What is the relationship between Tumor Cells | TAM | Exosomes?
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What is the relationship between Tumor Cells | TAM | Exosomes?
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What is the relationship between Tumor Cells | TAM | Exosomes?
Preface
Exosomes are nano-scale vesicles derived from intracellular lysosomes, which can shuttle and deliver a variety of biological molecules, such as nucleic acids, proteins, lipids, amino acids and metabolites, and play a key role in regulating cell-to-cell communication.
As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages ( TAM ) are affected by the tumor microenvironment and perform functions such as promoting tumor growth, immunosuppression, angiogenesis, and cancer cell proliferation.
Exosomes play an important role in mediating the intercellular information transmission between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor therapy.
External body
In 1981, exosomes were first described as nanovesicles secreted in vitro by different cell types, and their lipid composition was different from the plasma membrane, indicating that their source is different and more complex than simple membrane sprouting. E
xosomes can be secreted by almost all types of cells, including immune cells, blood cells, neuronal cells, epithelial cells, and cancer cells. They contain proteins retained from primitive cells through the process of biogenesis.
In addition, exosomes can also contain miRNA, mRNA, and even long non-coding RNA ( lncRNA ), which are significantly involved in the regulation of exosomes.
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The biologically active substances of exosomes can affect the metabolism of recipient cells in two main ways.
The first is the direct interaction between exosomal surface proteins and target cell receptors.
The second is the internalization of the contents, after fusion with the plasma membrane of the target cell, or through endocytosis or phagocytosis by macrophages. Exosomes have important clinical significance, especially in tumors.
The main function of exosomes is to transmit information between organism cells.
They more generally participate in the internal environment balance of cells and tissues by regulating the viability, state and function of cells, and they can significantly mediate tissue repair.
Exosomes also contribute to the occurrence and development of tumors, including the transformation of normal cells into malignant cells and angiogenesis.
Tumor-associated macrophages
TAM is functionally heterogeneous and is divided into two main subgroups, M1 and M2 macrophages. In response to lipopolysaccharide ( LPS ), IFN-γ and GM-CSF, M1 macrophages undergo classic activation and preferentially secrete antibacterial molecules and pro-inflammatory cytokines, including reactive oxygen species ( ROS ) and nitric oxide ( NO ) And IL-6.
M1 macrophages are the first line of defense against microbial infections. M1 macrophages also maintain a strong antigen presentation ability and induce a strong Th1 response.
On the contrary, M2 macrophages undergo selective activation by IL-4, IL-13, IL-10 and CSF-1, and preferentially secrete anti-inflammatory cytokines, including transforming growth factor β ( TGF-β ), IL- 10 and proteases ( such as arginase-1 and MPPs ).
M2 macrophages play a key role in limiting immune responses, inducing angiogenesis and tissue repair.
Therefore, the presence of M2-like TAM is related to tumor-promoting activity, and the presence of M1-like TAM is related to anti-tumor activity.
TAM creates a mutagenic microenvironment that is conducive to tumor initiation by secreting pro-inflammatory mediators, such as TNF-α and ROS.
In addition, TAM recruits Tregs by secreting the chemokine CCL22, and enhances the functions of Tregs by secreting TGF-β. Human TAM also secretes epidermal growth factor ( EGF ) to enhance the aggressiveness of tumor cells.
TAM up-regulates MMP, MMP degrades interstitial collagen, and up-regulates the synthesis and assembly of collagen to reshape TME, which is conducive to tumor cell invasion.
Regulation of TAM Polarization by Tumor-derived Exosomes
Many studies have proven that tumor-derived exosomes play a crucial role in the conversion of monocyte-derived macrophages into regulatory macrophages and in mediating cancer-related inflammation and tumor development.
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Exosomal protein
Studies have shown that some therapeutic fusion proteins can be absorbed by surrounding cells, thereby affecting tumor progression.
A new fusion protein Rab22a-NeoF1 and its binding partner PYK2 can be delivered by exosomes, promote cell migration and invasion by activating RhoA, promote M2 polarization to promote the formation of the niche before lung metastasis, and lead to osteosarcoma cells in the lungs Transfer.
These findings provide a new therapeutic strategy to block metastasis through iRGD peptides, thereby eliminating the association between Rab22a-NeoF1 and its binding protein.
Exosomes derived from tumor cells also contain immunomodulatory and angiogenic proteins, which can enhance immune suppression and angiogenesis.
For example, co-culture with apoptotic prostate cancer cells can increase the expression of milk fat globule EGF factor 8 ( MFG-E8 ) in macrophages , which are highly expressed in tissues and serum exosomes, and ultimately inhibit pro-inflammatory responses and stimulate macrophages Polarization is M2 phenotype.
