Tumor budding at the invasive front of colorectal cancer may not be associated with the epithelial-mesenchymal transition.
Tumor budding is thought to reflect the epithelial-mesenchymal transition (EMT). However, the molecular mechanism linking tumor buds and the EMT remains unclear. Here, we examined the induction of tumor budding and EMT and their association with EMT-related proteins (ZEB1, TWIST, SNAIL, and SLUG) in colorectal cancer (CRC). Immunohistochemical expression of pan-cytokeratin was examined for identification of tumor budding in 101 CRCs. Grading of tumor budding was classified into low- and high-grade groups. Tissue microarray was conducted to identify tumor budding sites. The expression of E-cadherin, ZEB1, TWIST, SNAIL, and SLUG was examined in areas of tumor budding and the surrounding tumor stroma using a double-immunostaining method. Specifically, pan-cytokeratin and EMT-related proteins were assessed by double immunostaining. Low or no expression of E-cadherin was found in areas of tumor budding. Moreover, ZEB1, TWIST, SNAIL, and SLUG were not expressed in regions of tumor budding. However, the expression level of ZEB1 in the stromal cells surrounding tumor budding was significantly more frequent than that of TWIST, SNAI, and SLUG. In addition, the expression of EMT-related proteins in surrounding stromal cells was significantly greater in areas of high-grade tumor budding than in low-grade areas. Our present results suggest that EMT-related proteins play a minor role in forming tumor buds. In addition, our findings suggest the existence of subtypes of stromal cells in CRC with phenotypical and functional heterogeneity.
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Noriyuki
N
Yamada
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan. Electronic address: tsugai@iwate-med.ac.jp.
Tamotsu
T
Sugai
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Makoto
M
Eizuka
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Koudai
K
Tsuchida
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Ryo
R
Sugimoto
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Yoshiharu
Y
Mue
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Masamichi
M
Suzuki
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Mitsumasa
M
Osakabe
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Noriyuki
N
Uesugi
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Kazuyuki
K
Ishida
Department of Surgery, School of Medicine, Iwate Medical University, Morioka 020-8505, Japan.
Kouki
K
Otsuka
Division of Gastroenterology, Department of Internal Medicine, Morioka 020-8505, Japan.
Takayuki
T
Matsumoto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000032:analysis; D010641:Phenotype; D000071250:Snail Family Transcription Factors / Q000032:analysis; D017154:Stromal Cells / Q000737:chemistry / Q000473:pathology; D046888:Tissue Array Analysis; D051879:Twist-Related Protein 1 / Q000032:analysis; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000032:analysis
D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D007633:Keratins
Colorectal cancer; Epithelial-mesenchymal transition; TWIST; Tumor budding; ZEB1