Classic Collection Plus: A Sign of Cancer (2)

Hallmarks of Cancer: The Next Generation is 10 years apart.
The second edition of the tumor monograph was published in Cell.
Compared with the previous edition, it has introduced four new features while retaining the six acquired characteristics of tumors.
They are: Deregulating cellular energetics, Avoiding immune destruction, Genome instability and mutation, and Tumor-promoting inflammation
.

Genome instability and tumor-promoting inflammation are the main mechanisms for tumor cells to acquire a series of capabilities for proliferation, invasion and metastasis.
Among them, genome instability and mutations are most closely related to the degree of malignancy of tumor cells.
Chromosome deletion, duplication, and inversion.
Changes in the composition or sequence of gene base pairs initiate or aggravate the occurrence and progression of tumors
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Tumor-promoting inflammation and immune escape are the same system with two different characteristics
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Inflammation is a defensive response of the body to stimuli, and it is also a double-edged sword.
In the process of killing tumor cells through immune response, it also accelerates the progression of the malignant degree of tumor cells
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For example, nuclear factor kappa B (NF-κB) signaling pathway, Toll-like receptor-mediated signal transduction pathway
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When doing tumor proliferation experiments, adding culture medium to tumor cell lines is to better observe the changes in tumor cell proliferation ability
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In the human body, tumor cells also create a nutrient-rich environment for themselves to achieve clonal value-added
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Abnormal energy metabolism is one of the methods used by tumor cells
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1.
Sustaining Proliferative Signaling Normal cells need the stimulation of growth signals to control the cell cycle and maintain a precise dynamic balance between cell division and death
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Most cell growth signal pathways are mediated by extracellular growth factors and transmembrane receptor tyrosine kinases
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In contrast, the abnormal regulation of extracellular signals, transmembrane receptors, and intracellular signals by cancer cells enables them to gain self-control of proliferation.
Not only do they secrete growth factors themselves, form a positive feedback regulation loop, but also have high expression levels.
The receptor increases the efficiency of signal transduction
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The most complicated part of the mechanism research is the abnormal changes in intracellular signal transduction after cancer cells receive growth signals
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Looking at the basic research on tumors in recent years, the hot spots in the country are just three mechanisms summarized in this review: somatic mutations activate downstream pathways, negative feedback failures that down-regulate proliferation, and excessive proliferation signals cause aging
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 Somatic mutations activate downstream pathways.
Somatic mutations refer to mutations that occur in somatic cells other than sex cells
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It will not cause genetic changes in offspring, but it can cause changes in the genetic structure of certain cells in the present age
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RNA sequencing is a means to detect mutations in human tissue cells
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In 2019, a study published in Science[1] found that there are a series of somatic mutations in normal human tissues, including gene mutations in cancer cells.
The load of somatic mutations in skin, esophageal mucosa, and lung tissues is higher than that in other tissues.

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Somatic mutations can accumulate gradually over the life of an individual
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Mutations can be divided into three major types: point mutations, chromosomal mutations and genomic mutations
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Among them, point mutations are the most common and important, including transition, transversion, insertion and deletion.
The first two belong to base substitution, and the latter two belong to shift.
Frame shift mutation
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Accumulation of intracellular mutations can cause a series of abnormal signaling pathways, such as the MAPK signaling pathway, which is an important transmitter of signals from the cell surface to the inside of the nucleus
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Mitogen-activated protein kinase (MAPK) is a group of serine-threonine that can be activated by different extracellular stimuli, such as cytokines, neurotransmitters, hormones, cell stress, and cell adhesion.
Protein kinase
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All eukaryotic cells can express MAPK
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The basic composition of the MAPK pathway is a three-level kinase model that is conserved from yeast to humans, including MAPK kinase kinase (MAP kinase kinase, MKKK), MAPK kinase (MAP kinase kinase, MKK), and MAPK.
Sequential activation, together regulating cell growth, differentiation, stress adaptation to the environment, inflammatory response and other important cellular physiological/pathological processes
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The MAPK chain is composed of three types of protein kinases MAP3K-MAP2K-MAPK, which transmit upstream signals to downstream response molecules through sequential phosphorylation
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MAPK belongs to the CMGC (CDK/MAPK/GSK3/CLK) kinase group
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The proteins closest to MAPKs are cyclin-dependent kinases (CDKs)
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Taking the RAS-RAF pathway as an example, the combination of growth factors and transmembrane receptors causes intracellular GRB2 to bind to SOS, stimulates the release of ATP from RAS protein, and the downstream Raf cascade activates MAPKKK-MAPKK-MAPK to promote transcription regulation.

