The latest advances in cell signaling and communication in cancer

In healthy cells, the dynamic processes of countless cells maintain good regulatory activities, including gene expression, energy and metabolic homeostasis, and cell division
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These processes are coordinated through cell signals, and through cell communication channels, signals are sent within and between cells
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The interruption of these sophisticated cell signaling pathways will lead to pathological conditions
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In cancer, mutations or epigenetic changes in genes that regulate signaling pathways can promote tumor transformation to malignancy
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Tumor cells can bypass the normal checks and balances of cells by triggering various pathological response mechanisms, leading to uncontrolled proliferation of tumor cells, avoiding apoptosis, abnormal differentiation, epithelial-mesenchymal transition (EMT), and inducing angiogenesis and inflammation Status and occurrence of tumor metastasis
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Therefore, tumors will be affected by the damage of genes or epigenetic elements involved in cell signal communication.
The specific epigenesis is that genetic elements regulate proliferation (such as growth factors, metabolism), apoptosis (such as cell cycle checkpoints, DNA repair checkpoints) ), differentiation, cell polarity, and extracellular matrix (ECM) modeling, angiogenesis, inflammation and inter-cell communication and the like
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This has also led researchers to pay attention to cancer genes related to these biological process signaling pathways; however, new candidate genes or mechanisms continue to be discovered and determined
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This article will briefly review the changes in some of the more mature cell signaling pathways in cancer, and focus on new directions that can be explored
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Proliferation/metabolism Under steady-state conditions, proliferation is regulated by nutrient utilization and growth factors; however, cancer cells can hijack these signaling pathways to maintain their uncontrolled and continuous proliferation, increasing the size of tumors in patients
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The oncogenic mutations that regulate cancer metabolism include phosphoinositide 3-kinase (PI3K/AKT/mTOR), MYC, RAS, HIF-1 and Hippo pathways.
These mutations enhance the substrate transporters involved in glucose, glutamine and fat.
Gene expression of metabolic enzymes enhances acid metabolism, increases energy and blocks the supply and proliferation of cancer cells
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Another aspect of metabolism refers to that signal transduction in cancer works through tumor metabolites, such as 2-hydroxyglutaric acid (2-HG)
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Isocitrate dehydrogenase is an enzyme of the tricarboxylic acid cycle.
This enzyme can give new forms of enzyme activity and change the substrate from natural alpha-chloroglutarate to 2-HG
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Subsequently, 2-HG changed the active enzymes of epigenetics, reshaped the epigenome and led to malignant transformation of tumor cells
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Recently, researchers have discovered metabolic intermediates that affect other signaling pathways, such as the effect of fumaric acid on EMT and the effect of hydroxybutyric acid on the Wnt signaling pathway, which can regulate cell differentiation, proliferation, and migration
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These examples all illustrate the connectivity in cancer signaling pathways, including the usual metabolic pathways in academia, while supporting proliferation, while also affecting EMT and tumor metastasis
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Cell cycle/DNA repair/apoptosis In addition, cancer cells can also evade apoptosis and continue to proliferate, usually through mutations or epigenetic changes to regulate cell cycle arrest and DNA signaling pathways
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For example, cancer cells will not respond to signals from cellular stress.
For example, if cancer cells do not perform DNA damage signal expression, they will not perform the task of apoptosis transmitted by the signal
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For a long time, a large number of cancer signal targets that have been tested and verified include tumor suppressor p53, BRCA1/2 and TGF-beta.
Recently newly developed candidate genes also include DNA modification proteins ATRX, ATM, RAD5, and cyclin-dependent kinases.
(CDKs), which can control the transition of the cell cycle
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Differentiation/tumor extracellular matrix remodeling/metastasis Cancer cells usually have the potential to spread far away from the primary tumor.
This process is also called tumor metastasis.
