Ager Eleanor I, Kozin Sergey V, Kirkpatrick Nathaniel D, Seano Giorgio, Kodack David P, Askoxylakis Vasileios, Huang Yuhui, Goel Shom, Snuderl Matija, Muzikansky Alona, Finkelstein Dianne M, Dransfield Daniel T, Devy Laetitia, Boucher Yves, Fukumura Dai, Jain Rakesh K
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston MA (EIA, SVK, NDK, GS, DPK, VA, YH, SG, MS, YB, DF, RKJ); Department of Surgery (Austin Health), University of Melbourne, Studley Road Heidelberg, VIC, Australia (EIA); Novogen, Hornsby, NSW, Australia (EIA); Novartis Institutes for BioMedical Research, Cambridge, MA (NDK); Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia (SG); Department of Biostatistics, Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts (AM, DMF); Department of Pathology, NYU Langone Medical Center and Medical School, New York, NY (MS); Dyax Corp., Burlington, MA (DTD, LD); Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (SG); Tokai Pharmaceuticals, Inc., Cambridge, MA (DTD); Merck Serono S. A., Geneva, Switzerland (LD).
J Natl Cancer Inst. 2015 Feb 20;107(4). doi: 10.1093/jnci/djv017. Print 2015 Apr.
Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects.
Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided.
DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm(3): control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors.
MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors.
基质金属蛋白酶（MMP）14可能通过血管和免疫调节作用介导肿瘤进展。
将原位小鼠乳腺肿瘤（4T1和E0771，分别具有高和低MMP14表达；每组n = 5 - 10）用抗MMP14抑制性抗体（DX - 2400）、IgG对照、分割放射治疗或它们的组合进行处理。我们评估了原发性肿瘤生长、转化生长因子β（TGFβ）和诱导型一氧化氮合酶（iNOS）表达、巨噬细胞表型和血管参数。采用带有重复观测值的线性混合模型，以及Mann - Whitney检验或经Bonferroni事后调整的方差分析来确定统计学显著性。所有统计检验均为双侧检验。
与IgG对照处理相比，DX - 2400抑制肿瘤生长，增加巨噬细胞数量，并使巨噬细胞表型向抗肿瘤的M1样转变。这些效应与活性TGFβ和SMAD2/3信号传导的减少相关。DX - 2400还短暂增加iNOS表达和肿瘤灌注，降低组织缺氧（中位面积百分比：对照，20.2%，四分位间距（IQR）= 6.4% - 38.9%；DX - 2400：1.2%，IQR = 0.2% - 3.2%，P = 0.044），并在4T1模型中协同增强放射治疗（生长至800mm³所需天数：对照，12天，IQR = 9 - 13天；DX - 2400加放射治疗，29天，IQR = 26 - 30天，P < 0.001）。选择性iNOS抑制剂1400W消除了DX - 2400对血管灌注和放射治疗的影响。另一方面，DX - 2400在E077肿瘤中不能诱导iNOS表达或与放射治疗协同作用。
MMP14阻断降低免疫抑制性TGFβ，使巨噬细胞极化至抗肿瘤表型，增加iNOS，并改善肿瘤灌注，导致原发性肿瘤生长减少并增强对放射治疗的反应，尤其是在高MMP14表达的肿瘤中。
