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.
Highlights
The extracellular matrix (ECM) affects many aspects of cell behavior, including the migratory properties of cells, their morphology, growth characteristics, and differentiation [1, 2]
Alterations in cell-cell adhesion molecules, protein kinases or phosphatases, integrin-associated signalling molecules or apoptosis regulators can lead to resistance to the physiologically occurring anoikis, conferring by this way a constitutive pro-survival signal allowing dissemination of metastatic cancer cells [5,6,7,8,9]
As expected for a nontumorigenic immortalized cell line, the great majority of these cells underwent apoptosis induced by adhesion blockade
Summary
The extracellular matrix (ECM) affects many aspects of cell behavior, including the migratory properties of cells, their morphology, growth characteristics, and differentiation [1, 2]. Most normal endothelial cells require continuous signals from their environment to survive (mediated via adhesive interactions with other cells or extracellular matrix proteins) and loss of contact induces a specialized form of apoptosis, anoikis. Failure to execute the anoikis program could result in adherent cells surviving under suspension conditions or proliferating at ectopic sites where the ECM proteins are different from the original ones. This deregulation in anoikis execution is emerging as a hallmark of cancer cells and contributes to the formation of metastasis in distant organs [4]. Alterations in cell-cell adhesion molecules, protein kinases or phosphatases, integrin-associated signalling molecules or apoptosis regulators can lead to resistance to the physiologically occurring anoikis, conferring by this way a constitutive pro-survival signal allowing dissemination of metastatic cancer cells [5,6,7,8,9]
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