ABSTRACT
Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
Subject(s)
Epithelial Cells/metabolism , Hematopoietic System/metabolism , Interleukin-17/metabolism , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Animals , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Carcinoma in Situ/prevention & control , Cell Transformation, Neoplastic , Chemoprevention , Hematopoietic System/cytology , Humans , Inflammation , Interleukin-17/antagonists & inhibitors , Interleukin-17/genetics , Mice , Mice, Transgenic , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/prevention & control , Receptors, Antigen, T-Cell, gamma-delta/biosynthesis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Interleukin-17/biosynthesis , Receptors, Interleukin-17/metabolism , Signal Transduction/genetics , Th17 Cells/immunologyABSTRACT
Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O(2)) than under 20% O(2) and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our (13)C NMR spectroscopic measurements indicate that (13)C-lactate is converted to (13)C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , Glycolysis/drug effects , Lactic Acid/pharmacology , Metabolic Networks and Pathways/drug effects , Stromal Cells/drug effects , Tumor Microenvironment/drug effects , Breast Neoplasms/pathology , Carcinoma/pathology , Cell Communication/drug effects , Cell Communication/physiology , Cell Line, Tumor , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Fibroblasts/physiology , Glycolysis/physiology , Humans , Hypoxia/metabolism , Hypoxia/pathology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Paracrine Communication/drug effects , Paracrine Communication/physiology , Stromal Cells/metabolism , Stromal Cells/pathology , Tumor Microenvironment/physiologyABSTRACT
Mesenchymal stem cells (MSCs) are a heterogeneous population of non-hematopoietic precursor cells predominantly found in the bone marrow. They have been recently reported to home towards the hypoxic tumor microenvironment in vivo. Interleukin-6 is a multifunctional cytokine normally involved in the regulation of the immune and inflammatory response. In addition to its normal function, IL-6 signaling has been implicated in tumorigenesis. Solid tumors develop hypoxia as a result of inadequate O(2) supply. Interestingly, tumor types with increased levels of hypoxia are known to have increased resistance to chemotherapy as well as increased metastatic potential. Here, we present evidence that under hypoxic conditions (1.5% O(2)) breast cancer cells secrete high levels of IL-6, which serve to activate and attract MSCs. We now report that secreted IL-6 acts in a paracrine fashion on MSCs stimulating the activation of both Stat3 and MAPK signaling pathways to enhance migratory potential and cell survival. Inhibition of IL-6 signaling utilizing neutralizing antibodies leads to attenuation of MSC migration. Specifically, increased migration is dependent on IL-6 signaling through the IL-6 receptor. Collectively, our data demonstrate that hypoxic tumor cells specifically recruit MSCs, which through activation of signaling and survival pathways facilitate tumor progression.