三阴型乳腺癌中CYP4A11和CYP4A22表达及其与M2型肿瘤相关巨噬细胞的关系
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摘要
目的评价CYP4A11和CYP4A22在三阴型乳腺癌(triple-negative breast carcinoma,TNBC)中的表达及其与临床病理特征以及M2型肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)的关系。方法收集72例TNBC根治病例及其临床病理资料,采用免疫组化和图像分析方法检测癌组织中CYP4A11和CYP4A22的表达以及肿瘤间质中巨噬细胞CD68和CD163的表达,分析CYP4A11和CYP4A22表达与TNBC临床病理特征以及M2型TAMs数量的关系。结果 TNBC癌组织中CYP4A11和CYP4A22的表达均较正常乳腺组织增高(P均<0. 001)。CYP4A11高表达与肿瘤直径增大(P <0. 001)、淋巴结转移(P <0. 001)、高临床分期(P <0. 001)和高Ki-67增殖指数(P=0. 011)有关。CYP4A11高表达组的肿瘤间质CD68和CD163阳性细胞比例均较低表达组增高(P=0. 021、P <0. 001)。癌组织CYP4A22高表达与淋巴结转移(P <0. 001)、高临床分期(P=0. 006)、高复发率(P <0. 001)和高Ki-67增殖指数(P=0. 040)有关。CYP4A22高表达组的肿瘤间质CD163阳性细胞比例较低表达组增高(P <0. 001)。结论 TNBC中CYP4A11和CYP4A22高表达均伴随肿瘤间质微环境中M2状态TAMs增加,并与癌细胞高增殖活性和转移相关。
Purpose To investigate the expression of CYP4 A11 and CYP4 A22 in triple-negative breast carcinoma( TNBC) and its relationship with clinicopathological features and M2 tumor-associated macrophages( TAMs). Methods 72 cases of TNBC with clinical and pathological data were collected. The expression of CYP4 A11 and CYP4 A22 in the carcinoma cells and the expression of CD68 and CD163 of the TAMs were detected by immunohistochemically and analyzed with image processing software. The relationship between the expressions of CYP4 A11 and CYP4 A22 with clinicopathologic features and its correlation of the M2 state of TAMs was studied. Results Both the immunohistochemically staining scores of CYP4 A11 and CYP4 A22 were higher in cancer tissues than that in breast tissues( P < 0. 001, P < 0. 001). The higher expression of CYP4 A11 was associated with tumor diameter increase( P <0. 001),lymph node metastasis( P < 0. 001),higher clinical stage( P < 0. 001) and higher Ki-67 index( P = 0. 011). Both the positive rates of CD68 and CD163 in the high expression group of CYP4 A11 were higher than those in the low expression group of CYP4 A11( P = 0. 021,P < 0. 001). The higher expression of CYP4 A22 was associated with lymph node metastasis( P < 0. 001),higher clinical stage( P = 0. 006),higher recurrence rate( P < 0. 001),and higher Ki-67 index( P = 0. 040).The positive rates of CD163 in the high expression group of CYP4 A22 was higher than that in the low expression group of CYP4 A22( P < 0. 001). Conclusion Both the expression of CYP4 A11 and CYP4 A22 may be associated with M2 polarization state of TAMs,high proliferative activity and lymph node metastasis in the TNBC.
Purpose To investigate the expression of CYP4 A11 and CYP4 A22 in triple-negative breast carcinoma( TNBC) and its relationship with clinicopathological features and M2 tumor-associated macrophages( TAMs). Methods 72 cases of TNBC with clinical and pathological data were collected. The expression of CYP4 A11 and CYP4 A22 in the carcinoma cells and the expression of CD68 and CD163 of the TAMs were detected by immunohistochemically and analyzed with image processing software. The relationship between the expressions of CYP4 A11 and CYP4 A22 with clinicopathologic features and its correlation of the M2 state of TAMs was studied. Results Both the immunohistochemically staining scores of CYP4 A11 and CYP4 A22 were higher in cancer tissues than that in breast tissues( P < 0. 001, P < 0. 001). The higher expression of CYP4 A11 was associated with tumor diameter increase( P <0. 001),lymph node metastasis( P < 0. 001),higher clinical stage( P < 0. 001) and higher Ki-67 index( P = 0. 011). Both the positive rates of CD68 and CD163 in the high expression group of CYP4 A11 were higher than those in the low expression group of CYP4 A11( P = 0. 021,P < 0. 001). The higher expression of CYP4 A22 was associated with lymph node metastasis( P < 0. 001),higher clinical stage( P = 0. 006),higher recurrence rate( P < 0. 001),and higher Ki-67 index( P = 0. 040).The positive rates of CD163 in the high expression group of CYP4 A22 was higher than that in the low expression group of CYP4 A22( P < 0. 001). Conclusion Both the expression of CYP4 A11 and CYP4 A22 may be associated with M2 polarization state of TAMs,high proliferative activity and lymph node metastasis in the TNBC.
引文
[1]Harbeck N,Gnant M.Breast cancer[J].Lancet,2017,389(10074):1134-1150.
[2]Lebert J M,Lester R,Powell E,et al.Advances in the systemic treatment of triple-negative breast cancer[J].Curr Oncol,2018,25(Suppl 1):S142-S150.
[3]Edson K Z,Rettie A E.CYP4 enzymes as potential drug targets:focus on enzyme multiplicity,inducers and inhibitors,and therapeutic modulation of 20-hydroxyeicosatetraenoic acid(20-HETE)synthase and fatty acidω-hydroxylase activities[J].Curr Top Med Chem,2013,13(12):1429-1440.
[4]Borin T F,Angara K,Rashid M H,et al.Arachidonic acid metabolite as a novel therapeutic target in breast cancer metastasis[J].Int J Mol Sci,2017,18(12):2661-2684.
