T umor tissues are comprised of tumor cells and stromal cells, including vascular cells, immune cells, and fbroblasts [1]. Crosstalk between tumor and non-tumor cells creates a specialized tumor microenvi- ronment that determines the behavior of the tumor [2]. An abundant deposition of extracellular matrix (ECM), a major component of the tumor microenvi- ronment, is associated with cancer progression. Since ECM remodeling is essential for multistep tumor growth, including invasion and metastasis, a number of studies have focused on matrix metalloproteinases (MMPs), a family of major ECM proteases [3]. ‘A dis- integrin-like and metalloproteinase with thrombospon- din type 1 motif (ADAMTS)’-family proteases were identifed as novel MMPs in a colon cancer cell line [4]. Te 19 members of the ADAMTS family play roles in various diseases, including cancer [5-9]. Previous studies have demonstrated that, among the ADAMTS family members, ADAMTS4 and ADAMTS5 — both known as aggrecanases because they degrade aggrecan [10] — are dysregulated during cancer development [11 , 12]. Although ADAMTS4 and ADAMTS5 are well characterized as critical factors for osteoarthritis (as Acta Med. Okayama, 2018 Vol. 2, No. 3, pp. 25ô266 $opyriHht⡥  by 0kayama 6OiWersity .eEical 4chool. http: // escholarship.lib.okayama- u.ac.jp / amo/ Original Article Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth Keiichi Asano a,b , Midori Edamatsu a , Omer F. Hatipoglu b , Junko Inagaki c , Mitsuaki Ono a , Takashi Ohtsuki b , Toshitaka Oohashi a , and Satoshi Hirohata b ＊ Departments of a Molecular Biology and Biochemistry and c Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, b Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan 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 Adamts4 LacZ/LacZ and Adamts5 LacZ/LacZ knockout mice. Interestingly, the Adamts4 LacZ/LacZ mice showed enhanced tumor growth compared to wild-type mice at 5-, 10- and 12-days post-inoculation, whereas the Adamts5 LacZ/LacZ mice did not show signifcant diferences in tumor growth. We next examined LacZ distribution in LLC tumor-bearing Adamts4 LacZ/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 Adamts4 LacZ/LacZ mice. Interestingly, β-gal-positive signals were not co-localized with biglycan afer 10 days post-inoculation, excluding the biglycan cleavage by host-derived ADAMTS4. Taken together, these fndings illustrate that host-derived ADAMTS4 was expressed at the tumor vessels and was associated with early-stage tumor growth. Key words: ADAMTS, metalloproteinase, extracellular matrix, tumor microenvironment, mouse Received November 2, 2017 ; accepted December 5, 2017. ＊ Corresponding author. Phone : +81-86-235-6897; Fax : +81-86-235-6897 E-mail : hirohas@cc.okayama-u.ac.jp (S. Hirohata) Confict of Interest Disclosures: No potential confict of interest relevant to this article was reported.