Role of inflammation, innate resistance, and immunity in carcinogenesis.

炎症、先天抵抗力和免疫在癌变中的作用。

• 批准号: 8763223
• 负责人: GIORGIO TRINCHIERI
• 金额: $ 87.22万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763223
• 关键词: Ablation; Adaptor Signaling Protein; Adenocarcinoma; Adenomatous Polyposis Coli; Adoptive Transfer; Apoptosis; Appearance; Attenuated; Automobile Driving; Azoxymethane; CCL2 gene; CD8-Positive T-Lymphocytes; CXCL10 gene; Cancer Biology; Cancer Model; Cell Proliferation; Cell Surface Receptors; Cells; Characteristics; Chemical Models; Chronic; Colon; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Communicable Diseases; Complement; Cyst; Cytokine Receptors; Cytotoxic T-Lymphocytes; DNA Repair; Defect; Dendritic Cells; Deterioration; Development; Diethylnitrosamine; Differentiation Antigens; Disease-Free Survival; Effector Cell; Environment; Epithelial; Epithelial Cells; Equilibrium; Exhibits; Family; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Healed; Hepatocarcinogenesis; Homeostasis; Homologous Gene; Human; Human Development; Immune; Immune response; Immunity; Immunosuppressive Agents; In Situ; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory Response; Injury; Interferon Type I; Interferon Type II; Interferons; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-6; Interleukins; Investigation; Kupffer Cells; Lesion; Light; Link; Liver; MAPK14 gene; Macrophage Activation; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Molecular; Molecular Profiling; Mononuclear; Morphogenesis; Mus; Mutation; Myeloid Cells; NF-kappa B; NFKB Signaling Pathway; Natural Killer Cells; Natural Resistance; Nature; Neoplasm Metastasis; Oncogenic; Organism; PIK3CA gene; Paralysed; Pathway interactions; Patients; Phagocytes; Phosphorylation; Phosphotransferases; Physiological; Play; Population; Preventive; Primary carcinoma of the liver cells; Process; Production; Prophylactic treatment; Proteins; Recruitment Activity; Regulation; Relative (related person); Reporting; Resistance; Resistance to infection; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Site; Skin; Skin Carcinogenesis; Sodium Dextran Sulfate; Solid Neoplasm; Source; Staging; Surface; T-Lymphocyte; TNF gene; TP53 gene; Time; Tissues; Toll-like receptors; Toxoplasma gondii; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins; Ulcer; Up-Regulation; Vaccines; acquired immunity; adaptive immunity; adenoma; autocrine; base; beta catenin; carcinogenesis; cell type; chemical carcinogenesis; chemokine; colitis associated cancer; colon carcinogenesis; cytokine; extracellular; healing; insight; interleukin-22; interleukin-23; intraperitoneal; keratinocyte; liver injury; macrophage; microbial; microbial community; monocyte; mouse model; pathogen; prevent; prognostic; programs; protein expression; receptor; response; stress-activated protein kinase 1; synergism; tumor; tumor growth; tumor progression; tumorigenesis

Progress has been made in several of the aims of the project: The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma(Cancer Res. 2012 ;72:3977-86). Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1beta, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-kB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer. NK cell-derived interferon-gamma orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection Innate resistance and pro-inflammatory cytokines in carcinogenesis (Immunity. 2012;36:1047-59). Dendritic cells (DCs), monocyte and/or macrophages initiate host-protective immune responses to intracellular pathogens in part through interleukin-12 (IL-12) production, although the relative contribution of tissue resident versus recruited cells has been unclear. Here we showed that after intraperitoneal infection with Toxoplasma gondii cysts, resident mononuclear phagocytes are replaced by circulating monocytes that differentiate in situ into inflammatory DCs (moDCs) and F4/80+ macrophages. Importantly, NK cell-derived interferon-gamma (IFN-gamma) was required for both the loss of resident mononuclear phagocytes and the local differentiation of monocytes into macrophages and moDCs. This newly generated moDC population and not the resident DCs (or macrophages) served as the major source of IL-12 at the site of infection. Thus, NK cell-derived IFN-gamma is important in both regulating inflammatory cell dynamics and in driving the local differentiation of monocytes into the cells required for initiating the immune response to an important intracellular pathogen. A very extensive investigation has been initiated to study the role of inflammatory receptors and cytokines in skin and colon chemical carcinogenesis. Signaling through the adaptor protein MyD88 promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/ dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88-/- mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding pro-inflammatory factors as well as pathways regulating cell proliferation, apoptosis, and DNA repair resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis (J Exp Med. 2012;209:1689-702 ). Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88(-/-) keratinocytes form only a few small tumors in orthotopic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1alpha, IL-1R, and MyD88 leading to phosphorylation of IkBalpha and NF-kB activation. Blocking IL-1alpha-mediated NF-kB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth (Nature. 2012;491:254-8). Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.

