1、Paper sharing:Hanahan D,Weinberg R.Hallmarks of Cancer:The Next Generation.Cell,2011,144(5):646-674.Dept.Medical Oncology,1st Affiliated Hospital*University1Six hallmarks of cancer proposed in 20002Emerging hallmarks 3Sustaining Proliferative Signaling The most fundamental trait of cancer cells invo
2、lves their ability to sustain chronic proliferation Normal tissues ensuring a homeostasis by carefully control thing the production and release of growth-promoting signals Cancer cells,by deregulating these signals,become masters of their own destinies.4 The enabling signals are conveyed in large pa
3、rt by growth factors that bind cell-surface receptors Cancer cells can acquire the capability to sustain proliferative signaling in a number of alternative ways5 Cancer cells can produce growth factor ligands Send signals to stimulate normal cells within the supporting tumor-associated stroma Elevat
4、ing the levels of receptor proteins displayed at the cancer cell surface Structural alterations in the receptor molecules Somatic mutations activate additional downstream pathways.EGFR mutation in NSCLC,B-Raf mutation in melanoma.67 Disruptions of negative-feedback mechanisms that attenuate prolifer
5、ative signaling Excessive proliferative signaling can trigger cell senescence:RAS,MYC.8Evading Growth Suppressors Cancer cells must circumvent powerful programs that negatively regulate cell proliferation Many of these programs depend on the actions of tumor suppressor genes Two prototypical tumor s
6、uppressors encode the RB and TP53 proteins To remove contact Inhibition Corruption of the TGF-b Pathway Promotes Malignancy,more elaborate than simple shutdown of its antiproliferative signaling circuitry activate EMT 9The RB protein integrates signals from diverse extracellular and intracellular so
7、urces and,in response,decides whether or not a cell should proceed through its growth-and-division cycleCancer cells with defects in RB pathway function are missing the services of a critical gatekeeper of cell-cycle progression whose absence permits persistent cell proliferation.10 TP53 receives in
8、puts from stress and abnormality sensors If the degree of damage to the genome is excessive,or if the levels of nucleotide pools,growth-promoting signals,glucose,or oxygenation are suboptimal,TP53 can call a halt to further cell-cycle progression until these conditions have been normalized.Alternati
9、vely,in the face of alarm signals indicating overwhelming or irreparable damage to such cellular subsystems,TP53 can trigger apoptosis.11Contact Inhibition the cell-to-cell contacts formed by dense populations of normal cells propagated in two-dimensional culture operate to suppress further cell pro
10、liferation,yielding confluent cellmonolayers.“contact inhibition”is abolished in various types of cancer cells in culture,suggesting that contact inhibition is an in vitro surrogate of a mechanism that operates in vivo to ensure normal tissue homeostasis 12Mechanisms of Contact Inhibition the NF2 ge
11、ne Merlin,the cytoplasmic gene product,orchestrates contact inhibition via coupling cell-surface adhesion molecules.Merlin strengthens the adhesivity of cadherin-mediated cell-to-cell attachments,by sequestering growth factor receptors,Merlin limits their ability to efficiently emit mitogenic signal
12、s LKB1 epithelial polarity protein which organizes epithelial structure and helps maintain tissue integrity overrule the mitogenic effects of the powerful Myc oncogene LKB1 expression is suppressed,epithelial integrity is destabilized,and epithelial cells become susceptible to Myc-induced transforma
13、tion13Resisting Cell Death Apoptosis Autophagy Necrosis14Apoptosis The concept that apoptosis serves as a natural barrier to cancer development has been established over the last two decades Apoptosis is attenuated in those tumors that succeed in progressing to states of high-grade malignancy and re
14、sistance to therapy15 The apoptotic machinery is composed of both upstream regulators and downstream effector components The regulators are divided into two major circuits,one receiving and processing extracellular death-inducing signals(the extrinsic apoptotic program,for example the Fas ligand/Fas
15、 receptor)The other sensing and integrating a variety of signals of intracellular origin(the intrinsic program).16Apoptosis signaling pathways 17Apoptosis-triggering mechanisms TP53 induces in response to substantial levels of DNA breaks and other chromosomal abnormalities.insufficient survival fact
16、or signaling,interleukin-3,IGF-1 Hyperactive signaling by certain oncoproteins,such as Myc18Strategies developed by cancer cells to circumvent apoptosis Most common is the loss of TP53 tumor suppressor function Increasing expression of antiapoptotic regulators(Bcl-2,Bcl-xL)or of survival signals Dow
