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
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
Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of ...Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.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 by National Key Research and Development Program of China[2020YFA0112300 and 2018YFC2000400 to C.C.]the National Natural Science Foundation of China[82072622,81860488,and 81560432 to Y.R.,81830087 and 31771516 to C.C.,81772847 to L.R.,81672639 to Z.Z.,and 81872414 and 81802671 to J.D.]+1 种基金Yunnan Leading Medical Talents Program[L-201610]to Y.R.,Yunnan Fundamental Research Projects[2019FB112]Yunnan excellent young scientist foundation(2020)to J.D.,and Project of Innovative Research Team of Yunnan Province[2018HC004 and 2019HC005].S.-C.J.Y.
文摘Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.
