FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2170607629> ?p ?o ?g. }

• W2170607629 endingPage "1925" @default.
• W2170607629 startingPage "1914" @default.
• W2170607629 abstract "•Intestinal tumorigenesis is suppressed in IKKα kinase mutant mice•Improved survival depends upon elevated IFNγ•Myeloid cells, rather than T or NK cells, are the source of IFNγ•Polarization of myeloid cells depends on interplay between tumor and immune cells The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy. The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy. An inflammatory microenvironment is an essential component of epithelial tumors that develop on the basis of chronic inflammatory conditions as well as of those malignancies that emerge in an inflammation-independent manner (Quante et al., 2013Quante M. Varga J. Wang T.C. Greten F.R. The gastrointestinal tumor microenvironment.Gastroenterology. 2013; 145: 63-78Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). In both instances, recruitment of various types of adaptive and innate immune cells can be observed. Depending on the dominating cell type and polarization profile of the infiltrating cells, tumorigenesis is promoted or suppressed (Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7295) Google Scholar). Recently, an immune score relying on the intratumoral localization of cytotoxic and memory T cells was established in colorectal cancer (CRC) (Fridman et al., 2012Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. The immune contexture in human tumours: impact on clinical outcome.Nat. Rev. Cancer. 2012; 12: 298-306Crossref PubMed Scopus (3018) Google Scholar). This immune score has a powerful prognostic value and exemplifies the importance of immune cells for this tumor entity. Moreover, a large number of functional in vivo studies have provided substantial evidence demonstrating a key role of myeloid cells in colorectal cancer as well as other tumor entities (Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7295) Google Scholar). In analogy to the Th1/Th2 classification of T cells, macrophages have been suggested to be grouped into classically activated M1 (in response to interferon γ [IFNγ] or microbial products) or alternatively activated M2 macrophages (in response to interleukin 4 [IL-4]; Gordon and Taylor, 2005Gordon S. Taylor P.R. Monocyte and macrophage heterogeneity.Nat. Rev. Immunol. 2005; 5: 953-964Crossref PubMed Scopus (3783) Google Scholar) In the context of tumor-associated macrophages, M1 macrophages are considered to behave in a tumoricidal manner whereas M2 macrophages promote tumorigenesis (Mantovani et al., 2002Mantovani A. Sozzani S. Locati M. Allavena P. Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends Immunol. 2002; 23: 549-555Abstract Full Text Full Text PDF PubMed Scopus (3824) Google Scholar). However, the exact molecular and cellular basis underlying the tumor-promoting lymphocyte and myeloid cell polarization within the tumor microenvironment is still poorly defined. Nuclear factor (NF)-κB activation leads to the establishment of a protumorigenic inflammatory microenvironment of various malignancies (Bollrath and Greten, 2009Bollrath J. Greten F.R. IKK/NF-kappaB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis.EMBO Rep. 2009; 10: 1314-1319Crossref PubMed Scopus (321) Google Scholar). NF-κB is tightly controlled by the IκB-kinase (IKK) complex, which consists of two catalytic subunits, namely the IKKα and IKKβ proteins, as well as the regulatory subunit IKKγ (Chariot, 2009Chariot A. The NF-kappaB-independent functions of IKK subunits in immunity and cancer.Trends Cell Biol. 2009; 19: 404-413Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). The classical NF-κB activation controls key functions for tumor initiation, promotion, and progression both in tumor as well as in infiltrating myeloid cells (Karin and Greten, 2005Karin M. Greten F.R. NF-kappaB: linking inflammation and immunity to cancer development and progression.Nat. Rev. Immunol. 2005; 5: 749-759Crossref PubMed Scopus (2495) Google Scholar). In contrast to classical IKKγ/IKKβ-dependent NF-κB signaling, alternative NF-κB activation depends solely on IKKα (Vallabhapurapu and Karin, 2009Vallabhapurapu S. Karin M. Regulation and function of NF-kappaB transcription factors in the immune system.Annu. Rev. Immunol. 2009; 27: 693-733Crossref PubMed Scopus (2023) Google Scholar). Moreover, IKKα comprises a nuclear localization signal and can therefore also confer important nuclear functions (Chariot, 2009Chariot A. The NF-kappaB-independent functions of IKK subunits in immunity and cancer.Trends Cell Biol. 2009; 19: 404-413Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). Whereas, in most malignancies, IKKβ-dependent NF-κB signaling clearly promotes tumorigenesis, the role of IKKα in this context is more complex. Inhibition of IKKα prolongs survival and suppresses occurrence of metastatic diseases in models of mammary and prostate cancer (Cao et al., 2007Cao Y. Luo J.L. Karin M. IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells.Proc. Natl. Acad. Sci. USA. 2007; 104: 15852-15857Crossref PubMed Scopus (126) Google Scholar, Luo et al., 2007Luo J.L. Tan W. Ricono J.M. Korchynskyi O. Zhang M. Gonias S.L. Cheresh D.A. Karin M. Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin.Nature. 2007; 446: 690-694Crossref PubMed Scopus (362) Google Scholar, Tan et al., 2011Tan W. Zhang W. Strasner A. Grivennikov S. Cheng J.Q. Hoffman R.M. Karin M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.Nature. 2011; 470: 548-553Crossref PubMed Scopus (509) Google Scholar, Zhang et al., 2013Zhang W. Tan W. Wu X. Poustovoitov M. Strasner A. Li W. Borcherding N. Ghassemian M. Karin M. A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1.Cancer Cell. 2013; 23: 647-659Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). In contrast, loss of IKKα enhances susceptibility to carcinogen-induced squamous cell carcinomas (SCC) in the skin and leads to development of spontaneous lung SCC (Liu et al., 2008Liu B. Xia X. Zhu F. Park E. Carbajal S. Kiguchi K. DiGiovanni J. Fischer S.M. Hu Y. IKKalpha is required to maintain skin homeostasis and prevent skin cancer.Cancer Cell. 2008; 14: 212-225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Xiao et al., 2013Xiao Z. Jiang Q. Willette-Brown J. Xi S. Zhu F. Burkett S. Back T. Song N.Y. Datla M. Sun Z. et al.The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas.Cancer Cell. 2013; 23: 527-540Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Interestingly, the latter depends in part on the development of an excessive inflammatory environment triggered by IKKα mutant macrophages (Xiao et al., 2013Xiao Z. Jiang Q. Willette-Brown J. Xi S. Zhu F. Burkett S. Back T. Song N.Y. Datla M. Sun Z. et al.The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas.Cancer Cell. 2013; 23: 527-540Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Globally sporadic CRC comprises the second most common cause of cancer in women and the third most common cause in men (Jemal et al., 2009Jemal A. Siegel R. Ward E. Hao Y. Xu J. Thun M.J. Cancer statistics, 2009.CA Cancer J. Clin. 2009; 59: 225-249Crossref PubMed Scopus (9867) Google Scholar). In over 80% of the cases, it is initiated by APC and CTNNB mutations that cause persistent activation of the Wnt pathway (Fearon, 2011Fearon E.R. Molecular genetics of colorectal cancer.Annu. Rev. Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1217) Google Scholar). We could recently demonstrate that proinflammatory IKKβ-dependent NF-κB signaling enhances β-catenin promoter binding, causing dedifferentiation of postmitotic epithelia and tumor stem cell expansion during Wnt-dependent tumor initiation (Schwitalla et al., 2013aSchwitalla S. Fingerle A.A. Cammareri P. Nebelsiek T. Göktuna S.I. Ziegler P.K. Canli O. Heijmans J. Huels D.J. Moreaux G. et al.Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell. 2013; 152: 25-38Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar). Moreover, canonical NF-κB activation controls development of epithelial-mesenchymal transition (EMT) and myeloid cell recruitment in Tp53-deficient invasive carcinomas (Schwitalla et al., 2013bSchwitalla S. Ziegler P.K. Horst D. Becker V. Kerle I. Begus-Nahrmann Y. Lechel A. Rudolph K.L. Langer R. Slotta-Huspenina J. et al.Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors.Cancer Cell. 2013; 23: 93-106Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). In contrast, IKKα directly phosphorylates β-catenin, thus increasing its abundance to promote cyclin D1 expression (Albanese et al., 2003Albanese C. Wu K. D’Amico M. Jarrett C. Joyce D. Hughes J. Hulit J. Sakamaki T. Fu M. Ben-Ze’ev A. et al.IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf.Mol. Biol. Cell. 2003; 14: 585-599Crossref PubMed Scopus (133) Google Scholar), and in colorectal cancer cells, an active IKKα isoform was described (Margalef et al., 2012Margalef P. Fernández-Majada V. Villanueva A. Garcia-Carbonell R. Iglesias M. López L. Martínez-Iniesta M. Villà-Freixa J. Mulero M.C. Andreu M. et al.A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer.Cell Reports. 2012; 2: 840-854Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). However, functional genetic evidence supporting a cell autonomous or nonautonomous role of IKKα and/or the alternative NF-κB activation pathway in colorectal carcinogenesis is lacking. To functionally examine the role of IKKα during early intestinal tumorigenesis, we employed IkkαAA/AA knockin mice, which contain alanines instead of serines in the activation loop of IKKα and express therefore a nonactivatable form of this kinase (Cao et al., 2001Cao Y. Bonizzi G. Seagroves T.N. Greten F.R. Johnson R. Schmidt E.V. Karin M. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development.Cell. 2001; 107: 763-775Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar). Whereas IkkαAA/AA mice are characterized by impaired development of Peyer’s patches (Senftleben et al., 2001Senftleben U. Cao Y. Xiao G. Greten F.R. Krähn G. Bonizzi G. Chen Y. Hu Y. Fong A. Sun S.C. Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.Science. 2001; 293: 1495-1499Crossref PubMed Scopus (1121) Google Scholar), intestinal epithelial cell (IEC) differentiation was indistinguishable from littermate controls. IkkαAA/AA mice displayed regular numbers and distribution of goblet cells, Paneth cells, as well as enteroendocrine cells (data not shown). Similarly, proliferation and apoptosis rates of unchallenged intestinal epithelial cells in small and large intestine were unaltered (data not shown). To induce intestinal tumorigenesis, IkkαAA/AA mice and littermate controls were repetitively challenged with the procarcinogen azoxymethane (AOM), which is commonly used to induce adenoma growth in the distal colon of rodents. Expression of mutant IKKα markedly reduced number of adenomas (>75%) when animals were analyzed 20 weeks after the first carcinogen exposure (Figure 1A). IkkαAA/AA mice developed only few relatively small tumors that displayed slower proliferation rates (Figures 1B and 1C). Instead, in IkkαAA/AA mice multifocal low-grade intraepithelial neoplasia was frequently observed. To confirm the IkkαAA/AA-dependent antitumorigenic effect in a genetic model of adenomatous polyposis, we crossed IkkαAA/AA mice to ApcMin/+ mice and monitored their survival. Similarly, loss of IKKα function conferred a protective effect and prolonged survival of ApcMin/+ mice significantly (median survival of 236.5 days in homozygous IkkαAA/AA mutants versus 184.5 days in heterozygous IkkαAA/WT mutants and 166 days in IkkαWT/WT wild-type ApcMin/+ mice; p < 0.0001; Figure 1D). Accordingly, when we analyzed 4-month-old ApcMin/+ animals, tumor incidence and size as well as proliferation of tumor epithelia was significantly decreased in IkkαAA/AA mutant mice (Figures 1E–1H; data not shown). Furthermore, consistent with lower tumor burden, anemia—usually developing in ApcMin/+ mice as tumorigenesis progresses—was normalized in ApcMin/+/IkkαAA/AA compound mutants (Figures 1I and 1J). Collectively, these results suggested that IkkαAA/AA mediated antiproliferative effects during early tumor stages, which led to marked tumor suppression in both models of intestinal tumorigenesis. Tamoxifen-inducible β-catc.a. mice comprise an excellent model to study Wnt-dependent tumor initiation. These mice are characterized by IEC-restricted stabilization of β-catenin causing rapid expansion of intestinal crypts and loss of differentiated IEC, and within 4 weeks, β-catc.a. mice succumb to this marked crypt hyperproliferation (Schwitalla et al., 2013aSchwitalla S. Fingerle A.A. Cammareri P. Nebelsiek T. Göktuna S.I. Ziegler P.K. Canli O. Heijmans J. Huels D.J. Moreaux G. et al.Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell. 2013; 152: 25-38Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar). Similarly to the results obtained in AOM-induced and Apc-dependent tumor models, mutant IKKα blocked proliferation and expansion of c-myc-expressing β-catenin mutant crypts within 2 weeks after tamoxifen induction (Figures 2A–2C). This was associated with decreased CDK1 and CDK2 activity when mice were analyzed 15 days after the first tamoxifen administration (Figures 2D and 2E). Accordingly, impaired IKKα activation prolonged survival of β-catc.a. mutant animals (Figure 2F). Interestingly, loss of NF-κB2/p100 did not affect survival, indicating that IKKα acted independently of the alternative NF-κB activation pathway (Hayden and Ghosh, 2004Hayden M.S. Ghosh S. Signaling to NF-kappaB.Genes Dev. 2004; 18: 2195-2224Crossref PubMed Scopus (3341) Google Scholar). In line with this notion, we also did not observe any differences in p100 processing in β-catc.a./IkkαAA/AA IEC (data not shown). To further explore the underlying IKKα-controlled proproliferative mechanism, we performed a microarray analysis comparing RNA isolated from wild-type, IkkαAA/AA, β-catc.a., or β-catc.a./IkkαAA/AA IEC 15 days after the first tamoxifen administration. A total of 732 genes were significantly differentially expressed. In IEC from β-catc.a./IkkαAA/AA compared to β-catc.a. mice, a general downregulation of Wnt-dependent transcripts rather than control of particular gene subsets was observed. These different transcription profiles supposedly reflected the observed differences in IEC morphology between the two genotypes (Figure 2A), but not distinct IKKα-controlled signaling events. Indeed, knockdown of IKKα did not decrease β-catenin binding to its Tcf/Lef motif in human embryonic kidney 293 cells when transfected with a constitutively active β-catenin mutant (Figure S1). Therefore, we focused our attention on the group of transcripts that were markedly upregulated in IEC from β-catc.a./IkkαAA/AA mice. These could be classified into genes associated with immune response and inflammatory functions when sorted by their membership in KEGG pathways (Figure 3A). More specifically, gene set enrichment analysis (GSEA) indicated an enrichment of type I and II IFN targets in β-catc.a./IkkαAA/AA IEC (Figure 3B), including Stat1, Irf1, Nos2, Oas1, Pkr, and Isg15, which could be confirmed by real-time PCR (Figure 3C). This was paralleled by a marked upregulation of IFNγ in whole mucosa of β-catc.a./IkkαAA/AA mice (Figure 3D). Moreover, immunoblot analysis confirmed activation of tyrosine-phosphorylated Stat1(Y701) as well as upregulation of Nos2 and IRF-1 in IKKα mutant IEC (Figure 3E). Because IFNγ/Stat1 signaling is known to suppress tumor cell proliferation, this raised the possibility that the decreased IEC proliferation in β-catc.a./IkkαAA/AA mice was non-cell-autonomous and IFNγ dependent. To confirm this hypothesis, we either adoptively transferred IkkαAA/AA bone marrow to β-catc.a. mice or used conditional IkkαF/F mutants to specifically delete IKKα in β-catc.a. IEC (Liu et al., 2008Liu B. Xia X. Zhu F. Park E. Carbajal S. Kiguchi K. DiGiovanni J. Fischer S.M. Hu Y. IKKalpha is required to maintain skin homeostasis and prevent skin cancer.Cancer Cell. 2008; 14: 212-225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). IEC-restricted deletion of IKKα only moderately protected β-catc.a. mice (Figure 4A). In contrast, adoptive transfer of IkkαAA/AA bone marrow extended survival of β-catc.a. mice almost to the same extent as it was otherwise seen in IkkαAA/AA whole-body mutants (Figure 4B). More importantly, loss of Ifng, but not blocking type I interferon signaling by Ifnar deletion, completely prevented IKKα-mediated survival advantage (Figure 4C). Collectively, these data provided clear evidence that mutant IKKα suppressed IEC proliferation in a paracrine type II interferon-dependent manner.Figure 4Improved Survival of β-catc.a./IkkαAA/AA Mice Depends on IFNγShow full caption(A) Kaplan-Meier survival graph of β-catc.a./IkkαΔIEC mice (violet line). Survival of β-catc.a./IkkαWT/WT and β-catc.a./IkkαAA/AA mice shown as comparison (dashed gray lines; p = not significant [n.s.]).(B) Kaplan-Meier survival graph of lethally irradiated β-catc.a./IkkαWT/WT mice transplanted with either IkkαWT/WT (n = 6; red line) or IkkαAA/AA (n = 7; blue line) bone marrow; ∗∗∗p < 0.001 by log rank test.(C) Kaplan-Meier survival graph of β-catc.a./IkkαWT/WT/Ifng−/− (n = 9; light blue line), β-catc.a./IkkαAA/AA /Ifng−/− (n = 5; red line; ∗∗p < 0.005), and β-catc.a./IkkαAA/AA/ Ifnar1−/− mice (n = 8; pink line; p > 0.05) mice. Survival of β-catc.a./IkkαWT/WT and β-catc.a./IkkαAA/AA mice shown as comparison (dashed gray lines).View Large Image Figure ViewerDownload (PPT) (A) Kaplan-Meier survival graph of β-catc.a./IkkαΔIEC mice (violet line). Survival of β-catc.a./IkkαWT/WT and β-catc.a./IkkαAA/AA mice shown as comparison (dashed gray lines; p = not significant [n.s.]). (B) Kaplan-Meier survival graph of lethally irradiated β-catc.a./IkkαWT/WT mice transplanted with either IkkαWT/WT (n = 6; red line) or IkkαAA/AA (n = 7; blue line) bone marrow; ∗∗∗p < 0.001 by log rank test. (C) Kaplan-Meier survival graph of β-catc.a./IkkαWT/WT/Ifng−/− (n = 9; light blue line), β-catc.a./IkkαAA/AA /Ifng−/− (n = 5; red line; ∗∗p < 0.005), and β-catc.a./IkkαAA/AA/ Ifnar1−/− mice (n = 8; pink line; p > 0.05) mice. Survival of β-catc.a./IkkαWT/WT and β-catc.a./IkkαAA/AA mice shown as comparison (dashed gray lines). The most common IFNγ-expressing cell types in the lamina propria are T and natural killer (NK) cells. Surprisingly, we did not detect any difference in the number of mucosa-infiltrating CD3+ T cells by immunohistochemistry (Figure 5A). Moreover, fluorescence-activated cell sorting (FACS) analysis did not indicate changes in the number of CD4+IFNγ+ or CD8+IFNγ+ T cells between β-catc.a. and β-catc.a./IkkαAA/AA mice when animals were analyzed 15 days after the first tamoxifen administration (Figure 5B). Moreover, when we differentiated naive T cells from either wild-type or IkkαAA/AA animals into either Th1 or Th2 cells ex vivo, we were not able to determine any significant changes between the two genotypes (Figure S2A). Consequently, athymic nude mice (NU-Foxn1nu) that lack T cells did not revert the survival advantage of β-catc.a./IkkαAA/AA mice (data not shown). In addition, also depletion of NK cells using α-asialo-GM-1 antibody (reduction of >90% of splenic DX5+ cells was confirmed by FACS; data not shown) did not affect survival of β-catc.a./IkkαAA/AA mice (Figure 5C), indicating that neither CD4+, CD8+ T cells, nor NK cells were responsible for the IFNγ-mediated survival extension of IkkαAA/AA mutant β-catc.a. mice. During carcinogenesis, polarization of myeloid cells into M1 or M2 macrophages or in the case of neutrophils into N1 or N2 has been suggested to play an important role for tumor development (Sica and Mantovani, 2012Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas.J. Clin. Invest. 2012; 122: 787-795Crossref PubMed Scopus (3797) Google Scholar). Depending on the prevailing polarization profile, M1 macrophages (typically expressing Ifng, Tnfa, Il12, Nos2, Cxcl9, Cxcl10, and Cxcl11) are considered tumoricidal, whereas M2 macrophages (characterized by high levels of Arg1, Mrc1, Ccl17, Ccl22, Ym1, and Fizz1) have been suggested to promote tumorigenesis (Sica and Mantovani, 2012Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas.J. Clin. Invest. 2012; 122: 787-795Crossref PubMed Scopus (3797) Google Scholar). Considering the lack of T and NK cell involvement in the pronounced expression of Nos2 and Ifng, we speculated that instead a general shift in macrophage polarization toward M1 could have been responsible for this. Indeed, besides Nos2 and Ifng, expression of several other genes encoding M1 markers were elevated in the lamina propria of β-catc.a./IkkαAA/AA mice 15 days after the first tamoxifen administration, whereas only Ccl17 among M2-associated genes was downregulated (Figure 6A). To examine whether IkkαAA/AA mutant macrophages per se would reveal an M1 phenotype, we stimulated bone-marrow-derived macrophages (BMDM) under M1- or M2-polarizing conditions. Interestingly, ex vivo IkkαAA/AA macrophages did not reveal an enhanced M1 polarization profile compared to control BMDM and did not show a preferred polarization (Figure 6B). Moreover, also Ifng expression was indifferent when BMDM of either genotype were stimulated with a combination of IL-12 and IL-18 (Figure S2C), thus ruling out a cell autonomous regulation in the generation of IkkαAA/AA M1-like cells in vivo. Elevated expression levels of myeloid-recruiting chemokines such as Cxcl1, Cxcl2, Cxcl5, and Ccl2 (Figure 6C) led to enhanced recruitment of macrophages, neutrophils, and dendritic cells into the lamina propria of β-catc.a./IkkαAA/AA mutants, as determined by real-time PCR of genes encoding surface markers Emr1, Ly6g, and Itgax (Figure 6D) as well as by FACS analysis (data not shown). Only Cxcl1 and Cxcl2 upregulation was observed in IKKα mutant epithelia (Figure 6C), indicating that Cxcl5 and Ccl2 were derived from infiltrating immune cells. Interestingly, apart from enhanced myeloid cell recruitment, also localization of both macrophages and neutrophils was distinct in β-catc.a./IkkαAA/AA mice, where they could be found interspersed in between IEC. In contrast, infiltration of F4/80+ and Gr-1+ myeloid cells was limited to the villus stroma in IKKα wild-type-expressing β-catc.a. mice (Figures 6E–6H). Importantly, immunofluorescence confirmed that indeed both macrophages and neutrophils expressed IFNγ (Figures 6I and 6J), indicating that an enhanced recruitment of M1-like myeloid cells was responsible for the IFNγ-dependent survival advantage of β-catc.a./IkkαAA/AA mice. Myeloid-cell-recruiting chemokines such as Cxcl1, Cxcl2, Cxcl5, and Ccl2 are controlled by classical NF-κB activation (Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7295) Google Scholar). To functionally confirm that indeed the enhanced recruitment of M1-like myeloid cells was responsible for the extended survival in β-catc.a./IkkαAA/AA mice, we reasoned that loss of IKKβ-dependent NF-κB activation in IEC should block recruitment of myeloid cells in IKKα mutant β-catc.a. animals. Thus, we intercrossed floxed Ikkβ mutants (IkkβF/F) with β-catc.a./IkkαAA/AA mice to generate β-catc.a./IkkαAA/AA/IkkβΔIEC as well as β-catc.a./IkkβΔIEC compound mutants. Expectedly, IKKβ deletion decreased Cxcl1 and Ccl2 as well as Emr1, Ly6g, and Itgax expression and prevented Ifng upregulation (Figure 7A). Immunofluorescence confirmed diminished F4/80+ and Gr-1+ cell infiltration into mucosa of β-catc.a./IkkαAA/AA/IkkβΔIEC animals (Figures 7B–7E). We recently demonstrated that loss of RelA/p65 expanded the life span of β-catc.a. mice (Schwitalla et al., 2013aSchwitalla S. Fingerle A.A. Cammareri P. Nebelsiek T. Göktuna S.I. Ziegler P.K. Canli O. Heijmans J. Huels D.J. Moreaux G. et al.Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell. 2013; 152: 25-38Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar). Similarly, deletion of Ikkβ prolonged survival of Ctnnb mutants (Figure 7F). However, consistent with a lack of Ifng induction, β-catc.a./IkkαAA/AA animals were no longer protected in the absence of IKKβ and their survival was now comparable to that of β-catc.a./IkkβΔIEC mice (Figure 7F). Thus, these data further supported the importance of IFNγ-expressing myeloid cells for the survival of β-catc.a./IkkαAA/AA mice and confirmed that M1-like polarization did not occur in a cell autonomous manner in IKKα mutant myeloid cells. Cell plasticity is an important phenomenon during carcinogenesis that affects basically all cells in the tumor microenvironment (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (41807) Google Scholar). Whereas induction of EMT altering tumor cells themselves is an essential prerequisite for invasion and metastasis, polarization of infiltrating immune cells provides the microenvironment-dominating cytokine milieu, which ultimately controls behavior of resident stromal and tumor cells. Depending on the cytokine milieu, carcinogenesis is promoted or suppressed (Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7295) Google Scholar). To decipher the cellular and molecular mechanisms that shape the cytokine milieu bears great therapeutic potential, because cytokine-producing immune cells are unlikely to develop resistance mechanisms in contrast to mutagenized tumor cells. Although IKKα has been suggested to control various cell autonomous tumor-promoting mechanisms in CRC (Albanese et al., 2003Albanese C. Wu K. D’Amico M. Jarrett C. Joyce D. Hughes J. Hulit J. Sakamaki T. Fu M. Ben-Ze’ev A. et al.IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf.Mol. Biol. Cell. 2003; 14: 585-599Crossref PubMed Scopus (133) Google Scholar, Margalef et al., 2012Margalef P. Fernández-Majada V. Villanueva A. Garcia-Carbonell R. Iglesias M. López L. Martínez-Iniesta M. Villà-Freixa J. Mulero M.C. Andreu M. et al.A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer.Cell Reports. 2012; 2: 840-854Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), here we provide evidence that IKKα comprises a central regulatory element in the suppression of M1-like myeloid cell controlled microenvironment rather than directly stimulating tumor cell proliferation. Elevated IFNγ levels in IkkαAA/AA mucosa are most likely responsible for growth arrest of initiated epithelial cells. However, considering the particular intraepithelial localization of mye" @default.
• W2170607629 created "2016-06-24" @default.
• W2170607629 creator A5002204711 @default.
• W2170607629 creator A5005500510 @default.
• W2170607629 creator A5010963523 @default.
• W2170607629 creator A5011137037 @default.
• W2170607629 creator A5014660731 @default.
• W2170607629 creator A5023039467 @default.
• W2170607629 creator A5028914425 @default.
• W2170607629 creator A5040094631 @default.
• W2170607629 creator A5040601582 @default.
• W2170607629 creator A5043839143 @default.
• W2170607629 creator A5053227531 @default.
• W2170607629 creator A5053880561 @default.
• W2170607629 creator A5060163841 @default.
• W2170607629 creator A5060908072 @default.
• W2170607629 creator A5068920358 @default.
• W2170607629 creator A5069550552 @default.
• W2170607629 creator A5070494503 @default.
• W2170607629 creator A5071969566 @default.
• W2170607629 creator A5072196720 @default.
• W2170607629 creator A5078000054 @default.
• W2170607629 date "2014-06-01" @default.
• W2170607629 modified "2023-10-17" @default.
• W2170607629 title "IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells" @default.
