Abstract
High tumor vascular endothelial growth factor (VEGF) levels are associated with poor treatment outcomes in prostate cancer (PCa), and immune deficiency in the PCa microenvironment, especially suppression of dendritic cell (DC) proliferation, has been confirmed. In this study, we (1) investigated whether VEGF participates in DC suppression in murine PCa cells (RM-1), (2) down-regulated VEGF expression using low-frequency ultrasound and microbubbles (UM), and (3) further explored any synergistic effect on immunological activation. DCs from the bone marrow of BALB/c mice were stimulated by the addition of cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4)), and we analyzed their proliferation status via flow cytometric recognition of the surface antigen markers CD11c and CD83. The results demonstrated that co-culture with RM-1 cells markedly inhibited expression of the general marker CD11c and the mature marker CD83; UM weakened this inhibition by down-regulating VEGF expression. T lymphocytes were extracted from murine spleens, and CD4 and CD8a were identified as the biomarkers of activated cells participating in the anti-tumor immune response. When DCs, T lymphocytes and RM-1 cells were co-cultured, cell migration and invasion assays and cytoactive detection showed that UM could not only directly suppress PCa cell evolution but also promote activation of anti-tumor immunocytes in the VEGF-inhibited microenvironment.
Highlights
Prostate cancer (PCa) is the most common non-cutaneous cancer and the second leading cause of cancer-related death in the United States in recent years; it is the most frequent cancer diagnosed in men in Europe[1]
Following exposure to tumor antigen, dendritic cell (DC) migrate to peripheral lymph nodes and induce activation of cytotoxic T lymphocytes (CTLs) via antigen presentation; this process further triggers the immune response and induces immunological surveillance[6, 7]
Gallucci reported that suppression of Vascular endothelial growth factor (VEGF) in a mouse model leads to increased antigen uptake and migration of tumor-associated DCs13
Summary
Prostate cancer (PCa) is the most common non-cutaneous cancer and the second leading cause of cancer-related death in the United States in recent years; it is the most frequent cancer diagnosed in men in Europe[1]. Vascular endothelial growth factor (VEGF), which induces neoangiogenesis and angiogenesis blockade, plays an important role in the development and metastasis of solid tumors, becoming a major target in cancer therapy[12]. It has been reported that the vascular endothelium is destroyed following treatment with ultrasound combined with a microbubble contrast agent (UCA)14; 1-MHz, low-intensity ultrasound had an impact of fragile and leaky angiogenic blood vessels in tumors[15]. Our preliminary work confirmed that low-frequency ultrasound in combination with a contrast agent was effective for reducing expression of VEGF or COX-2 in the vascular endothelium and cytoplasm of PCa tumors[16]. We down-regulated expression of VEGF in murine PCa cells using UCA and co-cultured these cells with marrow-derived DCs and spleen-derived T lymphocytes to determine whether VEGF participates in the differentiation of immune cells. We investigated the migration, proliferation and metastasis ability of RM-1 cells to assess anti-tumor synergy of UCA-mediated angiogenesis destruction and immune cell activation
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