*Weronika Bulska-Bedkowska, Jerzy Chudek
Markers of endothelial dysfunction in early and advanced breast cancer dissemination
Markery uszkodzenia śródbłonka we wczesnym i zaawansowanym rozsiewie raka piersi
Department of Internal Diseases and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Poland
Streszczenie
Śródbłonek jest wyspecjalizowaną wyściółką naczyń krwionośnych, zbudowaną z pojedynczej warstwy płaskich komórek, które pełnią czynność transportową i parakrynną. Coraz więcej danych sugeruje, że komórki śródbłonka ogrywają ważną rolę we wzroście nowotworów i procesie powstawania przerzutów. W związku z tym, że odległe przerzuty stanowią główną przyczynę zgonów, m.in. z powodu raka piersi, poszukiwane są markery wczesnego rozsiewu nowotworowego, niewykrywalnego dostępnymi metodami obrazowania, które mogłyby uzasadniać stosowanie bardziej agresywnej terapii neoadjuwantowej i adjuwantowej, jak również stanowić nowe cele terapeutyczne. Zainteresowanie onkologów wzbudziły adhezyny uczestniczące w regulacji procesów różnicowania, proliferacji, migracji i apoptozy. Spośród licznej grupy uznanych markerów uszkodzenia śródbłonka z grupy adhezyn, badania naukowe ograniczają się do E-selektyny, ICAM-1 i VCAM-1. Wzrost stężenia tych adhezyn pojawia się u chorych z rozsiewem odległym komórek raka sutka. Dostępne wyniki badań wskazują na potencjalne znaczenie prognostyczne tych markerów.
Summary
Endothelium is a specialized lining of blood vessels, made up of a single layer of simple squamous cells that carry out transport and paracrine activities. The increasing number of studies suggest that endothelial cells play an indirect role in tumor growth and metastasis. Due to the fact that distant metastases are the main cause of death in breast cancer, markers of early neoplastic dissemination, undetectable by available imaging methods, are sought and that could justify the use of more aggressive neoadjuvant and adjuvant therapies, as well as might be a new potential therapeutic goals. Adhesins involved in the regulation of processes of differentiation, proliferation, migration and apoptosis raised interest among oncologists. Among a large group of recognized markers of endothelial dysfunction, mostly adhesins: E-selectin, ICAM-1 and VCAM-1 were studied. Increase in the concentration of these adhesins occurs in patients with distant dissemination of breast cancer cells. Available research results indicate the potential prognostic significance of these markers.
Introduction
Endothelium is a specialized lining of blood vessels with the area up to 7 m2, made up of a single layer of 1-6 x 1013 simple squamous cells (1, 2). Endothelium was discovered in the 19th century by Friedrich von Recklinghausen (1).
Endothelial cells express paracrine activity and play a critical role in the regulation of blood flow, blood pressure, coagulation, angiogenesis, inflammatory response, and participate in the transport of substances from blood to the tissues (1). The increasing number of studies suggest that endothelial cells play an indirect, but important role in tumor growth and formation of metastases. As distant metastases are the main cause of death in patients with breast cancer, early markers of neoplastic dissemination, undetectable by available imaging techniques, are searched. They also may serve as new potential therapeutic goals. Markers of endothelial dysfunction are promising subjects of scientific research. A list of the markers includes cell adhesion molecules (CAM), which in physiological conditions are responsible for maintaining continuity of the tissue, through the interaction of cells between themselves and the extracellular matrix (3). In addition, CAM play an important role in the immune response, especially in the migration of leukocytes across the endothelium and their recruitment to inflammatory foci. As adhesins are involved in the regulation of processes of differentiation, proliferation, migration and apoptosis, they raised interest among oncologists (3, 4).
CAMs are physiologically bind to the cytoplasmic membrane. After cleavage, soluble forms can be detected in the circulation (soluble CAM, sCAM) (4). Endothelial activation by inflammatory mediators is associated with an increase in the levels of these soluble particles in the blood. Increased level of sCAM, observed in cancer patients is not only a result of endothelial dysfunction, but also their overproduction by tumor cells, as well as an immune response to the cancer (3, 4).
Markers of endothelial dysfunction belong to a group of adhesins, containing: E-selectin (CD62E), P-selectin (CD62P), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), vascular endothelial cadherin (VE-cadherin), endoglin (CD105). Most studies in oncology are limited to E-selectin, ICAM-1 and VCAM-1. In addition, the group includes cell adhesion molecule 1 (CADM-1), which expression on the endothelium was demonstrated for the first time several years ago, applying immunofluorescence method (5).
E-selectin
E-selectin (CD62E) is an adhesive molecule with a glycoprotein structure that consists of lectin domain, an epidermal grows factor-like domain, homological to complement control protein, transmembrane domain, and an intracellular cytoplasmic tail. The selectins exist in the form bound to cytoplasmic membrane and in a soluble form, deprived of the transmembrane and intracellular domains, circulating in the body fluids. E-selectin play an important role in neutrophil adhesion to activated endothelial cells. E-selectin is expressed on endothelial cells stimulated by inflammatory mediators, that are necessary to induce its production (4).
The first studies suggested that E-selectin may play a role in the adhesion of cancer cells to endothelium, contributing to the formation of distant metastases (6). E-selectin was detected (immunohistochemically) on venous endothelial cells in patients with breast cancer, that indicates endothelial activation in these patients (7). Recent studies support the hypothesis and explain the role of E-selectin in the adhesion and migration of cancer cells that is related to the interaction with CD44 receptors (8, 9). Current studies focus on the role of sE-selectin in adhesion and transmigration of breast cancer cells. It was shown, that sE-selectin may promote adhesion of CD44+ breast cancer cells to non-activated human microvascular endothelial cells (HMVEC) (9). The similar effect was not found for the CD44-tumor cell line. In vitro, the incubation of CD44+ cancer cells with sE-selectin triggered phosphorylation of focal adhesion kinase (FAK), while the adhesion of these cells to the endothelium induced an increase in the permeability of the cytoplasmic membrane in the endothelium.
In addition, concentration of sE-selectin was shown to correlate with breast cancer grading and staging, and the presence of metastases (10). Various studies have shown: a significantly higher concentration of sE-selectin in breast cancer in comparison to benign tumors (10-12), correlation between E-selectin concentration and tumor grading (10), TNM staging – tumor size, lymph nodes involvement (10), and the presence of liver (7, 13) and bone metastases (7). The sE-selectin concentration was also considered as a potential predictor of overall survival (13). In addition, there was a correlation between concentrations of sE-selectin (as well as: sVCAM-1, sICAM-1) and the level of tumor marker Ca 15-3 (11). Of interest, higher concentration was found in women with breast cancer without expression of estrogen receptors (10).
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