17、nregulating proapoptotic factors(Bax,Bim,Puma),or by short-circuiting the extrinsic ligand-induced death pathway19Autophagy Can be strongly induced in certain states of cellular stress,the most obvious of which is nutrient deficiency In this fashion,low-molecular-weight metabolites are generated tha
18、t support survival in the stressed,nutrient-limited environments experienced by many cancer cells20Autophagy is cytoprotective for cancer cells Nutrient starvation,radiotherapy,and certain cytotoxic drugs can induce elevated levels of autophagy Severely stressed cancer cells have been shown to shrin
19、k via autophagy to a state of reversible dormancy This survival response may enable the persistence and eventual regrowth of some late stage tumors following treatment with potent anticancer agents.21Necrosis Has Proinflammatory and Tumor-Promoting Potential Necrotic cells releasing their contents i
20、nto the local tissue microenvironment Immune inflammatory cells can be actively tumor promoting,given that such cells are capable of fostering angiogenesis,cancer cell proliferation,and invasiveness Necrotic cells can release bioactive regulatory factors,such as IL-1a22Enabling Replicative Immortali
21、tyMost normal cell lineages are able to pass through only a limited number of successive cell growth-and-division cycles.This limitation has been associated with two distinct barriers to proliferation senescence,a typically irreversible entrance into a nonproliferative but viable state,crisis,in whi
22、ch the great majority of cells in the population die.Cancer cells:able to proliferate in culture without evidence of either senes-cence or crisis(immortalization)Telomeres protecting the ends of chromosomes are centrally involved in the capability for unlimited proliferation23The telomeres,composed
23、of multiple tandem hexanucleotide repeats,shorten progressively in nonimmortalized cells propagated in culture,eventually losing the ability to protect the ends of chromosomal DNAs from end-to-end fusions2425 Telomerase,the specialized DNA polymerase that adds telomere repeat segments to the ends of
24、 telomeric DNA,is almost absent in nonimmortalized cells but expressed at functionally significant levels in the vast majority(90%)of immortalized cells,including human cancer cells Expression of the enzyme is correlated with a resistance to induction of both senescence and crisis/apoptosis Suppress
25、ion of telomerase activity leads to telomere shortening and to activation of one or the other of proliferative barriers.26 Delayed Activation of Telomerase May Both Limitand Foster Neoplastic Progression Clones of incipient cancer cells often experience telomere loss-induced crisis relatively early
26、during the course of multistep tumor progression due to their inability to express signficant levels of telomerase.The absence of TP53-mediated surveillance of genomic integrity may permit other incipient neoplasias to survive initial telomere erosion and attendant chromosomal breakage-fusion-bridge
27、(BFB)cycles.27 Overt carcinomas exhibited telomerase expression concordantly with the reconstruction of longer telomeres and the fixation of the aberrant karyotypes.The delayed acquisition of telomerase function serves to generate tumor-promoting mutations,whereas its subsequent activation stabilize
28、s the mutant genome and confers the unlimited replicative capacity28Inducing Angiogenesis Tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide.The process of angiogenesis,addresses these needs.The normal vasculature becom
29、es largely quiescent.In the adult,as part of physiologic processes such as wound healing and female reproductive cycling,angiogenesis is turned on,but only transiently29angiogenesis precocious capillary sprouting convoluted and excessive vessel branching,distorted and enlarged vessels,erratic blood
30、flow,microhemorrhaging,leakiness,abnormal levels of endothelial cell proliferation and apoptosis30 During tumor progression,an“angiogenic switch”is almost always activated and remains on,causing normally quiescent vasculature to continually sprout new vessels that help sustain expanding neoplastic g
31、rowths The angiogenic switch is governed by countervailing factors that either induce or oppose angiogenesis31 VEGF-Athree receptor tyrosine kinases(VEGFR-13)hypoxia and oncogene extracellular matrix(release and activation by extracellular matrix-degrading proteases)other proangiogenic signals(such
32、as FGF)32 angiogenesis inhibitors TSP-1 binds transmembrane receptors displayed by endothelial cells and thereby evokes suppressive signals that can counteract proangiogenic stimuli 33 Angiostatin Proteolytic cleavage of structural proteins Endostatin Physiologic regulators that modulate transitory
33、angiogenesis during tissue remodeling and wound healing34Pericytes is important for the maintenance of a functional tumor neovasculatureA variety of bone marrow-derived cells contribute to tumor angiogenesis macrophages,neutrophils,mast cells,and myeloid progenitors,the peri-tumoral inflammatory cel
