Signals from the tumor microenvironment (TME) have a profound influence on the maintenance and progression of cancers. Chronic inflammation and the infiltration of immune cells in breast cancer (BC) have been strongly associated with early carcinogenic events and a switch to a more immunosuppressive response. Cancer-associated fibroblasts (CAFs) are the most abundant stromal component and can modulate tumor progression according to their secretomes. The immune cells including tumor-infiltrating lymphocytes (TILs) (cytotoxic T cells (CTLs), regulatory T cells (Tregs), and helper T cell (Th)), monocyte-infiltrating cells (MICs), myeloid-derived suppressor cells (MDSCs), mast cells (MCs), and natural killer cells (NKs) play an important part in the immunological balance, fluctuating TME between protumoral and antitumoral responses. In this review article, we have summarized the impact of these immunological players together with CAF secreted substances in driving BC progression. We explain the crosstalk of CAFs and tumor-infiltrating immune cells suppressing antitumor response in BC, proposing these cellular entities as predictive markers of poor prognosis. CAF-tumor-infiltrating immune cell interaction is suggested as an alternative therapeutic strategy to regulate the immunosuppressive microenvironment in BC.
Objectives. This study aimed to investigate the association of hyperglycemia and advanced glycation end products (AGE) on the phenotypes and biological functions of neutrophils to understand their roles in diabetes-related atherosclerosis.Methodology. Healthy subjects (n=5) and type 2 diabetic patients grouped according to glycemic control [good control, HbA1c 7% or less, n=6; poor control, HbA1c more than 9%, n=6] were included in the study. Neutrophils were isolated from peripheral venous blood samples. To determine in vitro effects of high glucose and AGE, neutrophils derived from healthy subjectswere exposed to 5 mM glucose, 25 mM glucose, 100 µg/mL Bovine serum albumin (BSA) and AGE-BSA. We determined basal and phorbol 12-myristate 13-acetate (PMA)-stimulated production of reactive oxygen species (ROS), expression of CD11b and CD66b, release of myeloperoxidase (MPO), cell migration to IL-8 and adhesion to an endothelial cell layer.Results. In diabetic subjects, cells from well-controlled diabetics produced significantly higher basal and PMAstimulated ROS (p=0.014), while cells from poorly-controlled diabetics showed significantly increased expression of CD11b, CD66b and MPO production (p=0.021, 0.034, 0.05, respectively). The release of MPO was significantly increased after PMA stimulation in cells incubated in AGE-BSA, compared to those incubated in unmodified BSA. We observed significantly enhanced migration towards IL-8 and adherence to endothelial cells in neutrophils exposed to high glucose.Conclusions. Our findings indicate the activated status of neutrophils from diabetic patients. Neutrophils from healthy subjects exposed to conditions simulating hyperglycemia showed increased adhesive capacity. We made the novel finding of enhanced neutrophil migration toward IL-8 and adherence to endothelial cells upon exposure to high glucose conditions. These altered neutrophil functions may lead to the development and progression of atherosclerosis in diabetes.
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