Toll样受体信号通路作为结直肠癌潜在治疗靶点的研究进展
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摘要
Toll样受体(Toll-like receptors,TLRs)信号通路参与激活固有免疫和适应性免疫应答,在结直肠癌的发生发展中发挥重要作用。TLRs信号通路失调可导致上皮出血、慢性炎症以及促进结直肠癌的发展。现在有大量证据表明靶向这一途径将有益于结直肠癌的治疗,如卡介苗、单磷酰脂A、咪喹莫特等现已应用于临床。本文综述了目前有关TLRs在肿瘤发展中的不同功能及其在结直肠癌治疗中的应用。
Toll-like receptors(TLRs)signaling pathways are involved in the activation of innate and adaptive immune response and play an important role in the development of colorectal cancer.Deregulation of TLRs signaling pathway can lead to epithelial hemorrhage,chronic inflammation and the development of colorectal cancer.There is now lots of evidence that targeting this pathway will benefit the treatment of colorectal cancer,such as BCG,monophosphatidyl A,and iquimod,etc.,which are now in clinical use.This article reviews current different function of TLRs in tumor development and their application in the treatment of colorectal cancer.
Toll-like receptors(TLRs)signaling pathways are involved in the activation of innate and adaptive immune response and play an important role in the development of colorectal cancer.Deregulation of TLRs signaling pathway can lead to epithelial hemorrhage,chronic inflammation and the development of colorectal cancer.There is now lots of evidence that targeting this pathway will benefit the treatment of colorectal cancer,such as BCG,monophosphatidyl A,and iquimod,etc.,which are now in clinical use.This article reviews current different function of TLRs in tumor development and their application in the treatment of colorectal cancer.
引文
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2 DeSantis C,Lin C,Mariotto A,et al.Cancer treatment and survivorship statistics [J].CA Cancer J Clin,2014,64(4):252-271.
3 Goulopoulou S,Mccarthy CG,Webb RC.Toll-like receptors in the vascular system:sensing the dangers within [J].Pharmacol Rev,2016,68(1):142-167.
4 Medvedev AE.Toll-Like receptor polymorphisms,inflammatory and infectious diseases,allergies,and cancer [J].J Interferon Cytokine Res,2013,33(9):467-484.
5 Zhao S,Zhang Y,Zhang Q,et al.Toll-like receptors and prostate cancer [J].Front Immuno,2014,5:352.
6 Bryant CE,Symmons M,Gay NJ.Toll-like receptor signalling through macromolecular protein complexes [J].Mol Immunol,2015,63(2):162-165.
7 Hug H,Mohajeri MH,Fata GL.Toll-Like receptors:regulators of the immune response in the human gut [J].Nutrients,2018,10(2):203.
8 Liston A,Masters SL.Homeostasis-altering molecular processes as mechanisms of inflammasome activation [J].Nat Rev Immunol,2017,17(3):208-214.
9 Bortoluci KR,Medzhitov R.Control of infection by pyroptosis and autophagy:Role of TLR and NLR [J].Cell Mol Life Sci,2010,67(10):1643-1651.
10 Ioannou S,Voulgarelis M.Toll-Like receptors,tissue injury,and tumourigenesis [J].Mediators Inflamm,2010,2010:581837.
11 Lu Y,Li XR,Liu SS,et al.Toll-like receptors and inflammatory bowel disease [J] Front Immuno,2018,9:72.
12 Pradere JP,Dapito DH,Schwabe RF.The yin and yang of Toll-like receptors in cancer [J],Oncogene,33(27):3485-3495.
13 O'Leary DP,Bhatt L,Woolley JF,et al.TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1 [J].PLoS One,2012,7(10):e44176.
14 Fumi SK,Yao SY,Alast A,et al.Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer [J].JCI Insight,2017,2(18):e93397.
15 Lea SR,Reynolds SL,Kaur M et al.The effects of repeated Toll-like receptors 2 and 4 stimulation in COPD alveolar macrophages [J].Int J Chron Obstruct Pulmon Dis,2018,13:771-780.
