Exosomes: A Potential Therapeutic Tool Targeting Communications between Tumor Cells and Macrophages
Authors: Weihua Guo, Yashan Li, Wei Pang, Hong Shen
Journal: Molecular Therapy (2020)

Exosomes comprise extracellular vesicles (EVs) with diameters between 30 and 150 nm. They transfer proteins, RNA, and other molecules from cell to cell, playing an important role in the interactions between cells. The tumor microenvironment (TME) has been found to contain various cells and molecules that have an important impact on tumor development. In the TME, macrophages have been found to have an important relationship with tumor cells, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs), which promote tumor development. Recently, exosomes have been found to play a critical role in the interaction between tumor cells and macrophages. Thus, in this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages and the potential methods by which exosomes are used to target the communication between tumor cells and macrophages to treat cancer. Exosomes comprise extracellular vesicles (EVs) with diameters between 30 and 150 nm. They transfer proteins, RNA, and other molecules from cell to cell, playing an important role in the interactions between cells. The tumor microenvironment (TME) has been found to contain various cells and molecules that have an important impact on tumor development. In the TME, macrophages have been found to have an important relationship with tumor cells, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs), which promote tumor development. Recently, exosomes have been found to play a critical role in the interaction between tumor cells and macrophages. Thus, in this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages and the potential methods by which exosomes are used to target the communication between tumor cells and macrophages to treat cancer. Exosomes are the smallest extracellular vesicles (EVs) with diameters between 30 and 150 nm and play an important role in the interactions between cells.1Pegtel D.M. Gould S.J. Exosomes.Annu. Rev. Biochem. 2019; 88: 487-514Crossref PubMed Scopus (80) Google Scholar,2Farooqi A.A. Desai N.N. Qureshi M.Z. Librelotto D.R.N. Gasparri M.L. Bishayee A. Nabavi S.M. Curti V. Daglia M. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds.Biotechnol. Adv. 2018; 36: 328-334Crossref PubMed Scopus (49) Google Scholar Exosomes mainly contain proteins and RNAs and can also include glycoconjugates, lipids, and DNAs. Exosomal proteins include integral exosomal membrane proteins, lipid-anchored outer membrane proteins, peripheral surface proteins, lipid-anchored inner membrane proteins, inner peripheral membrane proteins, exosomal enzymes, and soluble proteins.1Pegtel D.M. Gould S.J. Exosomes.Annu. Rev. 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Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.Cancer Lett. 2018; 435: 80-91Crossref PubMed Google Scholar In this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages as well as the potential methods that use exosomes to target the communication between tumor cells and macrophages to treat cancer. Studies have shown that, in a variety of cancers, such as gastric cancer, breast cancer, hepatocellular carcinoma (HCC), and nasopharyngeal carcinoma, exosomes can be secreted into the TME to regulate the function of neighboring cells, thus creating an environment conducive to tumor development.18Zhang X. Shi H. Yuan X. Jiang P. Qian H. Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.Mol. Cancer. 2018; 17: 146Crossref PubMed Scopus (6) Google Scholar, 19Luga V. Zhang L. Viloria-Petit A.M. 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Zhang J. He Y. Feng D. Wang F. Li X. Liu Q. Li Y. et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages.Hepatology. 2019; 70: 241-258Crossref PubMed Scopus (223) Google ScholarOvarian cancermiR-222-3p–promoting M2 polarization28Ying X. Wu Q. Wu X. Zhu Q. Wang X. Jiang L. Chen X. Wang X. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages.Oncotarget. 2016; 7: 43076-43087Crossref PubMed Scopus (102) Google ScholarmiR-1246Cav1/p-gppromoting M2 polarization, resistance against paclitaxel29Kanlikilicer P. Bayraktar R. Denizli M. Rashed M.H. Ivan C. Aslan B. Mitra R. Karagoz K. Bayraktar E. Zhang X. et al.Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.EBioMedicine. 2018; 38: 100-112Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarHead and neck cancermiR-21–promoting M2 polarization30Hsieh C.H. Tai S.K. Yang M.H. Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering miR-21-abundant exosomes.Neoplasia. 2018; 20: 775-788Crossref PubMed Scopus (27) Google ScholarPancreatic cancermiR-301a-3pPTEN/PI3Kpromoting M2 polarization31Wang X. Luo G. Zhang K. Cao J. Huang C. Jiang T. Liu B. Su L. Qiu Z. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.Cancer Res. 2018; 78: 4586-4598Crossref PubMed Scopus (25) Google ScholarMIF–promoting pre-metastatic niches formation and metastasis32Costa-Silva B. Aiello N.M. Ocean A.J. Singh S. Zhang H. Thakur B.K. Becker A. Hoshino A. 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NSE from diffuse large B-cell lymphoma cells regulates macrophage polarization.Cancer Manag. Res. 2019; 11: 4577-4595Crossref PubMed Scopus (1) Google Scholaravβ5–promoting liver metastasis39Paolillo M. Schinelli S. Integrins and exosomes, a dangerous liaison in cancer progression.Cancers (Basel). 