title: WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma.
abstract: Esophageal cells overexpressing epidermal growth factor receptor (EGFR) and TP53 mutation can invade into the extracellular matrix when grown in 3D-organotypic cultures (OTC) and mimic early invasion in esophageal squamous cell carcinoma (ESCC). We have performed laser capture microdissection with RNA microarray analysis on the invasive and non-invasive tumor cells of p53(R175H)-overexpressing OTC samples to determine candidate genes facilitating tumor invasion. WNT10A was found to be >4-fold upregulated in the invasive front. Since WNT10A is also prominently upregulated during placode promotion in hair follicle development, a process that requires epithelial cells to thicken and elongate, in order to allow downward growth, we hypothesized that WNT10A may be important in mediating a similar mechanism of tumor cell invasion in ESCC. We have found that WNT10A expression is significantly upregulated in human ESCC, when compared with normal adjacent tissue. Furthermore, high WNT10A expression levels correlate with poor survival. Interestingly, we observe that WNT10A is expressed early in embryogenesis, but is reduced dramatically postnatally. We demonstrate that overexpression of WNT10a promotes migration and invasion, and proliferation of transformed esophageal cells. Lastly, we show that WNT10A overexpression induces a greater CD44(High)/CD24(Low) population, which are putative markers of cancer stem cells, and increases self-renewal capability. Taken together, we propose that WNT10A acts as an oncofetal factor that is highly expressed and may promote proper development of the esophagus. During tumorigenesis, it is aberrantly overexpressed in order to promote ESCC migration and invasion, and may be linked to self-renewal of a subset of ESCC cells.
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Apple
authors: A
authors: Long
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Véronique
authors: V
authors: Giroux
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Kelly A
authors: KA
authors: Whelan
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Kathryn E
authors: KE
authors: Hamilton
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Marie-Pier
authors: MP
authors: Tétreault
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Koji
authors: K
authors: Tanaka
authors: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and.
authors: Ju-Seog
authors: JS
authors: Lee
authors: Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Andres J
authors: AJ
authors: Klein-Szanto
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Hiroshi
authors: H
authors: Nakagawa
authors: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA anil2@mail.med.upenn.edu.
authors: Anil K
authors: AK
authors: Rustgi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004947:Esophagus / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C484142:WNT10A protein, human; D051153:Wnt Proteins