In addition to polarization, tumor-derived exosomes can also mediate the differentiation of monocytes into M2 macrophages. For example, in the exosomes of glioblastoma multiforme ( GBM ), a variety of abundant proteins were detected in these exosomes, including chondroitin sulfate proteoglycan 4, α-2-macroglobulin, lactomucosal Protein, EGFR and integrins induce monocytes to differentiate into the immunosuppressive M2 phenotype.
Exosomes can not only induce the differentiation of macrophages in the direction of M1 or M2, respectively, but also induce a “mixed” phenotype, which may contribute to a variety of tumor-promoting functions.
Extracorporeal miRNA
In recent years, a large number of studies have shown that exogenous miRNAs play a key role in tumor progression, stimulating angiogenesis and promoting metastasis.
In addition, tumor-derived exosomal miRNAs polarize macrophages and target a variety of signaling pathways, thereby positively or negatively affecting tumor progression.
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For example, exosomes carrying miR-203 from CRC cells are incorporated into monocytes, and exosomes derived from CRC cells carrying miR-145 and miR-934 are taken up by macrophages, and both are polarized as M2 tables. Type; exosomes secreted by colon cancer cells or gliomas can transmit miR-1246 and induce an inhibitory immune microenvironment.
In addition, miRNAs in tumor cell-derived exosomes also play an important role in regulating the reprogramming and M1 polarization of macrophages.
For example, exosomes containing miR-130 or miR-33 increase the expression of TAM’s M1 characteristic genes ( IRF5, MCP1, CD80 ) and the secretion of cytokines ( IL-1β and TNF-α ) by transforming M2 into M1 phenotype, thereby inhibiting tumor progression.
Exosomal lncRNAs
New research shows that lncRNAs play a key regulatory role in tumorigenesis, macrophage activation and polarization through different signal pathways, and lncRNA-mediated crosstalk between TAM and cancer cells contributes to tumor development.
For example, lncRNA RPPH1 transfers from CRC cell-derived exosomes to macrophages, mediates the M2 polarization of macrophages, increases the expression of vimentin and Ki67, and reduces the expression of E-cadherin, thereby promoting the growth of cancer cells. Metastasis and proliferation.
Exosomal circRNA
Studies have shown that CircRNA plays a role in the differentiation and polarization of macrophages.
For example, circASAP1 is considered to be a competitive endogenous RNA for inhibitory miR-326 and miR-532-5p, which directly targets MAPK1/CSF-1 and activates miR-326/miR-532-5p-MAPK1/CSF The -1 pathway mediates the infiltration of TAMs.
The study of circRNA carried by tumor-derived exosomes is still in the early stage, and its role in the regulation of TME needs to be further studied.
The effect of TAM-derived exosomes on tumors
Exosomes released by TAM are important mediators of cell-to-cell communication. They also deliver proteins, ncRNAs, lipids and other substances through TME, giving cancer cells different phenotypes and playing a vital role in tumor occurrence and metastasis.
Exosomal protein
Studies have shown that TAMs-derived exosomes have a very critical effect on tumor cells. For example, integrin αMβ2 ( CD11b/CD18 ) exists in exosomes derived from M2 macrophages and has significant specificity and effectiveness.
The transfer of exosomes-mediated CD11b/CD18 protein from TAM to HCC cells can activate the MMP-9 signaling pathway and enhance the migration ability of cells to support tumor migration.
In addition, apolipoprotein E (ApoE) is mainly enriched in M2 polarized macrophages and M2-derived exosomes.
M2 macrophage-derived exosomes mediate M2 macrophages to gastric cancer ( GC ) cells The cell-to-cell transmission of M2 maintains the connection between M2 exosomes and ApoE, which leads to activation of the PI3K/Akt signaling pathway to reshape the cytoskeleton and promote GC cell migration.
Extracorporeal miRNA
TAMs infiltration is related to the metastasis and growth of osteosarcoma ( OS ).
Overexpression of miR-221-3p enhances the growth of OS cells in vitro and in vivo, while exosomes enriched in miR-221-3p in TAMs aggravate the malignant behavior of OS cells by activating the SOCS3/JAK2/STAT3 pathway, such as Proliferation, colony formation, migration and invasion.
It has been proved that TAMs are beneficial to tumor angiogenesis, and exosomes derived from M2 macrophages can promote the angiogenesis of mouse aortic endothelial cells ( MAEC ) in vitro and in vivo .