该项目的几个目的已经取得了进展：促炎性髓样细胞受体TREM-1控制肝细胞癌的Kupffer细胞激活和发育（CancerRes。2012; 72：3977-86）。慢性炎症驱动肝癌发病机理，侵袭和转移。肝库普弗细胞在介导促进肝癌的炎症过程中具有至关重要的作用，但是尚未完全了解其贡献的机械基础。在这里，我们表明，库普弗细胞表达的促炎性髓样细胞表面受体Trem-1的表达是肝癌发育和进展的关键因素。小鼠中鼠同源物trem1的缺失减弱了由二乙基硝基胺触发的肝细胞癌（DEN）。 Trem1缺乏通过下调白介素（IL）-6，IL-1Beta，TNF，CCL2和CXCL10的转录和蛋白质表达来减弱库普弗细胞的激活。此外，Trem1消融减少了p38，细胞外调节激酶1/2，JNK，有丝分裂原激活的蛋白激酶和kupffer细胞中NF-KB信号通路的激活，导致肠道损伤后肝损伤减少。将野生型kupffer细胞转移到Trem1缺陷的小鼠中，补充了这些缺陷，并逆转了对DEN诱导的肝损伤和恶性发育的反应。总之，我们的发现提供了因果证据，表明TREM-1是肝癌发生中库普弗细胞激活的关键决定因素，从而加深了对慢性炎症如何支撑肝癌发展和进展的机理见解。 NK细胞衍生的干扰素γ可以在感染先天抗性和促炎性细胞因子的癌变部位策划细胞动力学以及单核细胞分化为树突状细胞（免疫。2012; 36：1047-59）。树突状细胞（DCS），单核细胞和/或巨噬细胞通过白介素12（IL-12）产生部分对细胞内病原体的宿主保护性免疫反应，尽管尚不清楚组织驻留细胞的相对贡献。在这里，我们表明，在腹膜内感染弓形虫弓形虫囊肿后，驻留的单核吞噬细胞被循环的单核细胞所取代，这些单核细胞将原位分化为炎性DCS（MODC）和F4/80+巨噬细胞。重要的是，NK细胞衍生的干扰素 - 伽马（IFN-Gamma）既丧失了居民单核吞噬细胞，又需要单核细胞为巨噬细胞和MODC的局部分化。该新生成的MODC人群，而不是居民DC（或巨噬细胞）在感染部位成为IL-12的主要来源。因此，NK细胞衍生的IFN-GAMMA在调节炎症细胞动力学以及将单核细胞的局部分化驱动到引发对重要细胞内病原体的免疫反应所需的细胞中很重要。已经开始了非常广泛的研究，以研究炎症受体和细胞因子在皮肤和结肠化学癌变中的作用。通过衔接蛋白MyD88发出的信号在几种癌症模型中促进了致癌作用。相比之下，MyD88信号传导在甲氧基甲烷（AOM）/葡萄糖硫酸钠（DSS）结肠炎相关癌症（CAC）的发展中具有保护作用。 Myd88 - / - 小鼠无法治愈损伤产生的溃疡会导致炎症环境改变，从而诱导编码促炎性因子的基因表达的早期改变，以及调节细胞增殖，凋亡，凋亡和DNA修复的途径，导致腺瘤和进展型的巨大促进性膜片的繁殖症状症状，并导致腺瘤的繁殖量迅速增加。 β-catenin基因。这项研究揭示了影响组织稳态和癌变的不同受体下游的MyD88活性的先前未知水平。 