16 Li TT,Ogino S,Qian ZR,et al.Toll-like receptor signaling in colorectal cancer:Carcinogenesis to cancer therapy [J].World J Gastroenterol,2014,20(47):17699-17708.
17 Chen CY,Kao CL,Liu CM.The cancer prevention,anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the TLR4 signaling pathway [J].Int J Mol Sci,2018,19(9):2729.
18 Wang EL,Qian ZR,Nakasono M,et al.High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer [J].Br J Cancer,2010,102(5):908-915.
19 Slattery ML,Herrick JS,Bondurant KL,et al.Toll-like receptor genes and their association with colon and rectal cancer development and prognosis [J].Int J Cancer,2012,130(12):2974-2980.
20 Fang H,Xu X,Huang X,et al.TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells [J].Cell Mol Immunol,2014,11(2):150-159.
21 Kuugbee E,Shang X,Gamallat Y,et al.Structural change in microbiota by a probiotic cocktail enhances the gut barrier and reduces cancer via TLR2 signaling in a rat model of colon cancer [J].Dig Dis Sci,2016,61(10):2908-2920.
22 Lowe E,Crother T,Rabizadeh S,et al.Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer [J].PLoS One,2010,5(9):e13027.
23 Isambert N,Paul C,Ferrand C,et al.Phase I study of OM-174,a lipid A analogue,with assessment of immunological response,in patients withrefractory solid tumors [J].BMC Cancer,2013,13(1):172.
24 Yuk J,Shin D,Song K,et al.Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy [J].Autophagy,2010,6(1):46-60.
25 Thaiss CA,Levy M,Itav S,et al.Integration of innate immune signaling [J].Trends Immunol,2016,37(2):84-101.
26 Belani C,Chakraborty B,Khamar B.ArandomizedtrialofTLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer [J].Ann Oncol,2016,82(2):298-304.
27 Davis M,Vasquez-Dunddel D,Fu J,et al.Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses [J].Clin Cancer Res,2011,17(12):3984-3992.
28 Cheng G,Yang S,Zhang G,et al.Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner [J].Onco Targets Ther,2016,9:7563-7571.
29 Wang BG,Yi DH,Liu YF,et al.TLR3 gene polymorphisms in cancer:a systematic review and meta-analysis [J].Chin J Cancer,2015,34(3):1-13.
30 Wang Q,Zhang X,Xiao T,et al.Prognostic role of Toll-like receptors in cancer:a meta-analysis [J].Ther Clin Risk Manag,2018,14:1323-1330.
31 Maitra R,Augustine T,Dayan Y,et al.Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer [J].Oncotarget,2017,8(21):35138-35153.
32 Forstneriˇc V,Iviˇcak-Kocjan K,Plaper T,et al.The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5 [J].PLoS Pathog,2017,13(8):e1006574.
33 Brackett CM,Kojouharov B,Veith J,et al.Toll-like receptor-5 agonist,entolimod,suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+T-cell axis [J].Proc Natl Acad Sci U S A,2016,113(7):874-883.
34 Ito H,Ando T,Arioka Y,et al.Inhibition of indoleamine.2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model [J].Immunology,2015,144(4);621-630.
35 Dumitru C,Antonysamy M,Tomai M,et al.Potentiation of the antitumor effects of imidazoquinoline immune response modifiers by cyclophosphamide [J].Cancer Biol Ther,2010,10(2):155-165.
36 Maria S,Asimina K,Maria S,et al.Evaluation of the detection of Toll-like receptors(TLRs)in cancer development and progression in patients with colorectal cancer [J].PLoS One,2018,13(6):e0197327.
37 Dong T,Yi T,Yang M,et al.Cooperation of α-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model [J].Biochem J,2015,473(1):7-19.
38 Weihrauch MR,Richly H,Hacker UJ,et al.Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours [J].Eur J Cancer,2015,51(2):146-156.
39 Ray A,Tian Z,Das D,et al.A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib [J].Leukemia,2014,28(8):1716-1724.
40 Kunlin W,Huihao Z,Yajuan F,et al,TLR4/MyD88 signaling determines the metastatic potential of breast cancer cells [J].Mol Med Rep,2018,18(3):3411-3420.
