- Department of Dermatology, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P. R. China;
In the tumor microenvironment, tumor-associated macrophage, as polarized macrophages M2 phenotype, can promote tumor progression and affect the prognosis of cancer. Significant attention has been drawn towards tumor-associated macrophage in recent years. In this review, we describe the polarization state of macrophages determined by tumor microenvironment and the recruitment of tumor-associated macrophage. We also pay special attention to the interaction between tumor-associated macrophages and tumors, discuss and summarize various targeted therapy strategies for tumor-associated macrophages, aiming to provide a reference for the future development of these novel and effective anti-cancer treatments.
Citation: XIE Yuyu, DUAN Xinsuo. Significance of polarization and targeted therapy of macrophages in tumor microenvironment. West China Medical Journal, 2021, 36(5): 679-685. doi: 10.7507/1002-0179.202001027 Copy
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6. | Jeannin P, Paolini L, Adam C, et al. The roles of CSFs on the functional polarization of tumor-associated macrophages. FEBS J, 2018, 285(4): 680-699. |
7. | Salmaninejad A, Valilou SF, Soltani A, et al. Tumor-associated macrophages: role in cancer development and therapeutic implications. Cell Oncol (Dordr), 2019, 42(5): 591-608. |
8. | Sica A, Schioppa T, Mantovani A, et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer, 2006, 42(6): 717-727. |
9. | Netea-Maier RT, Smit JWA, Netea MG. Metabolic changes in tumor cells and tumor-associated macrophages: a mutual relationship. Cancer Lett, 2018, 413: 102-109. |
10. | Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res, 2006, 66(2): 605-612. |
11. | Kielbassa K, Vegna S, Ramirez C, et al. Understanding the origin and diversity of macrophages to tailor their targeting in solid cancers. Front Immunol, 2019, 10: 2215. |
12. | van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM10). Am J Respir Crit Care Med, 2001, 164(5): 826-830. |
13. | Hamilton G, Rath B, Klameth L, et al. Small cell lung cancer: recruitment of macrophages by circulating tumor cells. Oncoimmunology, 2015, 5(3): e1093277. |
14. | Kortlever RM, Sodir NM, Wilson CH, et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell, 2017, 171(6): 1301-1315. e14. |
15. | Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol, 2017, 17(5): 306-321. |
16. | Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol, 2018, 2(1): 6. |
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- 1. Roma-Rodrigues C, Mendes R, Baptista PV, et al. Targeting tumor microenvironment for cancer therapy. Int J Mol Sci, 2019, 20(4): 840.
- 2. Morrison C. Immuno-oncologists eye up macrophage targets. Nat Rev Drug Discov, 2016, 15(6): 373-374.
- 3. Long KB, Collier AI, Beatty GL. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance. Mol Immunol, 2019, 110: 3-12.
- 4. Dehne N, Mora J, Namgaladze D, et al. Cancer cell and macrophage cross-talk in the tumor microenvironment. Curr Opin Pharmacol, 2017, 35: 12-19.
- 5. Ostuni R, Kratochvill F, Murray PJ, et al. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol, 2015, 36(4): 229-239.
- 6. Jeannin P, Paolini L, Adam C, et al. The roles of CSFs on the functional polarization of tumor-associated macrophages. FEBS J, 2018, 285(4): 680-699.
- 7. Salmaninejad A, Valilou SF, Soltani A, et al. Tumor-associated macrophages: role in cancer development and therapeutic implications. Cell Oncol (Dordr), 2019, 42(5): 591-608.
- 8. Sica A, Schioppa T, Mantovani A, et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer, 2006, 42(6): 717-727.
- 9. Netea-Maier RT, Smit JWA, Netea MG. Metabolic changes in tumor cells and tumor-associated macrophages: a mutual relationship. Cancer Lett, 2018, 413: 102-109.
- 10. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res, 2006, 66(2): 605-612.
- 11. Kielbassa K, Vegna S, Ramirez C, et al. Understanding the origin and diversity of macrophages to tailor their targeting in solid cancers. Front Immunol, 2019, 10: 2215.
- 12. van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM10). Am J Respir Crit Care Med, 2001, 164(5): 826-830.
- 13. Hamilton G, Rath B, Klameth L, et al. Small cell lung cancer: recruitment of macrophages by circulating tumor cells. Oncoimmunology, 2015, 5(3): e1093277.
- 14. Kortlever RM, Sodir NM, Wilson CH, et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell, 2017, 171(6): 1301-1315. e14.
