Jayatilaka Hasini, Umanzor Fatima G, Shah Vishwesh, Meirson Tomer, Russo Gabriella, Starich Bartholomew, Tyle Pranay, Lee Jerry S H, Khatau Shyam, Gil-Henn Hava, Wirtz Denis
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD, USA.
Oncotarget. 2018 Aug 24;9(66):32556-32569. doi: 10.18632/oncotarget.25863.
Matrix metalloproteinases (MMPs) may play a critical role in metastatic cancers, yet multiple human clinical trials targeting MMPs have surprisingly failed. Cancer cell density changes dramatically during the early growth of a primary tumor and during the early seeding steps of secondary tumors and has been implicated in playing an important role in regulating metastasis and drug resistance. This study reveals that the expression of MMPs is tightly regulated by local tumor cell density through the synergistic signaling mechanism of Interleukin 6 (IL-6) and Interleukin 8 (IL-8) via the JAK2/STAT3 complex. Local tumor cell density also plays a role in the responsiveness of cells to matrix metalloproteinases inhibitors (MMPI), such as Batimastat, Marimastat, Bryostatin I, and Cipemastat, where different migratory phenotypes are observed in low and high cell density conditions. Cell density-dependent MMP regulation can be directly targeted by the simultaneous inhibition of IL-6 and IL-8 receptors via Tocilizumab and Reparixin to significantly decrease the expression of MMPs in mouse xenograft models and decrease effective metastasis. This study reveals a new strategy to decrease MMP expression through pharmacological intervention of the cognate receptors of IL-6 and IL-8 to decrease metastatic capacity of tumor cells.
基质金属蛋白酶（MMPs）可能在转移性癌症中起关键作用，但多项针对MMPs的人体临床试验却出人意料地失败了。在原发性肿瘤的早期生长过程以及继发性肿瘤的早期播种步骤中，癌细胞密度会发生显著变化，并且被认为在调节转移和耐药性方面发挥重要作用。本研究表明，MMPs的表达通过白细胞介素6（IL-6）和白细胞介素8（IL-8）经由JAK2/STAT3复合体的协同信号机制受到局部肿瘤细胞密度的严格调控。局部肿瘤细胞密度在细胞对基质金属蛋白酶抑制剂（MMPI）（如batimastat、marimastat、bryostatin I和cipemastat）的反应性中也起作用，在低细胞密度和高细胞密度条件下观察到不同的迁移表型。通过托珠单抗和瑞帕霉素同时抑制IL-6和IL-8受体，可以直接靶向细胞密度依赖性的MMP调节，从而在小鼠异种移植模型中显著降低MMPs的表达并减少有效转移。本研究揭示了一种通过对IL-6和IL-8的同源受体进行药物干预来降低MMP表达，从而降低肿瘤细胞转移能力的新策略。