41 Xie L,Jiang F,Zhang L,et al.Targeting of MyD88 homodimerization by novel synthetic Inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer [J].J Natl Cancer Inst,2016,108(4):364.
42 Paarnio K,V?yrynen S,Klintrup K,et al.Divergent expression of bacterial wall sensing toll-like receptors 2 and 4 in colorectal cancer [J].World J Gastroenterol,2017,23(26):4831-4838.
43 Eiró N,González L,Andicoechea A,et al.Toll-like receptor-4 expression by stromal fibroblasts is associated with poor prognosis in colorectal cancer [J].J Immunother,2015,36(6):342-349.
44 Cammarota R,Bertolini V,Pennesi G,et al.The tumor microenvironment of colorectal cancer:Stromal TLR-4 expression as a potential prognostic marker [J].J Transl Med,2010,8(1):112.
2 DeSantis C,Lin C,Mariotto A,et al.Cancer treatment and survivorship statistics [J].CA Cancer J Clin,2014,64(4):252-271.
3 Goulopoulou S,Mccarthy CG,Webb RC.Toll-like receptors in the vascular system:sensing the dangers within [J].Pharmacol Rev,2016,68(1):142-167.
4 Medvedev AE.Toll-Like receptor polymorphisms,inflammatory and infectious diseases,allergies,and cancer [J].J Interferon Cytokine Res,2013,33(9):467-484.
5 Zhao S,Zhang Y,Zhang Q,et al.Toll-like receptors and prostate cancer [J].Front Immuno,2014,5:352.
6 Bryant CE,Symmons M,Gay NJ.Toll-like receptor signalling through macromolecular protein complexes [J].Mol Immunol,2015,63(2):162-165.
7 Hug H,Mohajeri MH,Fata GL.Toll-Like receptors:regulators of the immune response in the human gut [J].Nutrients,2018,10(2):203.
8 Liston A,Masters SL.Homeostasis-altering molecular processes as mechanisms of inflammasome activation [J].Nat Rev Immunol,2017,17(3):208-214.
9 Bortoluci KR,Medzhitov R.Control of infection by pyroptosis and autophagy:Role of TLR and NLR [J].Cell Mol Life Sci,2010,67(10):1643-1651.
10 Ioannou S,Voulgarelis M.Toll-Like receptors,tissue injury,and tumourigenesis [J].Mediators Inflamm,2010,2010:581837.
11 Lu Y,Li XR,Liu SS,et al.Toll-like receptors and inflammatory bowel disease [J] Front Immuno,2018,9:72.
12 Pradere JP,Dapito DH,Schwabe RF.The yin and yang of Toll-like receptors in cancer [J],Oncogene,33(27):3485-3495.
13 O'Leary DP,Bhatt L,Woolley JF,et al.TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1 [J].PLoS One,2012,7(10):e44176.
14 Fumi SK,Yao SY,Alast A,et al.Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer [J].JCI Insight,2017,2(18):e93397.
15 Lea SR,Reynolds SL,Kaur M et al.The effects of repeated Toll-like receptors 2 and 4 stimulation in COPD alveolar macrophages [J].Int J Chron Obstruct Pulmon Dis,2018,13:771-780.
16 Li TT,Ogino S,Qian ZR,et al.Toll-like receptor signaling in colorectal cancer:Carcinogenesis to cancer therapy [J].World J Gastroenterol,2014,20(47):17699-17708.
17 Chen CY,Kao CL,Liu CM.The cancer prevention,anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the TLR4 signaling pathway [J].Int J Mol Sci,2018,19(9):2729.
18 Wang EL,Qian ZR,Nakasono M,et al.High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer [J].Br J Cancer,2010,102(5):908-915.
19 Slattery ML,Herrick JS,Bondurant KL,et al.Toll-like receptor genes and their association with colon and rectal cancer development and prognosis [J].Int J Cancer,2012,130(12):2974-2980.
20 Fang H,Xu X,Huang X,et al.TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells [J].Cell Mol Immunol,2014,11(2):150-159.
