Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells - Implication of inflammation-associated carcinogenesis and tumor progression
Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells - Implication of inflammation-associated carcinogenesis and tumor progression
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DOI：
10.1016/s0002-9440(10)63580-8
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发表时间：
2003-12-01
影响因子：
6
通讯作者：
Hosokawa, M
中科院分区：
文献类型：
--
作者：
Tazawa, H;Okada, F;Hosokawa, M
QR-32肿瘤细胞是一种来源于鼠纤维肉瘤的克隆，当注射到同系C57 BL/6小鼠中时，其致瘤性差且无转移性。然而，一旦它们与异物（明胶海绵）共同植入皮下部位后在体内生长，它们就会转化为高度恶性的肿瘤。明胶海绵诱导的早期炎症参与转化，组织学分析显示主要是中性粒细胞浸润。本研究的目的是确定浸润性中性粒细胞的耗竭是否对肿瘤进展有任何影响。腹膜内施用单克隆抗粒细胞抗体RB 6 - 8 C5（RB 6），耗尽来自QR-32肿瘤细胞和明胶海绵共植入的小鼠中的外周血循环和局部发炎部位的中性粒细胞。RB 6施用不抑制肿瘤发展或QR-32肿瘤细胞的生长。相比之下，与从给予对照大鼠IgG或盐水的小鼠中获得的肿瘤细胞系相比，从给予RB 6的小鼠中建立的肿瘤细胞系显示转移发生率显着降低。当在早期阶段（从植入后第2天至第6天）给予RB 6时，转移能力被显著抑制;然而，在中期阶段（从第6天至第14天）或晚期阶段（从第14天至第22天）给予RB 6不影响转移能力。我们通过使用整合素β（2）敲除小鼠证实了这一现象，这些小鼠的炎症部位中性粒细胞浸润受损。在基因敲除小鼠中，中性粒细胞几乎不浸润到明胶海绵中，并且与野生型小鼠或裸鼠相比，肿瘤显示出显著抑制的转移表型。免疫组织化学分析表明，8-羟基-2 '-脱氧鸟苷和硝基酪氨酸的表达与中性粒细胞的存在平行。这些结果表明，炎症，特别是当中性粒细胞浸润到肿瘤组织中时，对于良性肿瘤细胞获得转移表型是主要重要的。
QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin beta(2) knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2'-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.