Takeuchi Taku, Hisanaga Michiyoshi, Nagao Mitsuo, Ikeda Naoya, Fujii Hisao, Koyama Fumikazu, Mukogawa Tomohide, Matsumoto Hiroshi, Kondo Shunya, Takahashi Chiaki, Noda Makoto, Nakajima Yoshiyuki
Department of Surgery, Nara Medical University, Kashihara-city, Nara, Japan.
Clin Cancer Res. 2004 Aug 15;10(16):5572-9. doi: 10.1158/1078-0432.CCR-03-0656.
RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue.
The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically.
RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score > or = MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression.
RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.
RECK是一种膜锚定的基质金属蛋白酶（MMP）调节剂，在健康组织中广泛表达，而在许多肿瘤衍生细胞系中表达水平较低。对小鼠和培养细胞的研究表明，RECK表达的恢复可抑制肿瘤侵袭、转移和血管生成。然而，这些发现的临床相关性仍有待充分记录。在此，我们检测了RECK及其靶点之一MMP-9在结直肠癌组织中的表达。
采用免疫组织化学技术检测53例患者结直肠癌样本中RECK和MMP-9的表达水平。对每种蛋白质的表达水平进行评分，并根据这些评分将患者分为两组。在33例病例中，我们进行了明胶酶谱分析以评估MMP-2和MMP-9的激活程度。还通过组织学评估了微血管密度和血管内皮生长因子（VEGF）的表达。
53例标本中有30例（56.6%）检测到RECK蛋白。重要的是，肿瘤表达相对高水平RECK的患者（高RECK组）的复发风险明显低于肿瘤表达相对低水平RECK的患者（低RECK组；P = 0.011）。此外，RECK占优势（RECK评分≥MMP-9评分）的患者的复发率明显低于MMP-9占优势的患者（P = 0.0003）。多变量分析显示，RECK/MMP-9平衡是一个独立的预后因素（P = 0.0122）。VEGF的表达和微血管密度与RECK表达水平呈负相关。
RECK/MMP-9平衡是结直肠癌的一个有价值的预后指标。我们的数据还表明，RECK可能通过限制肿瘤组织中VEGF的可用性来抑制肿瘤血管生成。
