RIPK1/RIPK3 promotes vascular permeability to allow tumor cell extravasation independent of its necroptotic function.
Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 1, 3 (RIPK1, RIPK3) and mixed lineage kinase domain-like protein (MLKL). The kinase of RIPK3 phosphorylates MLKL causing MLKL to form a pore-like structure, allowing intracellular contents to release and cell death to occur. Alternatively, RIPK1 and RIPK3 have been shown to regulate cytokine production directly influencing inflammatory immune infiltrates. Recent data suggest that necroptosis may contribute to the malignant transformation of tumor cells in vivo and we asked whether necroptosis may have a role in the tumor microenvironment altering the ability of the tumor to grow or metastasize. To determine if necroptosis in the tumor microenvironment could promote inflammation alone or by initiating necroptosis and thereby influencing growth or metastasis of tumors, we utilized a syngeneic tumor model of metastasis. Loss of RIPK3 in the tumor microenvironment reduced the number of tumor nodules in the lung by 46%. Loss of the kinase activity in RIPK1, a member of the necrosome also reduced tumor nodules in the lung by 38%. However, the loss of kinase activity in RIPK3 or the loss of MLKL only marginally altered the ability of tumor cells to form in the lung. Using bone marrow chimeras, the decrease in tumor nodules in the Ripk3-/-appeared to be due to the stromal compartment rather than the hematopoietic compartment. Transmigration assays showed decreased ability of tumor cells to transmigrate through the vascular endothelial layer, which correlated with decreased permeability in the Ripk3-/-mice after tumor injection. In response to permeability factors, such as vascular endothelial growth factor, RIPK3 null endothelial cells showed decreased p38/HSP27 activation. Taken together, our results suggest an alternative function for RIPK1/RIPK3 in vascular permeability leading to decreased number of metastasis.
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Kay
K
Hänggi
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Lazaros
L
Vasilikos
Biochemistry Center, Heidelberg University, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.
Aida Freire
AF
Valls
Biochemistry Center, Heidelberg University, Heidelberg, Germany.
Rosario
R
Yerbes
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Janin
J
Knop
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Lisanne M
LM
Spilgies
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Kristy
K
Rieck
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Tvisha
T
Misra
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
John
J
Bertin
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
Peter J
PJ
Gough
Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.
Thomas
T
Schmidt
Biochemistry Center, Heidelberg University, Heidelberg, Germany.
Carmen Ruiz
CR
de Almodòvar
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
W Wei-Lynn
WW
Wong
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000378:metabolism* / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse