Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence.
Cyclooxygenase-2 and prostaglandin E(2) (PGE(2)) levels are increased in colorectal cancers and a subset of adenomas. PGE(2) signaling through the EP4 receptor has previously been associated with colorectal tumorigenesis. However, changes in EP4 expression during adenoma to carcinoma progression have not been investigated, neither has whether levels of EP4 influence important markers of malignant potential, such as anchorage-independent growth or the tumors growth response to PGE(2). We report using immunohistochemistry that in vivo EP4 receptor protein expression was increased in colorectal cancers (100%) as well as adenomas (36%) when compared with normal colonic epithelium. EP4 expression was also higher in colorectal carcinoma compared with adenoma cell lines and increased with in vitro models of tumor progression. Adenoma (PC/AA/C1 and RG/C2) and carcinoma cell lines (HT29) were growth stimulated by PGE(2) up to 0.5 micromol/L. However, although carcinoma and transformed adenoma (PC/AA/C1SB10C, a transformed derivative of PC/AA/C1) cells remain stimulated by higher doses of PGE(2) (10 micromol/L), the adenoma cell lines were inhibited. Interestingly, enforced expression of EP4 in the adenoma cell line, RG/C2, resulted in stimulation of growth by 10 micromol/L PGE(2) and promoted anchorage-independent growth. Both in vivo and in vitro data from this study suggest that increased EP4 receptor expression is important during colorectal carcinogenesis. We propose that high levels of PGE(2) in a tumor microenvironment would select for cells with increased EP4 expression, and that the EP4 receptor may therefore represent an important target for colorectal cancer prevention and treatment.
Chell
Simon D
SD
Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Science, Bristol University, UK.
Witherden
Ian R
IR
Dobson
Richard R
RR
Moorghen
Morganaden
M
Herman
Andrew A
AA
Qualtrough
David
D
Williams
Ann C
AC
Paraskeva
Christos
C
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015232:Dinoprostone / Q000494:pharmacology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone