ABSTRACT
The chemokine stromal cell-derived-factor 1 (SDF)-1/CXCL12 acts by binding to its receptors, the CXC-4 chemokine receptor (CXCR4) and the CXC-7 chemokine receptor (CXCR7). The binding of CXCL12 to its receptors results in downstream signaling that leads to cell survival, proliferation and migration of tumor cells. CXCL12 and CXCR4 are highly expressed in breast cancer (BC) and glioblastoma (GBM) compared to normal cells. High expression of this chemokine axis correlates with increased therapy resistance and grade, tumor spread and poorer prognosis in these tumors. Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) that inhibits the expression of estrogen-regulated genes, including growth and angiogenic factors secreted by tumor cells. Additionally, TMX targets several proteins, such as protein kinase C (PKC), phospholipase C (PLC), P-glycoprotein (PgP), phosphatidylinositol-3-kinase (PI3K) and ion channels. This drug showed promising antitumor activity against both BC and GBM cells. In this review, we discuss the role of the CXCL12-CXCR4-CXCR7 chemokine axis in BC and GBM tumor biology and propose TMX as a potential modulator of this axis in these tumors. TMX modulates the CXCL12-CXCR4-CXCR7 axis in BC, however, there are no studies on this in GBM. We propose that studying this axis in GBM cells/patients treated with TMX might be beneficial for these patients. TMX inhibits important signaling pathways in these tumors and the activation of this chemokine axis is associated with increased therapy resistance.
Subject(s)
Breast Neoplasms , Glioblastoma , Humans , Female , Breast Neoplasms/drug therapy , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , Glioblastoma/drug therapy , Signal Transduction , Phosphatidylinositol 3-Kinase , Chemokine CXCL12 , Receptors, CXCR4ABSTRACT
Angiotensin-converting enzyme 2 (ACE2) is an important player of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II into angiotensin (1-7). While expressed on the surface of human cells, such as lung, heart, kidney, neurons, and endothelial cells (EC), ACE2 is the entry receptor for SARS-CoV-2. Here, we would like to highlight that ACE2 is predominant on the EC membrane. Many of coronavirus disease 2019 (COVID-19) symptoms have been associated with the large recruitment of immune cells, directly affecting EC. Additionally, cytokines, hypoxia, and complement activation can trigger the activation of EC leading to the coagulation cascade. The EC dysfunction plus the inflammation due to SARS-CoV-2 infection may lead to abnormal coagulation, actively participating in thrombo-inflammatory processes resulting in vasculopathy and indicating poor prognosis in patients with COVID-19. Considering the intrinsic relationship between EC and the pathophysiology of SARS-CoV-2, EC-associated therapies such as anticoagulants, fibrinolytic drugs, immunomodulators, and molecular therapies have been proposed. In this review, we will discuss the role of EC in the lung inflammation and edema, in the disseminate coagulation process, ACE2 positive cancer patients, and current and future EC-associated therapies to treat COVID-19.
Subject(s)
COVID-19/virology , Cardiovascular Diseases/virology , Endothelium, Vascular/virology , Inflammation/virology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/metabolism , Animals , Blood Coagulation , COVID-19/complications , COVID-19/therapy , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cardiovascular Diseases/therapy , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Host-Pathogen Interactions , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/therapy , Inflammation Mediators/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Pulmonary Edema/virology , Signal TransductionABSTRACT
BACKGROUND/AIM: Glioblastoma (GB) is the most aggressive type of tumor in the central nervous system and is characterized by resistance to therapy and abundant vasculature. Tumor vessels contribute to the growth of GB, and the tumor microenvironment is thought to influence tumor vessels. We evaluated the molecular communication between human GB cells and human brain microvascular endothelial cells (HBMEC) in vitro. MATERIALS AND METHODS: We investigated whether GB-conditioned media (GB-CM) influenced HBMEC proliferation and migration, as well as the levels of MMP-9, CXCL12, CXCR4, CXCR7, VEGFs, VEGFR-2, and WNT5a in HBMEC. RESULTS: Although HBMEC proliferation was not modified, increased HBMEC migration was detected after GB-CM treatment. Furthermore, treatment of HBMEC with GB-CM resulted in increased levels of MMP-9 and CXCR4. The levels of WNT5a, VEGFs and VEGFR-2 were not affected. CONCLUSION: GB-secreted factors lead to increased endothelial cell migration and to increased levels of MMP-9 and CXCR4.
