Browsing by Subject "MCP-1"

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Open Access
Chondroitin Sulfate Inhibits Monocyte Chemoattractant Protein-1 Release From 3T3-L1 Adipocytes: A New Treatment Opportunity for Obesity-Related Inflammation?
(Biomarker insights, 2017-01) Stabler, Thomas V; Montell, Eulàlia; Vergés, Josep; Huebner, Janet L; Kraus, Virginia Byers
Monocyte chemoattractant protein-1 (MCP-1) overproduction from inflamed adipose tissue is a major contributor to obesity-related metabolic syndromes. 3T3-L1 embryonic fibroblasts were cultured and differentiated into adipocytes using an established protocol. Adipocytes were treated with lipopolysaccharide (LPS) to induce inflammation and thus MCP-1 release. At the same time, varying concentrations of chondroitin sulfate (CS) were added in a physiologically relevant range (10-200 µg/mL) to determine its impact on MCP-1 release. Chondroitin sulfate, a natural glycosaminoglycan of connective tissue including the cartilage extracellular matrix, was chosen on the basis of our previous studies demonstrating its anti-inflammatory effect on macrophages. Because the main action of MCP-1 is to induce monocyte migration, cultured THP-1 monocytes were used to test whether CS at the highest physiologically relevant concentration could inhibit cell migration induced by human recombinant MCP-1. Chondroitin sulfate (100-200 µg/mL) inhibited MCP-1 release from inflamed adipocytes in a dose-dependent manner (P < .01, 95% confidence interval [CI]: -5.89 to -3.858 at 100 µg/mL and P < .001, 95% CI: -6.028 to -3.996 at 200 µg/mL) but had no effect on MCP-1-driven chemotaxis of THP-1 monocytes. In summary, CS could be expected to reduce macrophage infiltration into adipose tissue by reduction in adipocyte expression and release of MCP-1 and as such might reduce adipose tissue inflammation in response to pro-inflammatory stimuli such as LPS, now increasingly recognized to be relevant in vivo.
Open Access
The Role of MCP-1 in Epithelial to Mesenchymal Transition and Invasion during Early Mammary Carcinogenesis
(2013) Sweede, Matthew Aaron Thomas
Triple negative breast cancers are aggressive breast tumors that are characterized by the absence of estrogen receptor, progesterone receptor, and HER2. This absence of expression limits targeted therapeutic strategies. The result is a disease that is associated with a poor prognosis. The current survival rate for those afflicted with triple negative breast cancer is 77%. This survival rate is compared to a 93% survival rate for all other breast cancers combined. Furthermore, triple negative breast cancers disproportionately affect young and African American women.
The Carolina Breast Cancer Study demonstrated that obesity increased the risk of triple negative breast cancer in premenopausal women. These findings were supported by a meta-analysis of 11 epidemiological studies evaluating the association between triple negative breast cancer, obesity, and menopause status. Consequently, it is hypothesized that obesity in premenopausal women may contribute to the initiation and progression of triple negative breast cancer.
On average, adipose constitutes 70% of the breast. Obesity is a disease of increased adipose tissue, which can increase the adiposity of the breast. Studies show that obesity enhances the production of the inflammatory cytokines IL1β, IL6, IL8, TNFα, and MCP-1 in adipose tissue. Inflammatory cytokines contribute to proliferation and survival of malignant cells, migration and invasion, and induction of epithelial to mesenchymal transition (EMT).
The purpose of this study is to investigate the role of adipose derived cytokines in promotion of EMT and invasion in early mammary carcinogenesis. To study EMT and invasion in early mammary carcinogenesis, a co-culture was generated using adipose stromal cell (ASC) conditioned media and the non-transformed, mammary epithelial cell line MCF10A. ASC-conditioned media was characterized for cytokine production. Findings indicated that IL6, IL8, and MCP-1 were secreted into the media. Researchers have extensively studied IL6 and IL8 in breast EMT, but the relevance of MCP-1 in breast carcinogenesis has only recently emerged. MCP-1 is involved in monocyte and macrophage trafficking, renal fibrosis and EMT, as well as EMT in peritoneal disease. The role of MCP-1 in renal and peritoneal EMT suggests that MCP-1 may induce EMT in mammary epithelial cells.
MCP-1 did not alter the protein expression levels of either E-cadherin or Vimentin in 2D culture. MCP-1 treatment did, however, rapidly phosphorylate Erk1/2 at T202/Y204 and induce chemotaxis of MCF10A cells in a Boyden Chamber migration assay. Erk1/2 phosphorylation and chemotaxis were inhibited by pretreatment with PD98059, a potent small molecule inhibitor of Erk signaling.
In 3D, MCF10A acini treated with MCP-1 lost expression of E-cadherin, β-catenin, and localized areas of Integrin α6. Additionally, MCP-1 induced outgrowth away from the MCF10A spheroids and invasion into the extracellular matrix during a spheroid gel invasion assay. MCP-1 did not induce the secretion of MMP-2 or MMP-9 during invasion. When the MCP-1 treated acini and spheroids were co-treated with PD98059 E-cadherin loss and invasion were inhibited respectively. This inhibition suggests that Erk activation is necessary for E-cadherin loss and cell invasion. The data indicate that MCP-1 plays a potential role in the early EMT and invasion of non-transformed, mammary epithelial cells. This study provides a foundation for the study of MCP-1 induced EMT and invasion in MCF10A cells. Further work will need to be completed to elucidate the mechanism by which MCP-1 decreases E-cadherin and induces invasion.