Carcinoma cells induce lumen filling and EMT in epithelial cells through soluble E-cadherin-mediated activation of EGFR.
In epithelial cancers, carcinoma cells coexist with normal cells. Although it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression, it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a three-dimensional co-culture system comprising non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induce preneoplastic lumen filling and epithelial-mesenchymal transition (EMT) in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin (encoded by CDH1) from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation, resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway and triggered EMT through the sustained activation of the AKT pathway. Although it is known that sE-cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results, for the first time, demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells, which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells.
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA Nemours Center for Childhood Cancer Research, Department of Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
Pratima U
PU
Patil
Nemours Center for Childhood Cancer Research, Department of Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
Julia
J
D'Ambrosio
Thoracic and Esophageal disease, Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Landon J
LJ
Inge
Nemours Center for Childhood Cancer Research, Department of Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
Robert W
RW
Mason
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA Therapy Architects, LLC, 2700, Silverside Road, Wilmington, DE 19810, USA raj@therapyarchitects.com.
Ayyappan K
AK
Rajasekaran
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9
EGFR; MMP-9; Soluble E-cadherin; Transdifferentiation