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In tumor cells, there is no need for extracellular growth factor stimulation, mutations cause Raf conformational changes, self-initiating MAPK cascade activation, promote transcription (figure1)
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 PI3K is an intracellular phosphatidylinositol kinase.
PI3K itself has serine/threonine (Ser/Thr) kinase activity and also has phosphatidylinositol kinase activity
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After being signaled by tyrosine kinases and G protein-coupled receptors on the cell membrane, the p85 regulatory subunit of PI3K is recruited to the part adjacent to the plasma membrane, and then the second messenger PIP3 is produced, which contains the PH domain in the cell.
The signal protein AKT binds to PDK1 (phosphoinositide dependent kinase-1).
After activation, PDK1 phosphorylates the Ser308 region of the AKT protein, and finally activates AKT
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Activated AKT phosphorylates downstream factors such as a variety of enzymes, kinases, and transcription factors, thereby regulating cell functions (figure 2)
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After the mutation of the PI3K catalytic subunit in tumor cells does not rely on extracellular signals, it activates itself to generate a second messenger, continuously activates the downstream Akt pathway, and promotes tumor cell proliferation
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 Negative feedback failure to down-regulate proliferation There are some negative feedback regulation mechanisms in normal cells that inhibit excessive proliferation signals
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Cancer cells can inactivate the growth-inhibiting signal by changing the negative feedback regulation loop
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The proto-oncogene Ras and Ras protein are membrane-bound GTP/GDP binding proteins, which are stimulated by extracellular growth factors to deliver cell growth and differentiation signals
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The process of GTP→GDP releasing ATP is regulated by negative feedback, and when the Ras gene is mutated, Ras continues to activate the MAPK pathway to stimulate cell growth
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PTEN is a tumor suppressor gene, also known as MMAC1 and TEP1
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PTEN protein can inhibit the occurrence and development of tumors by antagonizing the activity of phosphorylases such as tyrosine kinases
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Loss of PTEN function can amplify the efficacy of PI3K signaling pathway and promote the generation of solid tumors
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Senescence of senescent cells caused by excessive proliferation signals means that cell growth is permanently blocked in the G1 phase of the cell cycle, and morphological, biochemical and epigenetic changes appear
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Senescence induced by oncogenes may be an innate defense against cancer [2]
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Oncogenes are inactivated due to mutations and lose their role in promoting tumor cell senescence.
For example, for normal cells, c-Myc can inhibit cell senescence, and inactivation promotes cancer cell senescence
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The expression of RAS, MYC, and RAF proteins can inhibit cell growth, proliferation, and promote cell senescence
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Inactivated RAS, MYC, and RAF genes cannot organize the immortal proliferation of tumor cells
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 2.
Evading Growth Suppressors (Evading Growth Suppressors) deletion of tumor suppressor gene Rb is a tumor suppressor gene
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Rb gene (Rb gene) is mutated in many different cancers.
The protein product of this gene is a transcription factor that can control the expression of important genes that drive cells into the division process
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In addition, more than 50% of all malignant tumors will have mutations in the p53 gene.
The protein encoded by this gene is also a transcription factor that controls the initiation of the cell cycle
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The mechanism by which RB protein inhibits cell proliferation is due to its ability to bind to the transcription factor E2F, which can activate gene transcription of enzymes involved in DNA replication
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When p105RB binds to E2F, E2F loses its activity
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The mutated RB loses its normal function, and cancer cells can continue to proliferate
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 The most important way for the loss of the normal function of P53 (blocking the cell cycle, maintaining genome stability, and inhibiting tumor angiogenesis) is gene mutation.
Through the analysis of a large number of mutants in tumors, it is confirmed that most of the mutations are located in one of the four mutation hotspots.
Missense mutation
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The four mutation hot spots are aa129-146, 171-179, 234-260, and 270-287
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Cells with inactive p53 gene also lose their self-monitoring and self-repair functions, and gradually turn into cancer cells [3]
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 Reduced tumor contact inhibition (NF2, LKB1) The mechanism by which tumor cells avoid contact inhibition may be related to the NF2 gene.
NF2 encodes the cell membrane and cytoskeleton protein merlin protein, which is coupled with E-Cad and EGFR, so that the EGFR signaling pathway cannot be continuously activated.
Expressed as contact inhibition
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However, in tumor cells, NF2 is mutated and the merlin protein function is lost, which weakens the effect of contact inhibition [4], and can still proliferate under the stimulation of growth signals
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 LKB1 (Liver kinase B1) gene, or STK 11, is located on chromosome 19
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LKB1 is widely expressed in a variety of human tissues, with the most common in young liver, testis, small intestine and skeletal muscle
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Somatic mutations of LKB1 gene are widely present in a variety of malignant tumors.
Therefore, LKB1 is generally considered to be a tumor suppressor gene
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The encoded product of LKB1 gene LKB1 protein is a serine/threonine kinase
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The direct substrates of LKB1 include AMPK (AMP-activated protein kinase) and twelve AMPK kinases
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LKB1 enhances the phosphorylation level of AMPK, which activates AMPK
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LKB1 can inhibit the activity of the positive regulator of eukaryotic cell growth mTORC1 (mammalian target of rapamycin complex 1) by activating AMPK, and mTORC1 can promote cell growth and cell cycle progress
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In many tumor cells, the activity of mTORC1 is abnormally activated
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In addition, the LKB1 gene can antagonize the mitogenic effect of MYC and maintain the integrity of the epidermis
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Mutations in the LKB1 gene in tumor cells also make it lose the mitogenic effect of antagonizing MYC, and the effect of inhibiting cell proliferation is weakened [5]
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 Escape from inhibiting the TGFβ pathway.
The transforming growth factor-β (TGF-β) signaling pathway is involved in many cellular processes in both mature organisms and developing embryos.
These processes include cell growth, cell differentiation, cell apoptosis, and cell homeostasis.
And other cell functions
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Although TGF-β regulates many cellular processes, these processes are relatively simple
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At the beginning of signal transduction, the TGFB superfamily ligand binds to the TGF-β type II receptor
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Type II receptor is a serine/threonine kinase receptor that catalyzes the phosphorylation of type I receptors.
Each ligand binds to a specific type II receptor
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Type I receptors rephosphorylate receptor-regulated SMAD proteins (R-SMAD), which then bind to coSMAD
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The R-SMAD/coSMAD complex, as a transcription factor, accumulates in the nucleus and participates in the regulation of target gene expression
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Studies have found that the main functions of TGFβ in normal cells include inhibition of proliferation, induction of apoptosis, activation of autophagy, and inhibition of angiogenesis, thereby maintaining the homeostasis of normal cells
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In tumor cells, the mutation of TGFβ participates in the immune escape of tumor cells, promotes tumor cell growth, and participates in epithelial-mesenchymal transition (EMT)
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TGFβ is a double-edged sword.
It can inhibit the tumor in the early stage and promote it in the late stage [6]
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  3.
The last edition of Resisting Cell Death only lists the mechanisms by which tumor cells inhibit apoptosis.
The 2010 edition adds autophagy and necrosis pro-inflammatory
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Apoptosis refers to the orderly and autonomous death of cells controlled by genes in order to maintain the stability of the internal environment
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Apoptosis is a process strictly controlled by multiple genes
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For example, Bcl-2 family, caspase family, oncogenes such as C-myc, tumor suppressor gene P53, etc.
, the process of cell apoptosis can be roughly divided into the following stages, receiving apoptotic signals → interactions between apoptosis regulatory molecules → Activation of proteolytic enzyme (Caspase) → enter the continuous reaction process
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Common apoptotic receptor ligand combinations mainly include IGF1-IGF1R and IL3-IL3R that transmit survival signals, and FAS-FASR and TNFα-TNFαR that transmit death signals
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The apoptotic effect is the caspase-8/9 system
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 The membrane receptor pathway of cell apoptosis refers to the opening or closing of a series of control switches in the cell after the cell feels the corresponding signal stimulation
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Different external factors initiate apoptosis in different ways, and the signal transduction caused by them is also different.
The current understanding of the signal transmission system in the process of apoptosis is still lacking.
The clearer pathways mainly include membrane receptor pathways and cells.
Pigment C pathway
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For the membrane receptor pathway, external factors are the initiators, which transmit apoptosis signals and cause cell apoptosis.
Take Fas-FasL as an example.
Fas is a transmembrane protein that belongs to the tumor necrosis factor receptor superfamily.
It is closely related to FasL.
The combination can initiate the transduction of apoptotic signals and cause cell apoptosis
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The apoptosis pathway induced by TNF is similar to this
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The biochemical pathway of cytochrome C release and Caspases activation Mitochondria is the regulatory center of apoptosis.
The biochemical pathway of cytochrome C release and Caspases activation of mitochondria means that the release of cytochrome C from mitochondria is a key step in cell apoptosis
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Cytochrome C released into the cytoplasm can bind to apoptosis-related factor 1 (Apaf-1) in the presence of dATP to form multimers, and promote caspase-9 to combine with it to form apoptotic bodies, caspase- 9 is activated, the activated caspase-9 cascade activates other caspases, thereby inducing cell apoptosis
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Although the detailed mechanism of the apoptosis process is not fully understood, it has been determined that Caspase is essential in the process of apoptosis.
The process of apoptosis is actually a cascade amplification reaction process of the irreversible limited hydrolyzed substrate of Caspase, which participates in the cell.
Apoptotic ones include caspase2,3,6,7,8,9.
10
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The p53 gene can promote the expression of the apoptotic protein Bax and promote the process of cell apoptosis.
When the p53 gene is mutated, the mechanism of inhibiting apoptosis is also impaired, resulting in tumor cells with the potential to resist apoptosis
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 Autophagy in the 1960s, when researchers first observed that the intracellular components of cells were wrapped in a membrane to form a cyst-like structure and transported to a small compartment (named "lysosome") responsible for recycling.
Inside, thereby degrading these components
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In this way, the metabolic needs of the cell itself and the renewal of certain organelles are realized
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Until the early 1990s, Osumi Yoshinori did a series of subtle experiments
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In the experiment, he used baker's yeast to identify the first genes essential for autophagy
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He studied the functions of the proteins encoded by these genes
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The results show that the process of autophagy is controlled by a large number of proteins and protein complexes
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Each protein is responsible for regulating the different stages of autophagosome initiation and formation
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There are three main forms of autophagy: microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA)
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 Under normal circumstances, autophagy can promote cell survival by accelerating the metabolic cycle of cells and assisting cells in adapting to the environment.
Some organelles and cytoplasmic autophagosomes can also cause cell death, that is, type II cell death
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The pivotal role is mTOR (mammalian target of rapamycin), which integrates signals from different cell homeostasis sensors
