The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use ...The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.展开更多
In 2011,Hanahan and Weinberg added“Deregulating Cellular Energetics”and“Avoiding Immune Destruction”to the six previous hallmarks of cancer.Since this seminal paper,there has been a growing consensus that these ne...In 2011,Hanahan and Weinberg added“Deregulating Cellular Energetics”and“Avoiding Immune Destruction”to the six previous hallmarks of cancer.Since this seminal paper,there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent.The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis,which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche,promoting malignant cell proliferation,maintenance and progression.The mechanisms by which altered metabolism contributes to immune impairment are multifactorial:(1)the metabolic demands of proliferating tumor cells and activated immune cells are similar,thus creating a situation where immune cells may be in competition for key nutrients;(2)the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype;and(3)the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites.From this perspective,we shed light on important considerations for the development of new classes of agents targeting cancer metabolism.These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.展开更多
文摘The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.
基金This work was supported by R01 CA217987(JCR),the Vanderbilt-Incyte Research Alliance(JCR),F30 CA247202(BIR)the American Association for Cancer Research(BIR and WKR)T32 GM00734742.The figures were made at Biorender.com.
文摘In 2011,Hanahan and Weinberg added“Deregulating Cellular Energetics”and“Avoiding Immune Destruction”to the six previous hallmarks of cancer.Since this seminal paper,there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent.The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis,which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche,promoting malignant cell proliferation,maintenance and progression.The mechanisms by which altered metabolism contributes to immune impairment are multifactorial:(1)the metabolic demands of proliferating tumor cells and activated immune cells are similar,thus creating a situation where immune cells may be in competition for key nutrients;(2)the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype;and(3)the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites.From this perspective,we shed light on important considerations for the development of new classes of agents targeting cancer metabolism.These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