[5]Tariq M,Zhang J,Liang G,et al.Macrophage polarization:anticancer strategies to target tumor-associated macrophage in breast cancer[J].J Cell Biochem,2017,118(9):2484-2501.
[6]Lao L,Fan S,Song E.Tumor associated macrophages as therapeutic targets for breast cancer[J].Adv Exp Med Biol,2017,1026:331-370.
[7]Chen X W,Yu T J,Zhang J,et al.CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis[J].Oncogene,2017,36(35):5045-5057.
[8]Allred D C,Harvey J M,Berardo M,et al.Prognostic and predictive factors in breast cancer by immunohistochemical analysis[J].Mod Pathol,1998,11(2):155-168.
[9]王娟,邬万新,陈彩萍,等.三阴型乳腺癌中S1PR1、S1PR4的表达及其临床意义[J].临床与实验病理学杂志,2018,34(1):16-20.
[10]Salgado R,Denkert C,Demaria S,et al.The evaluation of tumor infiltrating lymphocytes in breast cancer:recommendations by an International TILs Working Group 2014[J].Ann Oncol,2015,26(2):259-271.
[11]Alexanian A,Miller B,Roman R J,et al.20-HETE producing enzymes are up-regulated in human cancers[J].Cancer Genomics Proteomics,2012,9(4):163-169.
[12]Borin T F,Zuccari D A,Jardim-Perassi B V,et al.HET0016,a selective inhibitor of 20-HETE synthesis,decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice[J].PLo S One,2014,9(12):e116247.
[13]Alnabulsi A,Swan R,Cash B,et al.The differential expression of omega-3 and omega-6 fatty acid metabolizing enzymes in colorectal cancer and its prognostic significance[J].Br J Cancer,2017,116(12):1612-1620.
[14]Borin T F,Shankar A,Angara K,et al.HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model[J].PLo S One,2017,12(6):e0178830.
[15]Schultze J L,Schmieder A,Goerdt S.Macrophage activation in human diseases[J].Semin Immunol,2015,27(4):249-256.
[16]Jackute J,Zemaitis M,Pranys D,et al.Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer[J].BMC Immunol,2018,19(1):3-10.
[17]Yu W,Chen L,Yang Y Q,et al.Cytochrome P450 omegahydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer[J].Cancer Chemother Pharmacol,2011,68:619-629.
[18]Wang C,Li Y,Chen H,et al.Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma[J].Cancer Lett,2017,402:131-141.
[2]Lebert J M,Lester R,Powell E,et al.Advances in the systemic treatment of triple-negative breast cancer[J].Curr Oncol,2018,25(Suppl 1):S142-S150.
[3]Edson K Z,Rettie A E.CYP4 enzymes as potential drug targets:focus on enzyme multiplicity,inducers and inhibitors,and therapeutic modulation of 20-hydroxyeicosatetraenoic acid(20-HETE)synthase and fatty acidω-hydroxylase activities[J].Curr Top Med Chem,2013,13(12):1429-1440.
[4]Borin T F,Angara K,Rashid M H,et al.Arachidonic acid metabolite as a novel therapeutic target in breast cancer metastasis[J].Int J Mol Sci,2017,18(12):2661-2684.
[5]Tariq M,Zhang J,Liang G,et al.Macrophage polarization:anticancer strategies to target tumor-associated macrophage in breast cancer[J].J Cell Biochem,2017,118(9):2484-2501.
[6]Lao L,Fan S,Song E.Tumor associated macrophages as therapeutic targets for breast cancer[J].Adv Exp Med Biol,2017,1026:331-370.
[7]Chen X W,Yu T J,Zhang J,et al.CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis[J].Oncogene,2017,36(35):5045-5057.
[8]Allred D C,Harvey J M,Berardo M,et al.Prognostic and predictive factors in breast cancer by immunohistochemical analysis[J].Mod Pathol,1998,11(2):155-168.
[9]王娟,邬万新,陈彩萍,等.三阴型乳腺癌中S1PR1、S1PR4的表达及其临床意义[J].临床与实验病理学杂志,2018,34(1):16-20.
[10]Salgado R,Denkert C,Demaria S,et al.The evaluation of tumor infiltrating lymphocytes in breast cancer:recommendations by an International TILs Working Group 2014[J].Ann Oncol,2015,26(2):259-271.
[11]Alexanian A,Miller B,Roman R J,et al.20-HETE producing enzymes are up-regulated in human cancers[J].Cancer Genomics Proteomics,2012,9(4):163-169.
[12]Borin T F,Zuccari D A,Jardim-Perassi B V,et al.HET0016,a selective inhibitor of 20-HETE synthesis,decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice[J].PLo S One,2014,9(12):e116247.
[13]Alnabulsi A,Swan R,Cash B,et al.The differential expression of omega-3 and omega-6 fatty acid metabolizing enzymes in colorectal cancer and its prognostic significance[J].Br J Cancer,2017,116(12):1612-1620.
[14]Borin T F,Shankar A,Angara K,et al.HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model[J].PLo S One,2017,12(6):e0178830.
[15]Schultze J L,Schmieder A,Goerdt S.Macrophage activation in human diseases[J].Semin Immunol,2015,27(4):249-256.
[16]Jackute J,Zemaitis M,Pranys D,et al.Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer[J].BMC Immunol,2018,19(1):3-10.
[17]Yu W,Chen L,Yang Y Q,et al.Cytochrome P450 omegahydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer[J].Cancer Chemother Pharmacol,2011,68:619-629.
[18]Wang C,Li Y,Chen H,et al.Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma[J].Cancer Lett,2017,402:131-141.