Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression
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Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression. / Kemper, Marius; Schiecke, Alina; Maar, Hanna; Nikulin, Sergey; Poloznikov, Andrey; Galatenko, Vladimir; Tachezy, Michael; Gebauer, Florian; Lange, Tobias; Riecken, Kristoffer; Tonevitsky, Alexander; Aigner, Achim; Izbicki, Jakob; Schumacher, Udo; Wicklein, Daniel.
in: J EXP CLIN CANC RES, Jahrgang 40, Nr. 1, 26.06.2021, S. 214.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression
AU - Kemper, Marius
AU - Schiecke, Alina
AU - Maar, Hanna
AU - Nikulin, Sergey
AU - Poloznikov, Andrey
AU - Galatenko, Vladimir
AU - Tachezy, Michael
AU - Gebauer, Florian
AU - Lange, Tobias
AU - Riecken, Kristoffer
AU - Tonevitsky, Alexander
AU - Aigner, Achim
AU - Izbicki, Jakob
AU - Schumacher, Udo
AU - Wicklein, Daniel
PY - 2021/6/26
Y1 - 2021/6/26
N2 - BACKGROUND: Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.METHODS: Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.RESULTS: The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.CONCLUSION: Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
AB - BACKGROUND: Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.METHODS: Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.RESULTS: The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.CONCLUSION: Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
UR - https://doi.org/10.1186/s13046-021-01946-2
U2 - 10.1186/s13046-021-01946-2
DO - 10.1186/s13046-021-01946-2
M3 - SCORING: Journal article
C2 - 34174926
VL - 40
SP - 214
JO - J EXP CLIN CANC RES
JF - J EXP CLIN CANC RES
SN - 1756-9966
IS - 1
ER -