Synergistic Idea Development Award BC062166 (SCY, MHL)the Susan G.Komen Breast Cancer Research Foundation Promise Grant KG081048 (SCY, MHL)Vietnam Education Foundation, Rosalie B.Hite FoundationDepartment of Defense Breast Cancer Research Program (Award # W81XWH-10-0171)
文摘Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg's discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.
基金supported by National Key R&D Program of China(2020YFA0803300),the Basic and Applied Basic Research Program of Guangzhou City(202102020084)the Basic and Applied Basic Research Program of Guangdong Province(2023A1515030245),the Natural Science Foundation of Guangdong Province(2021A1515012081)+1 种基金the National Natural Science Foundation of China(81630072)the Guangzhou Science and Technology Program Project(202206010167).
文摘Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor.FBXW7 is a highly mutated gene in CRC,but its biological functions in cancer are not fully characterized.Here,we report that FBXW7β,a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC,is an E3 ligase of fatty acid synthase(FASN).Cancer-specific FBXW7βmutations that could not degrade FASN can lead to sustained lipogenesis in CRC.COP9 signalosome subunit 6(CSN6),an oncogenic marker of CRC,increases lipogenesis via interacting with and stabilizing FASN.Mechanistic studies show that CSN6 associates with both FBXW7βand FASN,and antagonizes FBXW7β’s activity by enhancing FBXW7βautoubiquitination and degradation,which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation,thereby regulating lipogenesis positively.Both CSN6 and FASN are positively correlated in CRC,and CSN6-FASN axis,regulated by EGF,is responsible for poor prognosis of CRC.The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab.Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC.Thus,CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.
基金National key research and development program,Grant/Award Numbers:2020YFA0803300,2018YFC0910300National Natural Science Foundation of China,Grant/Award Number:81630072+1 种基金Shenzhen Municipal Government of China,Grant/Award Number:KQTD20170810160226082China Association for Science and Technology,Grant/Award Numbers:2018YFC0910300,2020YFA0803300。
文摘It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the context of the microbiome.Owing to the availability of metagenome sequencing and multiomics studies,analyses of species characterization,host genetic changes,and metabolic profile of gut microbiota have become feasible,which has facilitated an exponential knowledge gain about microbiota composition,taxonomic alterations,and host interactions during tumorigenesis.However,the complexity of the gut microbiota,with a plethora of uncharacterized host-microbe,microbemicrobe,and environmental interactions,still contributes to the challenge of advancing our knowledge of the microbiota-cancer interactions.These interactions manifest in signaling relay,metabolism,immunity,tumor development,genetic instability,sensitivity to cancer chemotherapy and immunotherapy.This review summarizes current studies/molecular mechanisms regarding the association between the gut microbiota and the development of cancers,which provides insights into the therapeutic strategies that could be harnessed for cancer diagnosis,treatment,or prevention.
基金Fidelity Foundation,Grant/Award Number:2020YFA0803300Shenzhen Municipal GovernmentNationalNatural Science Foundation of China,Grant/Award Numbers:81702749,81630072,81773098,81803568,8160242.
文摘Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor progression.Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate reaction.The tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.
基金supported in part by the National Key R&D Program of China[2018YFC0910303]Foundation,Fidelity Foundation,the National Natural Science Foundation of China[81630072]National Key Clinical Discipline.
文摘Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbial genome encodes 500 times more genes than the human genome,and so it is tempting to consider human genes as noise in the storm of microbial signals[1].Recent data suggest that,while microbial signals modulate crucial functions of the healthy human body,there are also accumulating data suggesting that many human diseases have their origin in distorted gut microbiota composition[2].
文摘Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacteria,which makes it easier to underestimate their potential threat to health.However,fungal infections indeed participate in the onset and progression of many intestinal diseases,so they are crucially affecting our health[1,2].Recently,Li et al.described that C-type lectin receptors(CLRs)on myeloid cells,including Dectin-1,Dectin-2,Dectin-3,and Mincle,play an important role in the immune function induced by fungal pathogens of the intestinal microbiota[3].