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Rapamycin, extracellular amino acids, growth factors, starvation, intracellular calcium ions (this is related to endoplasmic reticulum stress), etc.
, all affect autophagy through mTOR
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There is a common pathway between autophagy and apoptosis, namely PI3K/AKT/mTOR
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When normal cells receive growth signals, they activate the PI3K/AKT pathway, inhibit autophagy and apoptosis, and positively promote the cell cycle
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In starvation, the PI3K pathway is blocked, which induces apoptosis and autophagy
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 Another star molecule related to autophagy is Beclin1.
Beclin1 and BH3 continue to bind to inhibit the occurrence of autophagy.
In the case of nutrient deficiency, Beclin1 and BH3 depolymerize, thereby triggering apoptosis
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 In addition to resisting apoptosis and autophagy, necrotic pro-inflammatory tumor cells are another mechanism to resist death [7]
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Unlike autophagy, after tumor cell necrosis, cytokines are released into the tumor microenvironment, and cytokines recruit immune cells to clear the necrotic tissue, but immunosuppressive cells can also promote tumor cell metastasis and enhance invasion ability
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In other words, tumor cells may promote inflammation through necrosis, using immunosuppressive cells to set up a barrier for themselves
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  4.
Enabling Replicative Immortality (Enabling Replicative Immortality) Telomere maintenance mechanism Cancer cells must proliferate to a degree visible to the naked eye, and the ability to proliferate indefinitely is essential
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Normal cells follow the Hayflick boundary and have a certain life span
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Tumor cells change the normal functions of telomeres and telomerase to achieve the goal of infinite division
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Compared with the review in the previous edition, two new mechanisms have been added to the 2010 edition, namely delayed activation of telomerase and new functions of telomerase
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The delayed activation mechanism of telomerase refers to the fact that cancer cells do not have the ability to express telomerase in the early stage of the tumor, and telomerase loss is in crisis, and short-term telomerase loss will accelerate the process of cell carcinogenesis.
[8]
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 After cancerous cells, telomerase is activated again to repair telomeres, allowing cancer cells to gain unlimited proliferation
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  Telomerase has some new functions.
In the past, the function of telomerase was to lengthen and maintain telomeres and protect the integrity of genetic information
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In recent years, studies have found that the expression of telomerase can be upregulated by the WNT pathway.
First, wnt protein binds to cell surface receptors and inhibits the downstream Axin/GSK/APC complex, making βcatenin increase intracellularly
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After entering the cell nucleus, Bcatenin can bind to transcription factors, promote the expression of telomerase, and then promote cell proliferation
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 5.
Inducing Angiogenesis (Inducing Angiogenesis) The Double Eleven event is going on hotly.
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Welcome to scan the code for consultation.
The malignant proliferation, invasion and metastasis of tumors are very dependent on angiogenesis to obtain more nutrient supply
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The old edition mainly discussed the role of anti-angiogenesis factors, pro-angiogenesis factors and angiogenesis switches in tumor neovascularization
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There is a regulatory imbalance between the process of anti-angiogenesis and pro-angiogenesis.
The pro-angiogenic factors represented by VEGF and FGF increase, and the anti-vascular factors represented by TSP-1 decrease
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The new review mainly discusses the effects of endogenous inhibitors, pericytes and bone marrow-derived cells on angiogenesis
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It has been found that there are about a dozen endogenous inhibitors and resistance to angiogenesis factors.
The more in-depth study is TSP-1, a membrane protein isolated from the platelet cell membrane after thrombin stimulation.
It can interact with a variety of cell membranes represented by CD36.
Surface receptor binding leads to the activation of intracellular non-tyrosine receptor-dependent phosphatase, which then performs the function of angiogenesis
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If TSP-1 is overexpressed in transgenic mice, tumor growth will be inhibited
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This suggests that TSP-1 may be the body's endogenous barrier against tumor angiogenesis [9]
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 Model: HRGP inhibits the antiangiogenic effect of TSP-1.
Pericytes promote angiogenesis.
Pericytes, also known as Rouget cells and parietal cells, are cells that surround the endothelial cells in capillaries and veins throughout the body and can shrink
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Pericytes are embedded in the basement membrane of capillary endothelial cells and communicate with endothelial cells through physical contact and paracrine signals to monitor and stabilize the maturation process of endothelial cells
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Certain pericytes can regulate the proliferation and differentiation of endothelial cells, thereby regulating angiogenesis
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For example, microvascular pericytes.
These pericytes may not contract due to lack of actin.
These cells communicate with endothelial cells through gap junctions to regulate endothelial cell proliferation or selectively inhibit.
Without this regulation, blood vessel proliferation And vascular malformations will occur
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Tumor angiogenesis is also closely related to pericytes [10]
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VEGF and other pro-angiogenesis factors break the homeostasis of mature blood vessels and dissociate pericytes attached to capillary endothelial cells.
Tumor blood vessels regenerate in a budding manner.
Under the action of cytokines, pericytes are recruited to form new blood vessels
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  Bone marrow-derived cells mainly include macrophages, neutrophils, hypertrophy, bone marrow progenitor cells, etc.
Under the action of cytokines, they can infiltrate around tumor tissues, trigger the switch of tumor angiogenesis, and maintain continuous angiogenesis related to tumor tissues[ 11]
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 Macrophages Promote Tumor Initiation, Progression, and Malignancy In short, tumor angiogenesis involves an imbalance in the regulation of pro-/anti-neoplastic mechanisms.
Endogenous inhibitors can resist angiogenesis, and pericytes and bone marrow-derived cells can promote angiogenesis.
The role of
.

