Asano Keiichi, Edamatsu Midori, Hatipoglu Omer F, Inagaki Junko, Ono Mitsuaki, Ohtsuki Takashi, Oohashi Toshitaka, Hirohata Satoshi
Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Acta Med Okayama. 2018 Jun;72(3):257-266. doi: 10.18926/AMO/56071.
Several research groups demonstrated that 'a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS)'-family proteases play roles in cancer progression. However, the origins and contributions of these proteases are not known. Here, we demonstrate an association between host-produced ADAMTS4 and early-stage tumor growth. Murine Lewis lung carcinoma (LLC) tumors showed marked expressions of Adamts4 and Adamts5. We examined the contributions and distributions of host-derived Adamts4 and Adamts5 on tumor growth, using Adamts4LacZ/LacZ and Adamts5LacZ/LacZ knockout mice. Interestingly, the Adamts4LacZ/LacZ mice showed enhanced tumor growth compared to wild-type mice at 5-, 10- and 12-days post-inoculation, whereas the Adamts5LacZ/LacZ mice did not show significant differences in tumor growth. We next examined LacZ distribution in LLC tumor-bearing Adamts4LacZ/LacZ mice by β-galactosidase (β-gal) staining. We found that the β-gal-positive signals were strictly localized at the interior areas of the tumor at 10 days post-inoculation. Multiple staining demonstrated that most of the β-gal-positive cells were localized at the tumor vasculature in Adamts4LacZ/LacZ mice. Interestingly, β-gal-positive signals were not co-localized with biglycan after 10 days post-inoculation, excluding the biglycan cleavage by host-derived ADAMTS4. Taken together, these findings illustrate that host-derived ADAMTS4 was expressed at the tumor vessels and was associated with early-stage tumor growth.
多个研究小组证明，“含血小板反应蛋白基序的解聚素样金属蛋白酶（ADAMTS）”家族蛋白酶在癌症进展中发挥作用。然而，这些蛋白酶的来源和作用尚不清楚。在此，我们证明宿主产生的ADAMTS4与肿瘤早期生长之间存在关联。小鼠Lewis肺癌（LLC）肿瘤显示Adamts4和Adamts5有明显表达。我们使用Adamts4LacZ/LacZ和Adamts5LacZ/LacZ基因敲除小鼠，研究了宿主来源的Adamts4和Adamts5对肿瘤生长的作用及分布情况。有趣的是，与野生型小鼠相比，Adamts4LacZ/LacZ小鼠在接种后5天、10天和12天肿瘤生长加快，而Adamts5LacZ/LacZ小鼠的肿瘤生长没有显著差异。接下来，我们通过β-半乳糖苷酶（β-gal）染色检查了LLC荷瘤Adamts4LacZ/LacZ小鼠中LacZ的分布。我们发现，接种后10天，β-gal阳性信号严格定位在肿瘤内部区域。多重染色显示，在Adamts4LacZ/LacZ小鼠中，大多数β-gal阳性细胞位于肿瘤血管处。有趣的是，接种后10天，β-gal阳性信号与双糖链蛋白聚糖不共定位，排除了宿主来源的ADAMTS4对双糖链蛋白聚糖的切割作用。综上所述，这些发现表明宿主来源的ADAMTS4在肿瘤血管处表达，并与肿瘤早期生长有关。
