title: Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production.
abstract: S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Wei-Yu
authors: WY
authors: Fang
authors: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Yi-Wen
authors: YW
authors: Chen
authors: Department of Otolaryngology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
authors: Jenn-Ren
authors: JR
authors: Hsiao
authors: Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
authors: Chiang-Shin
authors: CS
authors: Liu
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Yi-Zih
authors: YZ
authors: Kuo
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Yi-Ching
authors: YC
authors: Wang
authors: Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
authors: Kung-Chao
authors: KC
authors: Chang
authors: Department of Otolaryngology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.|Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
authors: Sen-Tien
authors: ST
authors: Tsai
authors: Department of Otolaryngology, National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
authors: Mei-Zhu
authors: MZ
authors: Chang
authors: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Siao-Han
authors: SH
authors: Lin
authors: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
authors: Li-Wha
authors: LW
authors: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D040502:Calgranulin B / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D040502:Calgranulin B; D015850:Interleukin-6; D016328:NF-kappa B; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: IL-6; S100A9; macrophages; oral cancer; recurrence