2017; 9: E95Crossref PubMed Scopus (17) Google ScholarLung adenocarcinomamiR-21targeting Pdcd4promoting bone metastasis40Xu Z. Liu X. Wang H. Li J. Dai L. Li J. Dong C. Lung adenocarcinoma cell-derived exosomal miR-21 facilitates osteoclastogenesis.Gene. 2018; 666: 116-122Crossref PubMed Scopus (19) Google ScholarNSCLCAREGEGFR pathwaypromoting bone metastasis41Taverna S. Pucci M. Giallombardo M. Di Bella M.A. Santarpia M. Reclusa P. Gil-Bazo I. Rolfo C. Alessandro R. Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway.Sci. 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Li Y. et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages.Hepatology. 2019; 70: 241-258Crossref PubMed Scopus (223) Google Scholar In pancreatic cancer, hypoxia-related exosomal miR-301a-3p promotes M2 polarization by inhibiting PTEN and activating the PI3Kγ signaling pathway.31Wang X. Luo G. Zhang K. Cao J. Huang C. Jiang T. Liu B. Su L. Qiu Z. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.Cancer Res. 2018; 78: 4586-4598Crossref PubMed Scopus (25) Google Scholar STAT1 is the main transcriptional factor that regulates M1 macrophage polarization, while STAT6 promotes M2 macrophage polarization.53Rahal O.M. Wolfe A.R. Mandal P.K. Larson R. Tin S. Jimenez C. Zhang D. Horton J. Reuben J.M. McMurray J.S. Woodward W.A. Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer.Int. J. Radiat. Oncol. Biol. Phys. 2018; 100: 1034-1043Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,54Gan Z.S. Wang Q.Q. Li J.H. Wang X.L. Wang Y.Z. Du H.H. Iron reduces M1 macrophage polarization in RAW264.7 macrophages associated with inhibition of STAT1.Mediators Inflamm. 2017; 2017: 8570818Crossref PubMed Scopus (27) Google Scholar Integrin β3 activates STAT1 signaling and suppresses STAT6 signaling, thereby promoting macrophage polarization into the M1 type. However, the expression of integrin β3 is promoted by STAT6 and inhibited by STAT1 to maintain a balance between STAT1 and STAT6 signal transduction. Thus, loss of integrin β3 disrupts this balance and promotes M2 polarization.55Su X. Esser A.K. Amend S.R. Xiang J. Xu Y. Ross M.H. Fox G.C. Kobayashi T. Steri V. Roomp K. et al.Antagonizing integrin β3 increases immunosuppression in cancer.Cancer Res. 2016; 76: 3484-3495Crossref PubMed Google Scholar In prostate cancer, the most abundant miRNAs in PC3 exosomes significantly downregulate integrin β3 expression, inducing macrophage M2 polarization.33Ferguson S. Kim S. Lee C. Deci M. Nguyen J. The phenotypic effects of exosomes secreted from distinct cellular sources: a comparative study based on miRNA composition.AAPS J. 2018; 20: 67Crossref PubMed Scopus (3) Google Scholar It is known that STAT6 signaling plays a critical role in promoting M2 polarization.53Rahal O.M. Wolfe A.R. Mandal P.K. Larson R. Tin S. Jimenez C. Zhang D. Horton J. Reuben J.M. McMurray J.S. Woodward W.A. Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer.Int. J. Radiat. Oncol. Biol. Phys. 2018; 100: 1034-1043Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar SOCS1 contains an SH2 domain that induces proteasomal degradation, which can suppress STAT6 signaling.56Ritz O. Guiter C. Dorsch K. Dusanter-Fourt I. Wegener S. Jouault H. Gaulard P. Castellano F. Möller P. Leroy K. STAT6 activity is regulated by SOCS-1 and modulates BCL-XL expression in primary mediastinal B-cell lymphoma.Leukemia. 2008; 22: 2106-2110Crossref PubMed Scopus (0) Google Scholar In oral squamous cell carcinoma (OSCC), OSCC-derived exosomes with captured miR-29a-3p directly target SOCS1 and downregulate its expression, thereby stimulating the STAT6 signal and promoting M2 macrophage polarization.35Cai J. Qiao B. Gao N. Lin N. He W. Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p.Am. J. Physiol. Cell Physiol. 2019; 316: C731-C740Crossref PubMed Scopus (7) Google Scholar The process by which cancer cells secrete exosomal miRNAs is regulated by many factors, including the physicochemical features of the TME and some transcriptional factors. One of the physicochemical features of the TME is hypoxia, and the harmful TME interferes with the ability of the endoplasmic reticulum (ER) to fold proteins, causing ER stress.57Wilson W.R. Hay M.P. Targeting hypoxia in cancer therapy.Nat. Rev. Cancer. 2011; 11: 393-410Crossref PubMed Scopus (1594) Google Scholar,58Cubillos-Ruiz J.R. Bettigole S.E. Glimcher L.H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer.Cell. 2017; 168: 692-706Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Both of them can promote cancer cells to secrete exosomal miRNAs. In epithelial ovarian cancer (EOC), hypoxia induces miRNAs in EOC cell-derived exosomes to promote M2 macrophage polarization via hypoxia-inducible factors (HIFs).17Chen X. Zhou J. Li X. Wang X. Lin Y. Wang X. Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.Cancer Lett. 2018; 435: 80-91Crossref PubMed Google Scholar In HCC, ER-stressed HCC cells release exosomal miR-23a-3p to upregulate PD-L1 expression in macrophages.27Liu J. Fan L. Yu H. Zhang J. He Y. Feng D. Wang F. Li X. Liu Q. 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