 6.
Activating invasion & metastasis The new version adds new features of invasion and metastasis.
Epithelial cell-mesenchymal transition (EMT) refers to the biological process of epithelial cells transforming into cells with mesenchymal phenotype through specific procedures
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Its main characteristics are the reduction of cell adhesion molecules (such as E-cadherin) expression, the conversion of cytokeratin cytoskeleton into vimentin-based cytoskeleton, and the morphological characteristics of mesenchymal cells
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Through EMT, epithelial cells lose cell polarity, lose their connection with basement membrane and other epithelial phenotypes, and acquire mesenchymal phenotypes such as high migration and invasion, anti-apoptosis, and ability to degrade extracellular matrix
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 EMT is an important biological process for malignant tumor cells derived from epithelial cells to acquire the ability of migration and invasion
.

Tumor cells undergo EMT to lose cell polarity, and the expression markers expressed are also changed accordingly.
Typical expressions of E-cad decrease, and N-cad and twist increase [12]
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To clarify the molecular mechanism that regulates the EMT process of malignant tumor cells, to clarify its pathological significance in the occurrence, development, and metastasis of malignant tumors, and to explore diagnostic methods based on key EMT molecules and therapeutic methods that target key EMT molecules are in tumor metastasis Key scientific issues in the study of EMT mechanism
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 EMT and MET in health and disease.
Stromal cells are also involved in tumor metastasis.
Mesenchymal stem cells (MSC) are a type of pluripotent stem cells belonging to the mesoderm.
They are mainly found in connective tissue and interstitium of organs, with bone marrow tissues most abundant in Abundant, because bone marrow is its main source, it is collectively referred to as bone marrow mesenchymal stem cells
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Bone marrow mesenchymal stem cells have strong proliferation ability and multi-directional differentiation potential, and can differentiate into muscle cells, hepatocytes, osteoblasts, adipocytes, chondrocytes, stromal cells and other cells in a suitable in vivo or in vitro environment.
Ability
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It has the function of immune regulation.
It inhibits the proliferation of T cells and their immune response through the interaction between cells and the production of cytokines, thereby exerting the function of immune reconstruction
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Under the stimulation of tumor cells, mesenchymal stem cells MSC secrete the cytokine CCL5, which acts on cancer cells to promote metastasis [13]
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In addition, tumor-associated macrophages TAM can secrete matrix degrading enzymes to promote local infiltration of cancer cells
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TAM can also secrete epidermal growth factor EGF to stimulate the growth and proliferation of cancer cells, while cancer cells produce CSF-1 to activate macrophages
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In short, the interaction between tumor and tumor tissue stromal cells can promote tumor invasion and metastasis
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  Invasive growth plasticity, mesenchymal phenotype epithelial-like transformation, MET is the reversal of EMT, restores epithelial phenotype, regains adhesion ability, facilitates tumor homing and forms new metastases
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When tumor cells undergo EMT, cell adhesion decreases, and their mobility and invasion capabilities are enhanced, which facilitates tumor cells to break away from the primary lesion and enter the surrounding blood vessels or lymphatic system, which becomes a prerequisite for distant tumor metastasis
.

