Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis

Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis a...

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Veröffentlicht in:Cancer cell Jg. 27; H. 4; S. 561
Hauptverfasser: von Karstedt, Silvia, Conti, Annalisa, Nobis, Max, Montinaro, Antonella, Hartwig, Torsten, Lemke, Johannes, Legler, Karen, Annewanter, Franka, Campbell, Andrew D, Taraborrelli, Lucia, Grosse-Wilde, Anne, Coy, Johannes F, El-Bahrawy, Mona A, Bergmann, Frank, Koschny, Ronald, Werner, Jens, Ganten, Tom M, Schweiger, Thomas, Hoetzenecker, Konrad, Kenessey, Istvan, Hegedüs, Balazs, Bergmann, Michael, Hauser, Charlotte, Egberts, Jan-Hendrik, Becker, Thomas, Röcken, Christoph, Kalthoff, Holger, Trauzold, Anna, Anderson, Kurt I, Sansom, Owen J, Walczak, Henning
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 13.04.2015
Schlagworte:
Animals
Apoptosis - genetics
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Cell Proliferation - genetics
Disease Progression
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, SCID
Models, Biological
Neoplasm Invasiveness - genetics
Prognosis
Proto-Oncogene Proteins p21(ras) - genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand - physiology
ISSN:1878-3686, 1878-3686
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Beschreibung
Zusammenfassung:Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2015.02.014