CD44S-hyaluronan interactions protect cells resulting from EMT against anoikis

Abstract

The detachment of normal epithelial cells from matrix triggers an apoptotic response known as anoikis, during homeostatic turnover. Metastatic tumor cells evade anoikis, by mechanisms that are only partly characterized. In particular, the epithelial–mesenchymal transition (EMT) in a subset of invasive tumor cells confers anoikis-resistance. In some cases, EMT up-regulates the cancer stem cell marker CD44S and the enzyme hyaluronic acid synthase-2 (HAS2). CD44S is the major receptor for hyaluronan in the extracellular matrix. Herein, we demonstrate that CD44S, unlike the CD44E isoform expressed in normal epithelial cells, contributes to the protection against anoikis. This protection requires the interaction of CD44S with hyaluronan (HA). CD44S–HA interaction is proposed to play an important role in tumor metastasis through enhanced cell survival under detached conditions.

Grainyhead-like 2 Reverses the Metabolic Changes Induced by the Oncogenic Epithelial–Mesenchymal Transition: Effects on Anoikis

“…We have previously reported that CD44S, which is upregulated in MSP cells, contributes to anoikis resistance (31). CD44 was shown elsewhere to decrease ROS by shifting metabolism from oxidative phosphorylation toward glycolysis and pentose phosphate pathways, thereby increasing reduced glutathione levels (32).…”

IGF-I/EGF and E2 signaling crosstalk through IGF-IR conduit point affects breast cancer cell adhesion

“…Moreover, their contribution is critical for the maintenance of malignant transformation and protection against apoptosis [21,51]. Cell adhesion is a critical event in the migration/ invasion step of cancer progression [52]. Cancer cell motility is highly dependent on components of the surrounding extracellular matrix [53,54].…”

Carcinoma Cell Hyaluronan as a “Portable” Cancerized Prometastatic Microenvironment

“…Thus, HA rich pericellular matrices facilitate intravasation and protect immigrant cells from anoikis during circulatory transit. They also contribute to the ectopic tissue colonization of foreign microenvironments [15]. For example, they can promote the adhesion of tumor cells to microvessel endothelium as has been demonstrated for metastatic prostate carcinoma cells in culture [9].…”

“…In particular, the standard CD44 isoform (CD44s), which binds to HA and lacks alternatively spliced domains, is structurally and functionally well characterized [4, 13, 15, 25]. CD44s is a type I transmembrane protein with an HA binding amino terminal link module that is structurally homologous to link modules found in other HA receptors such as LYVE-1 and in extracellular HA binding proteins such as TSG-6, versican [26, 27].…”