ABSTRACT
In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.
Subject(s)
Fibrosarcoma/pathology , Hyaluronan Receptors/metabolism , Interleukin-33/metabolism , Lung Neoplasms/pathology , Macrophages/immunology , Membrane Glycoproteins/metabolism , Neoplastic Stem Cells/pathology , Animals , Apoptosis , Cell Proliferation , Fibrosarcoma/etiology , Fibrosarcoma/metabolism , Gene Expression Regulation, Neoplastic , Humans , Hyaluronan Receptors/genetics , Interleukin-33/genetics , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred DBA , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Sarcoma, Experimental/etiology , Sarcoma, Experimental/metabolism , Sarcoma, Experimental/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Mucosal immunity at the intestinal level is constantly challenged by the presence of external food and microbial antigens and must be kept under strict control to avoid the rise of aberrant inflammation. Among cells of the innate immunity, macrophages expressing the chemokine receptor CX3CR1 are strategically located near the gut epithelial barrier. These cells contribute to the maintenance of homeostasis by producing the anti-inflammatory cytokine IL-10; however, their role in the control of full blown inflammation and tissue injury is controversial. In this study we investigated mice proficient or deficient for the expression of the CX3CR1 receptor in a model of dextran sulphate sodium (DSS) induced acute colitis. We found that KO mice (CX3CR1GFP/GFP) had a more severe disease compared to WT mice (CX3CR1GFP/+), both in terms of histological examination of colonic tissues and leukocyte infiltration, with an expansion of macrophages and CD4-Th17 lymphocytes. The expression of several inflammatory mediators (IL-1ß, IL-6, IFNγ, iNOS) was also significantly upregulated in KO mice, despite higher IL-10 production. Overall, our study demonstrates that macrophages expressing a functional CX3CR1 receptor have an important and non-redundant role in controlling the abnormal intestinal inflammation that may lead to tissue damage.
Subject(s)
CX3C Chemokine Receptor 1/metabolism , Colitis/etiology , Colitis/metabolism , Intestinal Mucosa/metabolism , Intestines/immunology , Macrophages/immunology , Macrophages/metabolism , Animals , Biomarkers , CX3C Chemokine Receptor 1/genetics , Colitis/pathology , Cytokines/metabolism , Disease Models, Animal , Immunophenotyping , Inflammation Mediators/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Intestines/pathology , Leukocytes/immunology , Leukocytes/metabolism , Leukocytes/pathology , Male , Mice , Mice, Knockout , PhenotypeABSTRACT
The telomerase complex allows telomere length maintenance, which is required for an unlimited cellular proliferation. Telomerase is virtually absent in normal human somatic cells, which are characterized by a definite proliferation potential, while it is present in the vast majority of tumors (around 90%). Restoring telomerase activity in normal somatic cells can indefinitely prolong cellular life span. However, evidence has been reported that this event can be associated with the acquisition of characteristics typical of cellular transformation. Moreover, analysis of telomerase immortalized cells, as well as of tumor cells in which telomerase is inactivated, has highlighted multiple functions of telomerase in tumorigenesis, besides telomere lengthening. In this paper, we will review telomerase immortalization of somatic cells, together with its possible consequences, and we will examine the complex role of telomerase in tumorigenesis.
