Pujarini Dash1, Souvik Ghatak1, Geriolda Topi1, Shakti Ranjan Satapathy1, Fredrik Ek2, Karin Hellman2, Roger Olsson2, Lubna M Mehdawi1, Anita Sjölander3. 1. Division of Cell Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden. 2. Chemical Biology & Therapeutics Group, Department of Experimental Medical Science, Lund University, Lund, Sweden. 3. Division of Cell Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden. Anita.Sjolander@med.lu.se.
Abstract
BACKGROUND: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC. METHODS: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression. RESULTS: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model. CONCLUSION: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells.
BACKGROUND: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC. METHODS: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression. RESULTS: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model. CONCLUSION: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells.
Authors: John Burn; Anne-Marie Gerdes; Finlay Macrae; Jukka-Pekka Mecklin; Gabriela Moeslein; Sylviane Olschwang; Diane Eccles; D Gareth Evans; Eamonn R Maher; Lucio Bertario; Marie-Luise Bisgaard; Malcolm G Dunlop; Judy W C Ho; Shirley V Hodgson; Annika Lindblom; Jan Lubinski; Patrick J Morrison; Victoria Murday; Raj Ramesar; Lucy Side; Rodney J Scott; Huw J W Thomas; Hans F Vasen; Gail Barker; Gillian Crawford; Faye Elliott; Mohammad Movahedi; Kirsi Pylvanainen; Juul T Wijnen; Riccardo Fodde; Henry T Lynch; John C Mathers; D Timothy Bishop Journal: Lancet Date: 2011-10-27 Impact factor: 79.321