肿瘤微环境在治疗胰腺癌中的研究进展
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摘要
胰腺癌是一种具有高度免疫抑制性的恶性肿瘤,近年来肿瘤微环境逐渐引起研究者们的重视,胰腺癌的研究也已进入新的阶段。研究者已陆续发现了一些极有潜力的分子靶点,有望应用于胰腺癌的靶向治疗和免疫治疗。如PEGPH20消除肿瘤微环境中的透明质酸而发挥促癌作用;CC趋化因子受体2激酶拮抗剂与集落刺激因子1受体抑制剂靶向肿瘤相关巨噬细胞而抑制癌细胞生长等。目前,更多关于肿瘤微环境中免疫、代谢反应中的治疗靶点还在进一步研究中。
Pancreatic cancer is a highly immunosuppressive malignancy with a poor prognosis. Therefore,it is of great significance to find new molecular therapeutic targets for the clinical diagnosis and treatment of pancreatic cancer. However,as the tumor microenvironment has gradually attracted the attention of researchers in recent years,the research of pancreatic cancer has also entered a new stage. Researchers have found some potential therapeutic targets in treating pancreatic cancer,for example,PEGPH20 eliminates hyaluronic acid in the tumor microenvironment promoting cancer; CC chemokine receptor2 kinase antagonist and colony stimulating factor 1 receptor inhibitor targets at tumor related macrophages and inhibits the growth of cancer cells. Currently,further research on immunity and metabolism in the tumor microenvironment is still in progress.
Pancreatic cancer is a highly immunosuppressive malignancy with a poor prognosis. Therefore,it is of great significance to find new molecular therapeutic targets for the clinical diagnosis and treatment of pancreatic cancer. However,as the tumor microenvironment has gradually attracted the attention of researchers in recent years,the research of pancreatic cancer has also entered a new stage. Researchers have found some potential therapeutic targets in treating pancreatic cancer,for example,PEGPH20 eliminates hyaluronic acid in the tumor microenvironment promoting cancer; CC chemokine receptor2 kinase antagonist and colony stimulating factor 1 receptor inhibitor targets at tumor related macrophages and inhibits the growth of cancer cells. Currently,further research on immunity and metabolism in the tumor microenvironment is still in progress.
引文
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[2]Rahib L,Smith BD,Aizenberg R,et al.Projecting cancer incidence and deaths to 2030:the unexpected burden of thyroid,liver,and pancreas cancers in the United States[J].Cancer Res,2014,74(11):2913-2921.
[3]Ioannides CG,Whiteside TL.T cell recognition of human tumors:Implications for molecular immunotherapy of cancer[J].Clin Immunol Immunopathol,1993,66(2):91-106.
[4]Fanhchaksai K,Okada F,Nagai N,et al.Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth[J].Int J Cancer,2016,138(3):630-641.
[5]Rajeshkumar NV,Yabuuchi S,Pai SG,et al.Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer[J].Br J Cancer,2016,115(4):442-453.
[6]Von Hoff DD,Ervin T,Arena FP,et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine[J].N Engl J Med,2013,369(18):1691-1703.
[7]Conroy T,Desseigne F,Ychou M,et al.FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer[J].N Engl J Med,2011,364(19):1817-1825.
[8]Marsh Rde W,Talamonti MS,Katz MH,et al.Pancreatic cancer and FOLFIRINOX:A new era and new questions[J].Cancer Med,2015,4(6):853-863.
[9]Wang-Gillam A,Li CP,Bodoky G,et al.Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy(NAPOLI-1):A global,randomised,open-label,phase 3 trial[J].Lancet,2016,387(10018):545-557.
[10]Swartz MA,Iida N,Roberts EW,et al.Tumor microenvironment complexity:Emerging roles in cancer therapy[J].Cancer Res,2012,72(10):2473-2480.
[11]张百红,岳红云.肿瘤微环境与肿瘤[J].国际肿瘤学杂志,2013,40(8):582-584.
[12]Senbanjo LT,Chellaiah MA.CD44:A multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells[J].Front Cell Dev Biol,2017,5:18.
[13]Porsch H,Bernert B,Mehi M,et al.Efficient TGFβ-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2[J].Oncogene,2013,32(37):4355-4365.
[14]Lataillade JJ,Albanese P,Uzan G.Implication of hyaluronic acid in normal and pathological angiogenesis.Application for cellular engineering[J].Ann Dermatol Venereol,2010,137 Suppl1:S15-22.
[15]Provenzano PP,Cuevas C,Chang AE,et al.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma[J].Cancer Cell,2012,21(3):418-429.
[16]Olive KP,Jacobetz MA,Davidson CJ,et al.Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer[J].Science,2009,324(5933):1457-1461.
[17]Hingorani SR,Harris WP,Beck JT,et al.Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer[J].Clin Cancer Res,2016,22(12):2848-2854.
[18]Ino Y,Yamazaki-Itoh R,Shimada K,et al.Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer[J].Br J Cancer,2013,108(4):914-923.
[19]Zheng X,Turkowski K,Mora J,et al.Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy[J].Oncotarget,2017,8(29):48436-48452.
[20]Hertzer KM,Donald GW,Hines OJ.CXCR2:A target for pancreatic cancer treatment?[J].Expert Opin Ther Targets,2013,17(6):667-680.
[21]Sanford DE,Belt BA,Panni RZ,et al.Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer:A role for targeting the CCL2/CCR2 axis[J].Clin Cancer Res,2013,19(13):3404-3415.
[22]Nywening TM,Wang-Gillam A,Sanford DE,et al.Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer:A single-centre,open-label,dose-finding,non-randomised,phase 1b trial[J].Lancet Oncol,2016,17(5):651-662.
[23]Qing X,Rogers L,Mortha A,et al.iRhom2 regulates CSF1R cell surface expression and non-steady state myelopoiesis in mice[J].Eur J Immunol,2016,46(12):2737-2748.
[24]Mitchem JB,Brennan DJ,Knolhoff BL,et al.Targeting tumorinfiltrating macrophages decreases tumor-initiating cells,relieves immunosuppression,and improves chemotherapeutic responses[J].Cancer Res,2013,73(3):1128-1141.
[25]Wang HW,Joyce JA.Alternative activation of tumor-associated macrophages by IL-4:Priming for protumoral functions[J].Cell Cycle,2010,9(24):4824-4835.
[26]Lu C,Paschall AV,Shi H,et al.The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion[J].J Natl Cancer Inst,2017,109(6).
[27]Feig C,Jones JO,Kraman M,et al.Targeting CXCL12 from FAPexpressing carcinoma-associated fibroblasts synergizes with antiPD-L1 immunotherapy in pancreatic cancer[J].Proc Natl Acad Sci U S A,2013,110(50):20212-20217.
[28]Nomi T,Sho M,Akahori T,et al.Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer[J].Clin Cancer Res,2007,13(7):2151-2157.
[29]Agarwal A,Saif MW.KRAS in pancreatic cancer[J].JOP,2014,15(4):303-305.
[30]Eibl G,Rozengurt E.KRAS,YAP,and obesity in pancreatic cancer:A signaling network with multiple loops[J].Semin Cancer Biol,2017.
[31]Eser S,Schnieke A,Schneider G,et al.Oncogenic KRAS signalling in pancreatic cancer[J].Br J Cancer,2014,111(5):817-822.