21 Kuugbee E,Shang X,Gamallat Y,et al.Structural change in microbiota by a probiotic cocktail enhances the gut barrier and reduces cancer via TLR2 signaling in a rat model of colon cancer [J].Dig Dis Sci,2016,61(10):2908-2920.
22 Lowe E,Crother T,Rabizadeh S,et al.Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer [J].PLoS One,2010,5(9):e13027.
23 Isambert N,Paul C,Ferrand C,et al.Phase I study of OM-174,a lipid A analogue,with assessment of immunological response,in patients withrefractory solid tumors [J].BMC Cancer,2013,13(1):172.
24 Yuk J,Shin D,Song K,et al.Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy [J].Autophagy,2010,6(1):46-60.
25 Thaiss CA,Levy M,Itav S,et al.Integration of innate immune signaling [J].Trends Immunol,2016,37(2):84-101.
26 Belani C,Chakraborty B,Khamar B.ArandomizedtrialofTLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer [J].Ann Oncol,2016,82(2):298-304.
27 Davis M,Vasquez-Dunddel D,Fu J,et al.Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses [J].Clin Cancer Res,2011,17(12):3984-3992.
28 Cheng G,Yang S,Zhang G,et al.Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner [J].Onco Targets Ther,2016,9:7563-7571.
29 Wang BG,Yi DH,Liu YF,et al.TLR3 gene polymorphisms in cancer:a systematic review and meta-analysis [J].Chin J Cancer,2015,34(3):1-13.
30 Wang Q,Zhang X,Xiao T,et al.Prognostic role of Toll-like receptors in cancer:a meta-analysis [J].Ther Clin Risk Manag,2018,14:1323-1330.
31 Maitra R,Augustine T,Dayan Y,et al.Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer [J].Oncotarget,2017,8(21):35138-35153.
32 Forstneriˇc V,Iviˇcak-Kocjan K,Plaper T,et al.The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5 [J].PLoS Pathog,2017,13(8):e1006574.
33 Brackett CM,Kojouharov B,Veith J,et al.Toll-like receptor-5 agonist,entolimod,suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+T-cell axis [J].Proc Natl Acad Sci U S A,2016,113(7):874-883.
34 Ito H,Ando T,Arioka Y,et al.Inhibition of indoleamine.2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model [J].Immunology,2015,144(4);621-630.
35 Dumitru C,Antonysamy M,Tomai M,et al.Potentiation of the antitumor effects of imidazoquinoline immune response modifiers by cyclophosphamide [J].Cancer Biol Ther,2010,10(2):155-165.
36 Maria S,Asimina K,Maria S,et al.Evaluation of the detection of Toll-like receptors(TLRs)in cancer development and progression in patients with colorectal cancer [J].PLoS One,2018,13(6):e0197327.
37 Dong T,Yi T,Yang M,et al.Cooperation of α-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model [J].Biochem J,2015,473(1):7-19.
38 Weihrauch MR,Richly H,Hacker UJ,et al.Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours [J].Eur J Cancer,2015,51(2):146-156.
39 Ray A,Tian Z,Das D,et al.A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib [J].Leukemia,2014,28(8):1716-1724.
40 Kunlin W,Huihao Z,Yajuan F,et al,TLR4/MyD88 signaling determines the metastatic potential of breast cancer cells [J].Mol Med Rep,2018,18(3):3411-3420.
41 Xie L,Jiang F,Zhang L,et al.Targeting of MyD88 homodimerization by novel synthetic Inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer [J].J Natl Cancer Inst,2016,108(4):364.
42 Paarnio K,V?yrynen S,Klintrup K,et al.Divergent expression of bacterial wall sensing toll-like receptors 2 and 4 in colorectal cancer [J].World J Gastroenterol,2017,23(26):4831-4838.
43 Eiró N,González L,Andicoechea A,et al.Toll-like receptor-4 expression by stromal fibroblasts is associated with poor prognosis in colorectal cancer [J].J Immunother,2015,36(6):342-349.
44 Cammarota R,Bertolini V,Pennesi G,et al.The tumor microenvironment of colorectal cancer:Stromal TLR-4 expression as a potential prognostic marker [J].J Transl Med,2010,8(1):112.