Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM

Abstract

Cells sorted from head and neck cancers on the basis of their high expression of CD44 have high potency for tumor initiation. These cells are also involved in epithelial to mesenchymal transition (EMT) and we have previously reported that cancer stem cells (CSCs) exist as two biologically distinct phenotypes. Both phenotypes are CD44 high but one is also ESA high and maintains epithelial characteristics, the other is ESA low , has mesenchymal characteristics and is migratory. Examining CD44-regulated signal pathways in these cells we show that CD44, and also RHAMM, act to inhibit phosphorylation of glycogen synthase kinase 3b (GSK3b). We show that inhibitory phosphorylation reduces the formation of both ''tumor spheres'' and ''holoclone'' colonies, functional indicators of stemness. GSK3b inhibition also reduces the expression of stem cell markers such as Oct4, Sox2, and Nanog and upregulates expression of the differentiation markers Calgranulin B and Involucrin in the CD44 high /ESA high cell fraction. Transition of CSCs out of EMT and back to the epithelial CSC phenotype is induced by GSK3b knockdown. These results indicate that GSK3b plays a central role in determining and maintaining the phenotypes and behavior of CSCs in vitro and are likely to be involved in controlling the growth and spread of tumors in vivo.

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

“…Among the most studied receptor proteins are CD44 and receptor for hyaluronan-mediated motility (RHAMM), as they participate in inflammation and cancer motility, migration and metastasis (Slevin et al, 2007; Lokeshwar et al, 2014; Tolg et al, 2014; Misra et al, 2015). Furthermore, both CD44 and RHAMM are associated with the development of stem cell and cancer stem cell (Jiang et al, 2013; Shigeishi et al, 2013; Kouvidi et al, 2014; Jordan et al, 2015). FAK/SRC-mediated ERK activation is involved in signaling event for stem cell development.…”

Expression of Betapapillomavirus Oncogenes Increases the Number of Keratinocytes with Stem Cell-Like Properties

“…For example, the immunophenotype of cancer stem cells in breast cancer is CD44 ϩ CD24 Ϫ EpCAM ϩ (epithelial cell adhesion molecule) (27) (31,32). In cutaneous SCC cell lines, CD44…”

“…high EpCAM high population, a shift toward CD44 low cell surface expression, and an increase in the expression of the differentiation marker Calgranulin B (32). EpCAM overexpression contributes to carcinogenesis by inducing anchorage-independent growth and by enhancing proliferation through upregulation of c-Myc and cyclins A and E (33,34).…”

Expression patterns of CD168 correlate with the stage and grade of squamous cell carcinoma of head and neck

“…), and is essential in cell migration and proliferation during embryogenesis (12). CD168 has been extensively studied in different tumor cell lines and a variety of tumor types, including lymphoid and myeloid malignancies, and colorectal, breast, ovarian and urothelial carcinoma (13)(14)(15)(16), although only a few studies have dealt with its expression and significance in the head-and-neck SCCs (17)(18)(19). It has been demonstrated that CD168 is required to facilitate proliferation of head-and-neck cancer cells (18).…”

“…CD168 is involved in the epithelial-to-mesenchymal transition (EMT) during the process of metastasis, and in the generation of breast cancer stem cells with enhanced resistance to therapy (19).…”