Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion.

Takamune Achiha,Haruhiko Kishima,Betty Luu,Kanji Mori,Michael D Taylor,Takehiro Uda,Masayuki Mano,Atsuko Harada,Namiko Nishida,Naohiro Tsuyuguchi,Yoshinori Kodama,Daisuke Sakamoto,Yonehiro Kanemura,Akihiro Inoue,Junya Fukai,Noriyuki Kijima,Naoki Kagawa,Manabu Kinoshita,Yusuke Tomogane,Ema Yoshioka,Masahiro Nonaka,Tomoko Shofuda,Daisuke Kanematsu,Yasunori Fujimoto,T Yamanaka ,Keiichiro Ishibashi

doi:10.1371/journal.pone.0243272

Abstract

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.

Highlights

Medulloblastoma (MB) is the most common pediatric malignant brain tumor of the cerebellum
activated leukocyte cell adhesion molecule (ALCAM) expression correlated with the WNT molecular subgroup of MB
We investigated ALCAM expression in 45 human formalin-fixed paraffin-embedded (FFPE) MB specimens using immunohistochemistry

Summary

Introduction

Medulloblastoma (MB) is the most common pediatric malignant brain tumor of the cerebellum. Patients with MB are clinically stratified into average or high-risk groups according to their age, metastatic status, and the presence of residual tumor following resection [1]. Integrated genomic analysis of MB showed that MB consists of at least four distinct molecular subgroups, WNT, SHH, Group 3, and Group 4 [2,3,4] This molecular classification of MB reflects distinct demographics and clinical features, including prognosis, transcriptomes, and genetics [2,3,4,5], and have been incorporated into the WHO classification of tumors of the central nervous system as revised in 2016 [6]. A further understanding of disease based on the molecular subgroups and the subsequent development of treatment strategies is necessary

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