- 15. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol, 2017, 17(5): 306-321.
- 16. Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol, 2018, 2(1): 6.
- 17. Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Compr Physiol, 2013, 3(2): 785-797.
- 18. Capece D, Fischietti M, Verzella D, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int, 2013, 2013: 187204.
- 19. Katsumoto A, Lu H, Miranda AS, et al. Ontogeny and functions of central nervous system macrophages. J Immunol, 2014, 193(6): 2615-2621.
- 20. Wu SY, Watabe K. The roles of microglia/macrophages in tumor progression of brain cancer and metastatic disease. Front Biosci (Landmark Ed), 2017, 22: 1805-1829.
- 21. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci, 2016, 19(1): 20-27.
- 22. Watters JJ, Schartner JM, Badie B. Microglia function in brain tumors. J Neurosci Res, 2005, 81(3): 447-455.
- 23. Coniglio SJ, Eugenin E, Dobrenis K, et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med, 2012, 18(1): 519-527.
- 24. Wang SC, Hong JH, Hsueh C, et al. Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model. Lab Invest, 2012, 92(1): 151-162.
- 25. Ku MC, Wolf SA, Respondek D, et al. GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis. Acta Neuropathol, 2013, 125(4): 609-620.
- 26. Held-Feindt J, Hattermann K, Müerköster SS, et al. CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp Cell Res, 2010, 316(9): 1553-1566.
- 27. Leung SY, Wong MP, Chung LP, et al. Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol, 1997, 93(5): 518-527.
- 28. Zhang J, Sarkar S, Cua R, et al. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis, 2012, 33(2): 312-319.
- 29. Hambardzumyan D, Squatrito M, Holland EC. Radiation resistance and stem-like cells in brain tumors. Cancer Cell, 2006, 10(6): 454-456.
- 30. Zhou W, Ke SQ, Huang Z, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol, 2015, 17(2): 170-182.
- 31. Ye XZ, Xu SL, Xin YH, et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol, 2012, 189(1): 444-453.
- 32. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol, 2017, 10(1): 58.
- 33. Chanmee T, Ontong P, Konno K, et al. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel), 2014, 6(3): 1670-1690.
- 34. Kogure A, Kosaka N, Ochiya T. Cross-talk between cancer cells and their neighbors via miRNA in extracellular vesicles: an emerging player in cancer metastasis. J Biomed Sci, 2019, 26(1): 7.
- 35. Shirabe K, Mano Y, Muto J, et al. Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today, 2012, 42(1): 1-7.
- 36. Tong H, Ke JQ, Jiang FZ, et al. Tumor-associated macrophage-derived CXCL8 could induce ERα suppression via HOXB13 in endometrial cancer. Cancer Lett, 2016, 376(1): 127-136.
- 37. Lindsten T, Hedbrant A, Ramberg A, et al. Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2. Int J Oncol, 2017, 51(1): 104-114.
- 38. Arima K, Komohara Y, Bu L, et al. Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer. Cancer Sci, 2018, 109(2): 462-470.
- 39. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141(1): 39-51.
- 40. Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci, 2018, 25(1): 20.
- 41. Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett, 2014, 352(2): 160-168.
- 42. Raghavan S, Mehta P, Xie Y, et al. Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments. J Immunother Cancer, 2019, 7(1): 190.
- 43. Chen XW, Yu TJ, Zhang J, et al. CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis. Oncogene, 2017, 36(35): 5045-5057.
- 44. Nielsen SR, Quaranta V, Linford A, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol, 2016, 18(5): 549-560.
- 45. Celus W, Di Conza G, Oliveira AI, et al. Loss of caveolin-1 in metastasis-associated macrophages drives lung metastatic growth through increased angiogenesis. Cell Rep, 2017, 21(10): 2842-2854.
- 46. Jung M, Ören B, Mora J, et al. Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis. Sci Signal, 2016, 9(434): ra64.
- 47. Weiss JM, Ridnour LA, Back T, et al. Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med, 2010, 207(11): 2455-2467.
- 48. Chen J, Yao Y, Gong C, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell, 2011, 19(4): 541-555.
- 49. Leek RD, Hunt NC, Landers RJ, et al. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol, 2000, 190(4): 430-436.
- 50. Sousa S, Määttä J. The role of tumour-associated macrophages in bone metastasis. J Bone Oncol, 2016, 5(3): 135-138.
- 51. Wyckoff J, Wang W, Lin EY, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res, 2004, 64(19): 7022-7029.
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