Chemokines and the extracellular matrix: Set of targets for tumor development and treatment.

The extracellular matrix (ECM) consists of various molecules that support tissue cells, including proteins, fibronectin, laminin, collagen IV, and glycosaminoglycans. In addition to interactions between the ECM and cells, the ECM also interacts with chemokines, and growth factors, and these interactions ensure cell survival, development, differentiation, and migration of both immune system cells and tumor cells. This review provides an overview of the mechanisms of interaction between the ECM and chemokines, focusing on the tumor microenvironment and the modulation of these elements as a target for therapies in several types of cancer.

The use of apocynin inhibits osteoclastogenesis.

Reactive oxygen species (ROS) are produced by NADPH oxidase (NOX), an enzyme that reduces oxygen by using NADPH as a substrate. Apocynin (APO) is a catechol that is used as a NOX inhibitor, and N-acetyl-cysteine ​​(NAC) can reduce intracellular ROS levels. In this work, the effect of APO and NAC on osteoclast formation were evaluated. APO and NAC significantly decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells and the osteoclast area. We analyzed bone-marrow derived monocyte-macrophages (BMMs) that differentiated into osteoclasts after RANKL stimulation. Stimulation was associated with either APO or NAC treatment and osteoclastogenesis marker expression, including NFATc1, MMP-9, and DC-STAMP, was evaluated. APO decreased the intracellular calcium concentration by calcium channels other than ITPR1 and TPC2. On the other hand, APO reduced Tnfrsf11a (RANK) expression and did not alter Fam102a (EEIG1) expression. Therefore, our results demonstrate that APO inhibits osteoclastogenesis by the RANK-RANKL-related signaling pathways, decreases osteoclast markers, and reduces intracellular calcium concentration.

Cell-adhesion molecules and their soluble forms: Promising predictors of "tumor progression" and relapse in leukemia.

Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept of cancer stem cells in carcinoma. Among these surface markers are proteins involved in cell-cell adhesion or cell-matrix adhesion, and they may play a role in the relapse of leukemia, similar to metastasis in carcinomas. The most important are epithelial cadherin, neural cadherin, epithelial cell-adhesion molecule, and CD44, which can be cleaved and released, and their soluble forms were found increased in serum levels of cancer patients, being implicated, in some cases, with progression, metastases, and relapse. In this review, we highlighted the role of these four adhesion molecules in carcinomas and hematological malignancies, mainly leukemia, and discuss if the serum levels of soluble forms can be correlated with the surface protein status on the leukemic cells. Accession of the soluble forms looks attractive, but their use as markers in cancer must be studied in association with other parameters, as there are significant changes in levels in other pathological conditions besides cancer. Studies correlating the levels of the forms with the status of the membrane-bound proteins in leukemic (stem) cells and correlating those parameters with relapse in leukemia may afford important knowledge and applicability of those serum markers in clinical practice. For instance, the expression of the membrane-bound forms of these adhesion proteins may have promising clinical use in leukemia and other hematological malignancies.

Reactivation of natural killer cells with monoclonal antibodies in the microenvironment of malignant neoplasms.

Natural killer cells are critical players in the antitumor immune response due to their ability to destroy target cells through cytotoxic activity and other means. However, this response is inhibited in the tumor microenvironment, where a crippling hypoxic environment and several inhibitory molecules bind to NK cells to trigger an anergic state. Inhibitory receptors such as PD-1, NK2GA, KIR, TIGIT, and LAG-3 have been associated with inhibition of NK cells in multiple cancer types. Binding to these receptors leads to loss of cytotoxicity, lower proliferation and metabolic rates, and even apoptosis. While these receptors are important for avoiding auto-immunity, in a pathological setting like malignant neoplasms they are disadvantageous for the individual's immune system to combat cancer cells. The use of monoclonal antibodies to block these receptors contributes to cancer therapy by preventing the inhibition of NK cells. In this review, the impact of NK cell inhibition and activation on cancer therapy was summarized and an overview of the blockade of inhibitory pathways by monoclonal antibodies was provided.

Current perspectives of osteoclastogenesis through estrogen modulated immune cell cytokines.

Estrogen is a hormone responsible for modulating several physiological processes such as immune response and bone homeostasis. Physiological fluctuations of estrogen concentration are one of the defining principles behind its mechanism. In cases of estrogen deficiency, such as in menopausal women, a more intense bone resorption may occur due to an increase in osteoclast activity. One of the main factors that influence osteoclast formation and response is the immune system, mainly through cytokines secreted by B and T cells. The purpose of this review is to highlight how estrogen can modulate the secretion of cytokines that can alter bone physiology, thereby establishing an axis between estrogen, immune cells, and osteoclastogenesis.

The Recombinant Protein Based on Trypanosoma cruzi P21 Interacts With CXCR4 Receptor and Abrogates the Invasive Phenotype of Human Breast Cancer Cells.

Trypanosoma cruzi P21 is a protein secreted by the parasite that plays biological roles directly involved in the progression of Chagas disease. The recombinant protein (rP21) demonstrates biological properties, such as binding to CXCR4 receptors in macrophages, chemotactic activity of immune cells, and inhibiting angiogenesis. This study aimed to verify the effects of rP21 interaction with CXCR4 from non-tumoral cells (MCF-10A) and triple-negative breast cancer cells (MDA-MB-231). Our data showed that the MDA-MB-231 cells expressed higher levels of CXCR4 than did the non-tumor cell lines. Besides, cytotoxicity assays using different concentrations of rP21 showed that the recombinant protein was non-toxic and was able to bind to the cell membranes of both cell lineages. In addition, rP21 reduced the migration and invasion of MDA-MB-231 cells by the downregulation of MMP-9 gene expression. In addition, treatment with rP21 blocked the cell cycle, arresting it in the G1 phase, mainly in MDA-MB-231 cells. Finally, rP21 prevents the chemotaxis and proliferation induced by CXCL12. Our data showed that rP21 binds to the CXCR4 receptors in both cells, downregulates CXCR4 gene expression, and decreases the receptors in the cytoplasm of MDA-MB-231 cells, suggesting CXCR4 internalization. This internalization may explain the desensitization of the receptors in these cells. Thus, rP21 prevents migration, invasion, and progression in MDA-MB-231 cells.