• W2170607629 cites W1491499843 @default.
• W2170607629 cites W1501881225 @default.
• W2170607629 cites W1966796558 @default.
• W2170607629 cites W1974140746 @default.
• W2170607629 cites W1976857316 @default.
• W2170607629 cites W1977872674 @default.
• W2170607629 cites W1988924112 @default.
• W2170607629 cites W1995287289 @default.
• W2170607629 cites W2000999630 @default.
• W2170607629 cites W2001717792 @default.
• W2170607629 cites W2015141049 @default.
• W2170607629 cites W2017180102 @default.
• W2170607629 cites W2027266715 @default.
• W2170607629 cites W2049491375 @default.
• W2170607629 cites W2053242489 @default.
• W2170607629 cites W2061965920 @default.
• W2170607629 cites W2070855360 @default.
• W2170607629 cites W2079377885 @default.
• W2170607629 cites W2085328161 @default.
• W2170607629 cites W2085872402 @default.
• W2170607629 cites W2091605033 @default.
• W2170607629 cites W2098100644 @default.
• W2170607629 cites W2101653431 @default.
• W2170607629 cites W2101995865 @default.
• W2170607629 cites W2105269215 @default.
• W2170607629 cites W2106503814 @default.
• W2170607629 cites W2117692326 @default.
• W2170607629 cites W2118278569 @default.
• W2170607629 cites W2122044177 @default.
• W2170607629 cites W2124076790 @default.
• W2170607629 cites W2130410032 @default.
• W2170607629 cites W2132478490 @default.
• W2170607629 cites W2142127071 @default.
• W2170607629 cites W2142770698 @default.
• W2170607629 cites W2143109770 @default.
• W2170607629 cites W2148119611 @default.
• W2170607629 cites W2150625137 @default.
• W2170607629 cites W2155494802 @default.
• W2170607629 cites W2163872065 @default.
• W2170607629 cites W2166189096 @default.
• W2170607629 doi "https://doi.org/10.1016/j.celrep.2014.05.006" @default.
• W2170607629 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7676455" @default.
• W2170607629 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24882009" @default.
• W2170607629 hasPublicationYear "2014" @default.
• W2170607629 type Work @default.
• W2170607629 sameAs 2170607629 @default.
• W2170607629 citedByCount "20" @default.
• W2170607629 countsByYear W21706076292015 @default.
• W2170607629 countsByYear W21706076292016 @default.
• W2170607629 countsByYear W21706076292017 @default.
• W2170607629 countsByYear W21706076292018 @default.
• W2170607629 countsByYear W21706076292019 @default.
• W2170607629 countsByYear W21706076292020 @default.
• W2170607629 countsByYear W21706076292021 @default.
• W2170607629 countsByYear W21706076292022 @default.
• W2170607629 crossrefType "journal-article" @default.
• W2170607629 hasAuthorship W2170607629A5002204711 @default.
• W2170607629 hasAuthorship W2170607629A5005500510 @default.
• W2170607629 hasAuthorship W2170607629A5010963523 @default.
• W2170607629 hasAuthorship W2170607629A5011137037 @default.
• W2170607629 hasAuthorship W2170607629A5014660731 @default.
• W2170607629 hasAuthorship W2170607629A5023039467 @default.
• W2170607629 hasAuthorship W2170607629A5028914425 @default.
• W2170607629 hasAuthorship W2170607629A5040094631 @default.
• W2170607629 hasAuthorship W2170607629A5040601582 @default.
• W2170607629 hasAuthorship W2170607629A5043839143 @default.
• W2170607629 hasAuthorship W2170607629A5053227531 @default.
• W2170607629 hasAuthorship W2170607629A5053880561 @default.
• W2170607629 hasAuthorship W2170607629A5060163841 @default.
• W2170607629 hasAuthorship W2170607629A5060908072 @default.
• W2170607629 hasAuthorship W2170607629A5068920358 @default.
• W2170607629 hasAuthorship W2170607629A5069550552 @default.
• W2170607629 hasAuthorship W2170607629A5070494503 @default.

• next