title: Biological significance of tumor budding at the invasive front of human             colorectal carcinoma cells.
abstract: At the invasive front of colorectal carcinoma (CRC), the existence of tumor budding (TB), the detachment and migration of small clusters of tumor cells from the neoplastic epithelium, correlates with high incidence of local invasion and distant metastasis; however, the molecular background of TB is still unknown. In human CRC-derived SW480 cells, CD133+ cells showed cancer stem cell (CSC)-like properties, high tumorigenicity and pluripotency. By a comparative study of gene expression between CD133+ and CD133- SW480 cells, high sensitivity against transforming growth factor-β (TGF-β) was suggested in CD133+ SW480 cells. Interestingly, treatment with recombinant TGF-β1 increased the numbers of cells expressing CD133 and SNAI1. Furthermore, in CD133- SW480 cells, the SNAI1-induced epithelial-mesenchymal transition (EMT) restored the population of CD133+ cells and increased tumorigenicity, cell motility/invasiveness and matrix metalloproteinase 2 (MMP2) expression. In stage II CRC tissues, TB was associated with increased levels of SNAI1 expression as well as high incidence of metachronous lymph node metastasis post-surgical resection. These findings suggest that TGF-β regulates not only the induction of EMT but also the restoration of CSCs in CRC. The tumor microenvironment at the invasive front is important for the formation of tumor buds in CRC.
authors.affiliation: Division of Pathology, Department of Pathology, Kobe University                     Graduate School of Medicine, Kobe, Japan.
authors.lastname: Yusra
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokozaki
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014746:Vimentin / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C513384:CDH1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D015820:Cadherins; D006023:Glycoproteins; D018398:Homeodomain Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014746:Vimentin