Abstract
CD44 expression is elevated in basal-like breast cancer (BLBC) tissue, and correlates with increased efficiency of distant metastasis in patients and experimental models. We sought to characterize mechanisms underpinning CD44-promoted adhesion of BLBC cells to vascular endothelial monolayers and extracellular matrix (ECM) substrates. Stimulation with hyaluronan (HA), the native ligand for CD44, increased expression and activation of β1-integrin receptors, and increased α5-integrin subunit expression. Adhesion assays confirmed that CD44-signalling potentiated BLBC cell adhesion to endothelium and Fibronectin in an α5B1-integrin-dependent mechanism. Co-immunoprecipitation experiments confirmed HA-promoted association of CD44 with talin and the β1-integrin chain in BLBC cells. Knockdown of talin inhibited CD44 complexing with β1-integrin and repressed HA-induced, CD44-mediated activation of β1-integrin receptors. Immunoblotting confirmed that HA induced rapid phosphorylation of cortactin and paxillin, through a CD44-dependent and β1-integrin-dependent mechanism. Knockdown of CD44, cortactin or paxillin independently attenuated the adhesion of BL-BCa cells to endothelial monolayers and Fibronectin. Accordingly, we conclude that CD44 induced, integrin-mediated signaling not only underpins efficient adhesion of BLBC cells to BMECs to facilitate extravasation but initiates their adhesion to Fibronectin, enabling penetrant cancer cells to adhere more efficiently to underlying Fibronectin-enriched matrix present within the metastatic niche.
Highlights
Extravasation, a critical step within the metastatic cascade concerns the arrest and adherence of circulating tumor cells (CTCs) on the vascular endothelium within distant tissues and organs
Our observations extend our understanding of CD44promoted adhesion, revealing a role for this receptor in initiating signaling events that promote cell adhesion to a matrix substrate Fibronectin, an extracellular matrix (ECM) substrate reported to be enriched in the metastatic niche [17]
Using cellbased models of basal-like breast cancer (BLBC), we observe that exogenous HA administration initiates a cascade of CD44-dependent events that both promote the expression and activation of specific integrin receptors to mediate adhesion
Summary
Extravasation, a critical step within the metastatic cascade concerns the arrest and adherence of circulating tumor cells (CTCs) on the vascular endothelium within distant tissues and organs. This process requires an initial arrest on the endothelial cells after which the adherent tumor cells traverse the endothelial barrier to gain access to the stroma of the underlying tissue. Cancer cell extravasation is considered to be dependent upon multiple receptor dependent interactions between the tumor cell and the endothelium to regulate “rolling” and “arrest” on the endothelium, prior to exit of the cell from the circulation [2]. Our prior observations demonstrate the importance of www.impactjournals.com/oncotarget
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