34、ls Help to trip the angiogenic switch in previously quiescent tissue Sustain ongoing angiogenesis Protect the vasculature from the effects of drugs targeting therapy35Activating Invasion and Metastasisinvasion-metastasis cascade36E-cadherin,a key cell-to-cell adhesion molecule E-cadherin helps to as
35、semble epithelial cell sheets and maintain the quiescence of the cells within these sheets.Increased expression of E-cadherin was well established as an antagonist of invasion and metastasis Increased expression of E-cadherin was well established as an antagonist of invasion and metastasis,；reductio
36、n of its expression was known to potentiate these phenotype Frequently observed down regulation and occasional mutational inactivation of E-cadherin in human carcinomas provided strong support for its role as a key suppressor of this hallmark capability37The epithelial-mesenchymal transition(EMT)Bro
37、adly Regulates Invasion and MetastasisMotilityInasivenessResistance to apoptosis 38 EMT：transformed epithelial cells can acquire the abilities to invade,to resist apoptosis,and to disseminate Embryonic morphogenesis and wound healing Carcinoma cells can concomitantly acquire multiple attributes that
38、 enable invasion and metastasis.EMT are able to orchestrate most steps of the invasion-metastasis cascade3940mesenchymal-epithelial transition(MET)MET results in the formation of new tumor colonies of carcinoma cells exhibiting a histopathology similar to those of carcinoma cells in the primary tumo
39、r41Contributions of Stromal Cells to Invasionand Metastasis Crosstalk between cancer cells and cells of the neoplastic stroma is involved in the acquired capability for invasive growth and metastasis Mesenchymal stem cells(MSCs)present in the tumor stroma have been found to secrete CCL5/RANTES in re
40、sponse to signals released by cancer cells;CCL5 then acts reciprocally on the cancer cells to stimulate invasive behavior Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases 42Emerging hallmark
41、s43Genome Instability and Mutation Gene disorders Multiple hallmarks depends in large part on a succession of alterations in the genomes of neoplastic cells.Multistep tumor progression can be portrayed as a succession of clonal expansions,each of which is triggered by the acquisition of an enabling
42、mutant genotype.4445 Cancer cells often increase the rates of mutation The accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis The role of TP53 is central
43、 guardian of the genome46A diverse array of defects of theDNA-maintenance machinery-caretakers of the genome Detect-ing DNA damage and activating the repair machinery Directly repairing damaged DNA Inactivating or intercepting mutagenic molecules before they have damaged the DNA47Tumor-Promoting Inf
44、lammation Virtually every neoplastic lesion contains immune cells Historically,such immune responses were largely thought to reflect an attempt by the immune system to eradicate tumors Antitumoral responses48 By 2000,there were already clues that the tumor-associated inflammatory response had the un
45、anticipated,paradoxical effect of enhancing tumorigenesis and progression49Contribution of inflammation to cancer cells Supplying bioactive molecules to the tumor microenvironment:growth factors;survival factors;proangiogenic factors,et al.Is demonstrably capable of fostering the development of inci
46、pient neoplasias into full-blown cancers Release chemicals,notably reactive oxygen species,that are actively mutagenic for nearby cancer cells,accelerating their genetic evolution toward states of heightened malignancy5051Reprogramming Energy Metabolism Under aerobic conditions,normal cells process
47、glucose,first to pyruvate via glycolysis in the cytosol and thereafter to carbon dioxide in the mitochondria;under anaerobic conditions,glycolysis is favored 52 Cancer cells can reprogram their glucose metabolism “aerobic glycolysis”Upregulating glucose transporters,notably GLUT1,which substantially
48、 increases glucose import into the cytoplasm53Why cancer cells reprogram their glucose metabolism?18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation.Increased glycolysis allows the diversion of glycolytic intermediates into various b
49、iosynthetic pathways,including those generating nucleosides and amino acidsSome tumors have been found to contain two subpopulations of cancer cells that differ in their energy-generating pathways.One subpopulation consists of glucose-dependent cells that secrete lactate,whereas cells of the second
50、subpopulation preferentially import and utilize the lactate produced by their neighbors as their main energy source,employing part of the citric acid cycle to do so 54Evading Immune Destruction The immune system operates as a significant barrier to tumor formation and progression Deficiencies in the