IL-1R-MYD88角质形成细胞转化和癌变中的信号传导（J ExpMed。2012; 209：1689-702）。组成型活性RA在人类癌症的发展中起着核心作用，足以在两阶段的皮肤致癌作用中诱导肿瘤。 RAS介导的肿瘤形成通常与细胞因子和趋化因子的上调有关，这些因子和趋化因子介导被认为与肿瘤相关的炎症反应。在这项研究中，我们报告说，缺乏IL-1R或MYD88的小鼠对局部皮肤致癌的敏感性不如各自的野生型（WT）对照。 MyD88（ - / - ）或IL-1R（ - / - ）角质形成细胞表达致癌性RA的角质细胞是过度增殖的，并且无法上调促炎基因或下调ras表达ras wt wt wt wt peratinococtes的特征。尽管表达RAS的MyD88（ - / - ）角质形成细胞仅形成原位移植物中的几个小肿瘤，但IL-1R缺乏的表达角构细胞保留了形成正聚合物中肿瘤的能力。使用遗传学方法和药理学方法，我们发现致癌细胞中致癌Ras的分化和促炎作用需要通过IL-1Alpha，IL-1R和MYD88建立自分泌环，从而导致Ikbalpha和NF-KB活化的磷酸化。在表达RAS的WT角质形成细胞中阻断IL-1Alpha介导的NF-KB激活会逆转分化缺陷，并抑制促炎基因表达。总的来说，这些结果表明MyD88在角质形成细胞的RAS介导的转化中发挥了细胞中性功能。腺瘤相关的屏障缺陷和微生物产物驱动IL-23/IL-17介导的肿瘤生长（自然2012; 491：254-8）。大约2％的大肠癌与现有的炎症有关，称为结肠炎相关癌症，但大多数患者在没有炎症性肠病的患者中发育。结直肠癌经常遵循遗传途径，通过该途径，随着肿瘤的出现和进展，β-RAS，PIK3CA和TP53中的β-catenin抑制剂的丧失和β-catenin的激活在K-RAS，PIK3CA和TP53之后是突变。然而，奇怪的是，在结直肠癌中，与结肠炎相关癌症的“炎症特征”基因也被上调。此外，像大多数实体瘤一样，大肠癌表现出免疫/炎症性浸润，称为“肿瘤引起的炎症”。 Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free生存。尽管具有致病性的重要性，但对肿瘤引起的炎症出现的机制知之甚少。许多上皮癌近端发展到微生物群落，它们通过上皮屏障在物理上与免疫细胞分离。我们研究了导致肿瘤引起的炎症的机制，在结直肠肿瘤发生的小鼠模型中，与人类结直肠癌一样，它也表现出IL-23和IL-17的上调。在这里，我们表明IL-23信号传导促进了肿瘤的生长和进展，以及肿瘤IL-17反应的发展。 IL-23主要是由肿瘤相关的髓样细胞产生的，这些细胞可能被微生物产物激活，这些细胞穿透了肿瘤但没有邻近组织。早期和晚结直肠肿瘤都表现出几种屏障蛋白的缺陷表达。我们提出，结直肠癌引发遗传病变引起的障碍降低导致微生物产物侵袭腺瘤，从而引发肿瘤引起的炎症，从而导致肿瘤生长。