Department of Surgery, Jikei University School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, Jikei University School of Medicine, Tokyo, Japan.
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan; Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
Surgery. 2019 Dec;166(6):991-996. doi: 10.1016/j.surg.2019.05.044. Epub 2019 Jul 26.
Liver metastasis is a common problem after pancreatectomy for pancreatic cancer. In pancreatic cancer cells, nuclear factor-κB is activated constitutively. Nuclear factor-κB activates matrix metalloproteinase-2/9, which plays an important role in cancer metastasis. Because the serine protease inhibitor FUT-175 suppresses nuclear factor-κB, we hypothesized that perioperative treatment with FUT-175 for pancreatic cancer may help to prevent liver metastasis.
We compared in vitro cell viability, cell invasiveness, nuclear factor-κB signaling, and the expression levels of matrix metalloproteinase signals between the control group (C group) and the FUT-175 group (F group) using the murine pancreatic cancer cells PAN02. In addition, we evaluated the in vivo effect of pretreatment with FUT-175 using an established model of liver metastasis in mice. Metastatic liver lesions were assessed with magnetic resonance imaging. Liver recurrence and overall survival were evaluated. Also, the antimetastatic effect of systemic administration of FUT-175 was examined.
FUT-175 did not suppress the cell viability of PAN02 cells at or after 24 hours of treatment (P > .05); however, cell invasion was suppressed in the F group compared with the C group (P < .05). The levels of nuclear factor-κB activation, membrane type-1 (MT-1) matrix metalloproteinase (MMP)/matrix metalloproteinase-14 (MMP-14), and matrix metalloproteinase-2/9 (MMP-2/9) were lower in the F group compared with the C group. In vivo, both disease-free and overall survivals were prolonged in the F group compared with the C group. Systemic administration was also effective in suppressing the number of metastases.
Perioperative treatment with FUT-175 may help to prevent early liver metastasis after pancreatectomy for pancreatic cancer.
胰腺癌手术后肝转移是常见问题。在胰腺癌细胞中，核因子-κB 持续激活。核因子-κB 激活基质金属蛋白酶-2/9，在癌症转移中发挥重要作用。由于丝氨酸蛋白酶抑制剂 FUT-175 能抑制核因子-κB，我们推测胰腺癌围手术期应用 FUT-175 治疗可能有助于预防肝转移。
我们使用小鼠胰腺癌细胞 PAN02 比较了对照组（C 组）和 FUT-175 组（F 组）的体外细胞活力、细胞侵袭性、核因子-κB 信号和基质金属蛋白酶信号的表达水平。此外，我们使用建立的小鼠肝转移模型评估了 FUT-175 预处理的体内效果。采用磁共振成像评估转移灶。评估肝复发和总生存情况。还检查了 FUT-175 全身给药的抗转移作用。
FUT-175 在治疗后 24 小时内不会抑制 PAN02 细胞的细胞活力（P>.05）；然而，F 组的细胞侵袭性较 C 组降低（P<.05）。F 组核因子-κB 激活、膜型 1（MT-1）基质金属蛋白酶（MMP）/基质金属蛋白酶-14（MMP-14）和基质金属蛋白酶-2/9（MMP-2/9）水平均低于 C 组。在体内，F 组的无病生存和总生存均长于 C 组。全身给药也能有效抑制转移灶的数量。
胰腺癌手术后围手术期应用 FUT-175 可能有助于预防肝转移。