The reverse process of the above process is called MET.
Under the influence of the microenvironment, the tumor cells that have undergone EMT transformation reverse the epithelial phenotype and regain the adhesion ability, which is conducive to the "homing" and proliferation of tumor cells, and the formation of metastases [14 ], and tumor metastasis can be roughly divided into 9 steps: 1.
The primary tumor invades normal tissues; 2.
Cancer cells gain the ability to metastasize through EMT; 3.
EMT cells may have small residual lesions; 4.
Residual lesions may be Local recurrence; 5.
EMT cells exudate from the basement membrane and enter blood vessels or lymphatics; 6.
Form circulating tumor cells; 7.
Invasive tumor cells proliferate and grow on the inner wall of blood vessels to form intravascular tumors.
Tumor cells can also Through extravasation, it crosses endothelial blood vessels and enters connective tissue; 8) aggressive tumor cells form new micrometastasis in the extracellular matrix; 9) aggressive tumor cells disperse to the distal end to generate MET, forming new metastases
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 Putative EMT and MET transitions in carcinoma progression.
Invasion affects many types of cancer.
Common types of invasion include EMT, collective invasion, and amoeboid invasion
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Collective is highly metastatic and amoeboid invasion is highly deformable, which is conducive to cancer cells sliding in the matrix [15]
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Amoeboid Cell Movement through Interstitial Tissue The above are the six features summarized in the new version, including activation of proliferation, evasion of inhibition, resistance to death, infinite proliferation, and invasion and metastasis, which are also the six features proposed in the old version.
On this basis, the new version has updated some of the content
.

The author compares the signal pathways in tumor cells to circuit boards.
The pathways that mainly involve tumor characteristics include Wnt, NF-κB, PI3K, MAPK, etc.
, 2010 edition.
The author classifies these pathways according to the acquired characteristics of the tumor
.

The following figure shows the pathways related to cell movement in gray, green represents proliferation, blue represents cell viability, and red represents cell differentiation
.

These signal paths are connected to each other and form a network
.

 Intracellular Signaling Networks Regulate the Operations of the Cancer Cell 7.
Genome Instability and Mutation.
Genome Instability and Mutation is also known as mutation.
It is the seventh acquired feature, also known as the cause-causing feature
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The acquired characteristics of tumor cell invasion and metastasis are based on the development of pro-cause characteristics
.

Normally, normal cells have a low mutation load, and the body can maintain the stability of the genome through mechanisms such as immune surveillance and repair
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A large number of genetic mutations have caused cancer cells to acquire the characteristics of invasion
.

The mechanism of clearing DNA damage and repairing the genome is called the genome guardian, and the p53 gene is one of them [16]
.

p53 regulates cell proliferation and apoptosis by regulating the cell cycle.
High expression of p53 can block cell proliferation.
When cell damage cannot be repaired, p53 can trigger cell apoptosis
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Cancer cells have mutations in the p53 gene and lose their monitoring and repair functions
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 A model for the function of p53 Telomeres play an important role in maintaining genome stability.
On the one hand, telomeres and telomerase give cancer cells the ability to proliferate indefinitely.
On the other hand, if telomere DNA is lost, chromosomal instability will occur.
Sex, the phenomenon of chromosome loss occurs.
During the cell cycle, a part of telomere DNA is lost every time a cell divides.
Once telomeres are exhausted, the stability of chromosomes cannot be guaranteed
.

At this time, the P53 gene is activated, which promotes cell senescence and self-metabolism
.

If p53 is mutated and its function is lost, the chromosome will continue to replicate and break, which will eventually lead to the malignant proliferation of malignant cells [17]
.

 Telomere shortening activates p53 and drives formation of epithelial cancers through gene amplification and deletion 8.
Tumor-Promoting Inflammation Like mutations, tumor-promoting inflammation is also a tumor-promoting feature, so it also has the characteristics of promoting invasion and metastasis, angiogenesis, etc.
Appear
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Inflammation can remove necrotic tissue and tumors, but molecules released during inflammation can promote tumor progression.
For example, immune cells can release growth factors, extracellular degrading enzymes and other cytokines, activate related cancer-related pathways, and promote angiogenesis and angiogenesis.
Invasion and transfer
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In addition, inflammation can release EMT signals and produce chemical substances represented by reactive oxygen species, which further promote the invasion and metastasis of tumor cells
.

Inflammation in the early stage of tumor is more obvious, which promotes the evolution of cancer
.

 Role of Inflammation in Tumor Initiation and Promotion 9.
Deregulating Cellular Energetics has two pathways for glucose metabolism, mitochondrial oxidative phosphorylation and glycolysis
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In normal mammalian cells, glycolysis is inhibited (Pasteur Effect) under aerobic conditions
.

However, in 1920, German biochemist Warburg found that the glycolytic activity of liver cancer cells was more active than normal liver cells.

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It is proposed that under sufficient oxygen, the glycolysis of malignant tumor cells is also active.
The metabolic characteristic of this aerobic glycolysis is called the Warburg effect, which is characterized by high glucose uptake rate, active glycolysis, and high metabolite lactic acid content.

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In the process of tumor cell proliferation, it consumes sugar but does not efficiently produce energy.
The Warburg effect explains this phenomenon well
.

Under aerobic conditions, cancer cells change from oxidative phosphorylation to oxygen glycolysis [18]
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The more glucose uptake, the more lactic acid is produced
.

 Metabolic stress during tumor development Glucose transporter (GLUT) is a family of transmembrane proteins that regulates the entry of extracellular glucose into the cell, and is involved in processes such as glucose metabolism, inflammatory response and immune response
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Glucose transport in cells of the body is regulated by GLUT1 [19].
Up-regulation of GLUT1 by cancer cells can promote a large amount of glucose into cancer cells, significantly increase the uptake and utilization of glucose, and provide raw materials for glycolysis
.

