Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.

2.50
Hdl Handle:
http://hdl.handle.net/10033/98457
Title:
Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.
Authors:
Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried
Abstract:
Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.
Affiliation:
Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany. jja@gbf.de
Citation:
Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. 2010, 120 (4):1151-64 J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
Apr-2010
URI:
http://hdl.handle.net/10033/98457
DOI:
10.1172/JCI37223
PubMed ID:
20237412
Type:
Article
Language:
en
ISSN:
1558-8238
Appears in Collections:
publications of the research group molecular Immunology (MOLI)

Full metadata record

DC FieldValue Language
dc.contributor.authorJablonska, Jadwigaen
dc.contributor.authorLeschner, Saraen
dc.contributor.authorWestphal, Kathrinen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorWeiss, Siegfrieden
dc.date.accessioned2010-05-11T10:39:18Z-
dc.date.available2010-05-11T10:39:18Z-
dc.date.issued2010-04-
dc.identifier.citationNeutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. 2010, 120 (4):1151-64 J. Clin. Invest.en
dc.identifier.issn1558-8238-
dc.identifier.pmid20237412-
dc.identifier.doi10.1172/JCI37223-
dc.identifier.urihttp://hdl.handle.net/10033/98457-
dc.description.abstractAngiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CD11ben
dc.subject.meshFemaleen
dc.subject.meshGenes, mycen
dc.subject.meshInterferon-betaen
dc.subject.meshKiller Cells, Naturalen
dc.subject.meshLung Neoplasmsen
dc.subject.meshMelanoma, Experimentalen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshNeovascularization, Pathologicen
dc.subject.meshNeutrophil Infiltrationen
dc.subject.meshNeutrophilsen
dc.subject.meshRadiation Toleranceen
dc.subject.meshSTAT3 Transcription Factoren
dc.titleNeutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.en
dc.typeArticleen
dc.contributor.departmentMolecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany. jja@gbf.deen
dc.identifier.journalThe Journal of clinical investigationen

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