Acquisition of Anoikis Resistance Up-Regulates Syndecan-4 Expression in Endothelial Cells

Abstract

Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent-independent cell growth and attachment to an inappropriate matrix, thus avoiding colonization of distant organs. Cell adhesion plays an important role in neoplastic transformation. Tumors produce several molecules that facilitate their proliferation, invasion and maintenance, especially proteoglycans. The syndecan-4, a heparan sulfate proteoglycan, can act as a co-receptor of growth factors and proteins of the extracellular matrix by increasing the affinity of adhesion molecules to their specific receptors. It participates together with integrins in cell adhesion at focal contacts connecting the extracellular matrix to the cytoskeleton. Changes in the expression of syndecan-4 have been observed in tumor cells, indicating its involvement in cancer. This study investigates the role of syndecan-4 in the process of anoikis and cell transformation. Endothelial cells were submitted to sequential cycles of forced anchorage impediment and distinct lineages were obtained. Anoikis-resistant endothelial cells display morphological alterations, high rate of proliferation, poor adhesion to fibronectin, laminin and collagen IV and deregulation of the cell cycle, becoming less serum-dependent. Furthermore, anoikis-resistant cell lines display a high invasive potential and a low rate of apoptosis. This is accompanied by an increase in the levels of heparan sulfate and chondroitin sulfate as well as by changes in the expression of syndecan-4 and heparanase. These results indicate that syndecan-4 plays a important role in acquisition of anoikis resistance and that the conferral of anoikis resistance may suffice to transform endothelial cells.

Epidermal growth factor–induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasisviaup‐regulation of fibronectin

“…As shown in our studies, EGF-induced PDK1 expression enhanced fibronectin expression, thereby promoting HNSCC metastasis. Elevated PKM2 expression has been demonstrated in many carcinomas, such as colon carcinoma (34), renal cell carcinoma (RCC) (35), and lung carcinoma (36). Expression of hexokinase 2, PDK1, PKM1, and PKM2, which are involved in glycolytic metabolism, is strongly increased in pancreatic tumor cells, which leads to a significant induction of aerobic glycolytic metabolism (37)(38)(39)(40)(41).…”

The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis

“…Increased syndecan-4 and heparanase expression have been reported in anoikis-resistant rat endothelial cells ( Carneiro et al, 2014 ). Studying these cell lines, Carneiro et al (2014) also detected increased level of HS in the culture medium, whereas cell lysates contained increased levels of CS.…”

Altered shear stress on endothelial cells leads to remodeling of extracellular matrix and induction of angiogenesis

“…Rabbit aortic endothelial cells (EC-clone CIPs), an immortalized cell culture were kindly provided by Dr. Vincenzo Buonassisi [13,14]. This cell line has been a model in our laboratory for over 30 years [14][15][16][17][18][19][20] and this cell line has many endothelial characteristics including blood compatibility, expression of von Willebrand factor, tissue factor pathway inhibitor, and estrogen receptor, production of anticoagulant heparan sulfate, and fibronectin as well as development of capillary-like structures in vitro [14,[21][22][23][24][25][26][27][28][29]. The endothelial cells (ECs), 8 th passage, were maintained in F12 medium (Cultilab, Campinas, SP, Brazil) supplemented with 10% fetal bovine serum (Gibco1), streptomycin and penicillin (both 100 IU/ml) (Sigma-Aldrich, St. Louis, MO) and 20 mM sodium bicarbonate at 37˚C in a humidified atmosphere (2.5% CO 2 ) [14].…”