In addition, RNA sequencing and qPCR analysis proved that M2 macrophage-derived exosomes contain miR-155-5p and miR-221-5p, which can be transferred to MAEC. These findings confirm the interaction between TAM and tumor angiogenesis through exosomes.
Exosomal lncRNAs
Similar to miRNAs, multiple lncRNAs also directly or indirectly participate in the crosstalk between the microenvironment and tumor cells.
For example, lncRNA AFAP1-AS1 can be transferred to KYSE410 cells through M2 macrophage-derived exosomes, and then down-regulate the level of miR-26a and up-regulate the expression of ATF2, thereby promoting the invasion of esophageal cancer and lung metastasis in vitro.
In addition, TAM delivers myeloid-specific lncRNA, HIF-1α stable long non-coding RNA ( HISLA ) through exosomes to promote aerobic glycolysis and drug resistance of BC cells.
Exosomal lipids
Studies have found that COX1 and TXA synthetase 1 ( TBXAS1 ) are significantly enriched in TAM exosomes, and are almost undetectable in MC38 exosomes; MC38 cells transfected with TAM exosomes are induced to produce TXB2, indicating that TAM is derived The exosomes deliver the enzymes required for TXs synthesis.
These results confirm that exosomes-mediated transfer of functional lipids from macrophages to tumor cells ultimately helps cancer cells survive.
Tumor immunotherapy based on exosomes
Therapies based on exosomes are emerging, which are cutting-edge strategies to inhibit tumor progression or enhance anti-tumor immunity.
Studies have shown that exosomes can easily cross biological barriers, such as the blood-brain barrier, and can be modified to increase efficiency.
Due to its transfer ability, lipid bilayer structure and unique surface protein, exosomes can be used as nanoparticle carriers for drugs, nucleic acids and proteins for recipient cancer cells.
In view of the fact that macrophages play a vital role in exosome-mediated crosstalk, regulating macrophages is an effective strategy for tumor treatment.
Exosomes can be used as carriers for drugs and siRNA to reverse the immunosuppression caused by M2 TAM.
In addition, reprogramming the TAM to the M1 phenotype is another strategy.
The simulated nanovesicle treatment with exosomes derived from M1 macrophages can stimulate the polarization of M2 macrophages to the M1 phenotype in vitro and in vivo, and intravenous injection of animal models inhibits tumor growth in vivo; after combined use with PD-L1, The anti-tumor effect is further enhanced.
Photoacoustic imaging technology can be used to observe tumor-derived modified exosomes loaded with chlorine e6 photosensitizer ( Ce6-R-Exo ), and can effectively produce reactive oxygen species in tumor cells under laser irradiation.
They can also increase the release of cytokines, indicating that R-Exos can be used as a drug carrier and immunotherapeutic drugs.
Exosomes contain tumor antigens and can be used as vaccines for cancer immunotherapy. DC-derived exosomes can be loaded with a variety of peptide antigens ( such as MHC I, MHC II ) to stimulate CD4 + helper T cells and CD8 + CTL to induce anti-tumor responses.
For example, subcutaneous injection of TAE-DC vaccine can significantly restore the activated T cells in TME and improve the therapeutic effect.
Current treatment strategies mainly focus on inhibiting the production of exosomes derived from cancer cells and preventing target cells from ingesting specific exosomes.
GW4869 is an inhibitor of exosomal secretion and neutral sphingomyelinase, which can inhibit the production of exosomes and achieve anti-tumor effects.
Exosomes loaded with chemotherapeutic drugs ( such as doxorubicin and paclitaxel ) can be used as a new type of nano-preparation, showing highly effective anti-cancer ability in mice with cancer metastasis.
Summary
Exosomes and its contents in mediating swollen plays a vital role in the reprogramming and crosstalk between the host immune response in the tumor and TAM.
TAMs are related to immune escape, can inhibit anti-tumor immunity and promote tumor progression.
Therefore, targeting exosomes and inhibiting their harmful effects on TAM has opened up a new perspective for the development of active anti-tumor drugs.
Reprogramming TAM to M1 phenotype by modifying exosomes can be used as an effective way to inhibit tumor growth. The strategy of hope.
Although some substantial achievements have been made in this field, the communication network of exosomes in organisms is still far from being fully understood.
Therefore, a further understanding of the information transmission mechanism and mechanism of action between exosomes, TAM and tumor cells will help further therapeutic development and clinical applications.
references:
1.Exosome-Mediated Crosstalk Between Tumorand Tumor-Associated Macrophages. Front Mol Biosci. 2021; 8: 764222.
What is the relationship between Tumor Cells | TAM | Exosomes?
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