Caveolin-1-dependent tenascin C inclusion in extracellular vesicles is required to promote breast cancer cell malignancy.

Background: Elevated expression of CAV1 in breast cancer increases tumor progression. Extracellular vesicles (EVs) from CAV1-expressing MDA-MB-231 breast cancer cells contain Tenascin C (TNC), but the relevance of TNC remained to be defined. Methods: EVs were characterized by nanotracking analysis, microscopy and western blotting. The uptake of EVs by cells was studied using flow cytometry. The effects of EVs on breast cancer cells were tested in migration, invasion, colony formation and in vivo assays. Results: EVs were taken up by cells; however, only those containing TNC promoted invasiveness. In vivo, EVs lacking TNC ceased to promote tumor growth. Conclusion: CAV1 and TNC contained in breast cancer cell-derived EVs were identified as proteins that favor progression of breast cancer.

Caveolin-1 (CAV1) is a protein that in breast cancer increases with disease progression. Extracellular vesicles (EVs) from breast cancer cells with CAV1 also contain Tenascin C (TNC) protein, but the importance of TNC remained to be defined. EVs were identified by size, microscopy and protein analysis. The effects of EVs on breast cancer cells were studied using cells and experiments in animals. CAV1 expression promotes TNC inclusion into EVs, which increased the aggressiveness of recipient breast cancer cells. In animals, only EVs with TNC increased features associated with cancer spread, while EVs lacking TNC reduced tumor growth.

Platelets, a Key Cell in Inflammation and Atherosclerosis Progression.

Platelets play important roles in thrombosis-dependent obstructive cardiovascular diseases. In addition, it has now become evident that platelets also participate in the earliest stages of atherosclerosis, including the genesis of the atherosclerotic lesion. Moreover, while the link between platelet activity and hemostasis has been well established, the role of platelets as modulators of inflammation has only recently been recognized. Thus, through their secretory activities, platelets can chemically attract a diverse repertoire of cells to inflammatory foci. Although monocytes and lymphocytes act as key cells in the progression of an inflammatory event and play a central role in plaque formation and progression, there is also evidence that platelets can traverse the endothelium, and therefore be a direct mediator in the progression of atherosclerotic plaque. This review provides an overview of platelet interactions and regulation in atherosclerosis.

Endothelial transmigration of platelets depends on soluble factors released by activated endothelial cells and monocytes.

Cardiovascular diseases (CVDs) remain leading causes of death worldwide. While platelet-mediated thrombus formation following the rupture of an atherosclerotic plaque is one of the key pathophysiologic events in CVDs, the role of platelets in previous or more advanced stages of atherosclerosis is less known. Interestingly, the presence of platelets has been observed at the core of the atherosclerotic plaque.In order to study the conditions necessary for platelets to migrate toward an atherosclerotic lesion, we designed an in vitro co-culture model. Platelets were co-cultured with monocytes in Transwell inserts covered with a confluent endothelium and the number of migrating platelets and/or monocytes was determined under different conditions. Platelets were also exposed to media conditioned obtained from co-cultures prior to migration assays.Here we show that coculturing platelets and monocytes increased platelet transmigration, with a considerable number of transmigrated platelets found not associated to monocytes. Interestingly, conditioned media from platelet-monocyte co-cultures also increased platelet transmigration and aggregation, suggesting the existence of soluble factors secreted by monocytes that enhance the migratory and pro-aggregating capabilities of platelets.We conclude that platelets have the machinery to migrate through an activated endothelium, a response that requires the interaction with secreted factors produce in the context of the interaction with monocytes under atherogenic conditions.

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells.

: The renin-angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the antimetastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDAMB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.

Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis.

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure.

Niveles Plasmáticos de Citoquinas Proinflamatorias en Cáncer de Próstata / Serum levels of proinflammatory cytokines in prostate cancer

INTRODUCTION: Prostate cancer has become an important public health problem affecting millions of men worldwide every year. Like other malignant tumors, prostate cancer shows evidence of a strong inflammatory component that is dependent on the release of pro-inflammatory cytokines, which might play a major role in the development and progression of the tumor, helping in its early stage, progression and aggressiveness. AIMS: The goal of this study was to determine the relationships between the serum levels of pro-inflammatory cytokines and the different stages of prostate cancer. To this end, sera from patients enrolled by The Laboratory of Metabolic Diseases and Cancer of the Faculty of Pharmacy and Biochemistry at the University Juan Agustín Maza in Argentina, were analyzed through ELISA and their pro-inflammatory cytokines (IL-6, TNF-α and MCP-1) quantified. Patients were first classified into three groups (Control, at Risk, and Cancer subjects) and anthropometric, biochemical and histological parameters of prostate were then determined for all groups. RESULTS AND CONCLUSIONS: Despite displaying elevated serum concentrations of IL-6 and TNF-α in the Cancer and the Risk groups compared to the Control group, the differences did not reach significance. However, there was a positive correlation between these cytokines only in the Risk and Cancer groups, showing a general inflammatory behavior in these patients. The results obtained provide general data about the behavior of pro-inflammatory cytokines in prostate cancer. However, they do not demonstrate a direct correlation between serum levels and neoplastic progression. Nevertheless, these findings do not rule out a possible relationship between prostate cancer and serum levels of pro-inflammatory cytokines.

High fat diet induces adhesion of platelets to endothelium in two models of dyslipidemia.

Cardiovascular diseases (CVD) represent about 30% of all global deaths. It is currently accepted that, in the atherogenic process, platelets play an important role, contributing to endothelial activation and modulation of the inflammatory phenomenon, promoting the beginning and formation of lesions and their subsequent thrombotic complications. The objective of the present work was to study using immunohistochemistry, the presence of platelets, monocytes/macrophages, and cell adhesion molecules (CD61, CD163, and CD54), in two stages of the atheromatous process. CF-1 mice fed a fat diet were used to obtain early stages of atheromatous process, denominated early stage of atherosclerosis, and ApoE(-/-) mice fed a fat diet were used to observe advanced stages of atherosclerosis. The CF-1 mice model presented immunostaining on endothelial surface for all three markers studied; the advanced atherosclerosis model in ApoE(-/-) mice also presented granular immunostaining on lesion thickness, for the same markers. These results suggest that platelets participate in atheromatous process from early stages to advance d stages. High fat diet induces adhesion of platelets to endothelial cells in vivo. These findings support studying the participation of platelets in the formation of atheromatous plate.