Tumor metastasis is usually clinically directly related to poor patient prognosis
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Mutations or epigenetic changes that regulate cell signaling pathways, polarity (that is, the directionality of asymmetrically shaped cells) and adhesion between cells, will promote tumor cell extracellular matrix (ECM) remodeling and metastasis
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Therefore, gene damage involved in development and differentiation in the human body (such as Hedgehog, Notch and Wnt) may cause various cancers
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Researchers have also newly discovered other related genes, especially those related to ECM remodeling, including integrin signaling, YAP/TAZ signaling and type II transmembrane serine protease
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Angiogenesis Abnormal angiogenesis is also a sign of tumors, which can use tumors to support growth and metastasis
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Some signaling pathways are involved in stimulating the growth of new blood vessels, many of which belong to receptor tyrosine kinases (RTKs), which play a role in cell proliferation and differentiation
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Certain receptor tyrosine kinases will affect angiogenesis signal pathways to a large extent and are highly related to cancer.
The most significant ones are VEGFR, FGF2, DGFR and some chemokines
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After chemokines bind to receptors, they play a role in the inflammatory response through chemotaxis of inflammatory cells and immune activation
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Inflammation Inflammation and changes in tumor-infiltrating immune cells are one of the typical characteristics of cancer
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Immune cells send signals through chemokines and cytokines
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In cancer patients, changes in immune signals can lead to chronic inflammation, tumor growth, and new blood vessels
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In recent years, new inflammatory signaling pathways are considered to be related to the occurrence of cancer, including the stimulator of the cyclic GMP-AMP synthetase (cGAS) interferon gene in the innate immune pathway
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cGAS can sense double-stranded DNA from virus-infected or senescent/apoptotic cells and initiate IFN-gamma response
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cGAS-STING signal has anti-tumor and tumorigenic properties; in the early stage, tumor DNA can activate antigen-presenting cells, such as dendritic cells, to stimulate cGAS-STING signal and immune cell-mediated cancer clearance
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However, in the later stage, chronic cGAS spin activation inhibits the production of IFN-gamma and induces an immunosuppressive environment
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Another emerging direction of cancer signal transduction is pyrolysis, which is the death of inflammatory cells induced by the activation of inflammasomes, leading to tumor proliferation, invasion and metastasis
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Similarly, the interaction of these inflammatory signaling pathways with other cellular processes (such as proliferation) highlights the overall connectivity of cell signaling pathways in cancer
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Cell-to-cell communication The tumor cells communicate with the target organ to which they are transferred over a long distance
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Exosomes and extracellular vesicles (ev), as media of recent hot attention, can cause cell proliferation, metastasis and EMT
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Exosomes and extracellular vesicles can sprouting from the endosome and release outside the cell, and carry RNA, protein, and metabolites
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In cancer, due to their influence on tumor characteristics, exosomes and extracellular vesicles can be used as biomarkers for diagnosis and prognosis
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Cell signaling network As mentioned above, because multiple genes and their downstream targets have multiple effects on tumor characteristics, mutations or changes in the epigenome can disrupt cell signaling in multiple channels, including the crossover of cell signaling in metabolism.
And epigenetics or inflammation occurs
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With the advent of tumor metastasis, large-scale, big-data methods are expected to solve this problem, including transcriptomics, epigenomics, and proteomics
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Highly related to signal transduction in cancer is phosphorylation proteomics, which can characterize the active kinase group, that is, the accumulation of signal kinases present in the system
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Kinetics analysis revealed many candidate genes whose molecular characteristics have not yet been determined, and they may also be related to cancer (such as pseudokinase)
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The research of the kinetics group may also be used to develop cancer treatments and extend to individuals
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Another key aspect of personalized medical cell signaling network is to build a framework to understand the mechanism of drug development to resist tumors
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This method does not focus on specific signal sensors, but attempts to reveal all potential drug candidates involved in the progression of resistance.
It is expected to develop methods to overcome this problem.

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In addition to the signal cytokines itself, there is also a non-coding RNA (ncRNA) transcriptome network, which regulates the transduction of signal cancers in other biological processes
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ncRNA is connected to known protein signaling molecules and pathways, such as tumor suppressor p53 and Hippo, as well as glutamine decomposition and cancer metabolism.
At the same time, ncRNA may also participate in the evolution of tumor resistance
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Reference article: TN_Listicle_Cancer Cell Signaling_2021_1_3_translate