In addition, mutations of the proto-oncogenes RAS, MYC, and P53 will affect the expression of key molecules in the process of glucose metabolism and affect the abnormal metabolism of cancer cells
.

For example, after Ras mutation, it can activate the PI3K-AKT pathway, thereby regulating the expression of GLUT1
.

Tumor cells also activate glycolytic pathways under hypoxic conditions
.

Different cell subgroups have different levels of energy metabolism and have their own characteristics
.

According to the Warburg effect, some cell subpopulations rely on glycolysis production capacity, while the other part can utilize the tricarboxylic acid cycle production capacity
.

 Molecular Mechanisms of Cancer-Specific Metabolic Reprogramming 10.
Avoiding Immune Destruction The last acquired feature of tumor cells, immune escape
.

In 2002, after a systematic review and summary, Schreiber et al.
proposed the tumor immunoediting theory for the first time and divided it into three stages: immune clearance, immune balance, and immune escape
.

The theory believes that the body’s immune system can recognize, monitor, and ultimately "clear" most of the malignant cells; however, there may be a small number of malignant cells that escape the clearance and enter the "equilibrium" phase, during which the immune system and the malignant cells shape each other but The body does not show clinical symptoms, and the equilibrium period can even cover the entire life process of the body in extreme cases; but once the active action of malignant tumor cells breaks this equilibrium state, the tumor cells will successfully "escape" and lead to the loss of the immune system to the tumor.
Control of cell growth
.

 Immunoediting and immunosuppression play an important role in the process of tumor immune escape
.

Studies have found that tumors in immunodeficient mice have a higher probability of immune escape and a faster production rate
.

CD8+ T cells and CD4+ helper T cells, mice with defective NK cell function have stronger tumorigenicity
.

For mice with combined NK and T cell defects, it is more likely to cause tumors
.

Experiments on transplanted tumors have shown that it is usually difficult to cause secondary tumors for cancer cells from immunodeficient mice of the same host.
However, cancer cells from mice with normal immune systems can show the same tumor formation as the original host.
Activity, this is mainly due to the emergence of immune editing
.

The body controls tumor growth and remodels immunogenicity through immunoediting.
This process mainly includes three stages: clearance, balance, and escape
.

It has also become the 3E doctrine [20]
.

In the immune escape stage, the proliferation of weakly immunogenic cancer cells increases, resulting in solid tumors visible to the naked eye
.

 Tumor cells may also suppress the host's immune system
.

For example, cancer cells can release immunosuppressive factors represented by TGF-β, thereby inhibiting the functions of CTLs and NK cells
.

In addition, there are immunosuppressive cells in the tumor microenvironment, such as regulatory T cells and MDSCs, which can inhibit the action of T cells and promote immune escape
.

MDSC suppress antitumor immunity through a variety of diverse mechanisms has found that the growth signal of tumor cells is partly derived from matrix components
.

Stromal cells release growth-promoting factors, which is the view that heterogeneous cell communication promotes tumor cell proliferation
.

In the 2010 version of the review, the author summarized this phenomenon as the tumor microenvironment, including cancer stem cells CSC, endothelial cells EC, pericytes PC, inflammatory cells IC, and tumor-associated fibroblasts CAF
.

The traditional view is that tumor cells are produced by somatic mutations, but they cannot explain the acquired characteristics of tumor cells' unlimited replication.
The growth and proliferation of tumor cells are very similar to the characteristics of stem cells
.

The proposal of cancer stem cells has opened up a new field for the clinical treatment of cancer
.

  The Cells of the Tumor Microenvironment summarizes that in recent years, the targeted therapy of tumors has progressed rapidly, and most of the targeted drugs used in clinics correspond to the ten characteristics of tumors, such as VEGF inhibitory anti-vascular agents
.

So far, the interpretation of the two editions of hallarkers of cancer has been completed.
The 2021 edition of the review does not focus on the new features of tumors, but on the progress of EMT
.

I believe that reading the two editions of the review will give you an overview of the research hotspots in the field of oncology in the past ten years.
The star molecules under the various characteristics proposed in the two editions of the review are also active in the National Nature Project
.

In order to give everyone a summary understanding of basic tumor articles, follow-up interpretations mainly involve celebrity pathways and celebrity molecules
.

With these contents as the background, isn't it more professional to talk to you about scientific research? Therapeutic Targeting of the Hallmarks of Cancer Reference 1.
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