CD44 Attenuates Activation of the Hippo Signaling Pathway and Is a Prime Therapeutic Target for Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy. Cancer Res; 70(6); 2455-64. ©2010 AACR.

Three-Dimensional Culture of Mouse Renal Carcinoma Cells in Agarose Macrobeads Selects for a Subpopulation of Cells with Cancer Stem Cell or Cancer Progenitor Properties

“…, and Oct4 þ ) similar or parallel to those already described for other solid tumors (11)(12)(13)(35)(36)(37)(38)(39)(40)(41)(42)(43). Second, analysis of gene microarray data from the cells in the macrobeads indicate that pathways which have been associated with stem cells, such as the Wnt pathway, are enhanced compared with the same gene pathways in the total population of RENCA cells in monolayer culture.…”

Moesin Is a Glioma Progression Marker That Induces Proliferation and Wnt/β-Catenin Pathway Activation via Interaction with CD44

“…Signaling through CD44 has been previously investigated, and downstream ERK and PI3K-Akt pathway activation or Hippo cascade inhibition were described (36)(37)(38)(39)(40). Moesin overexpression in glioblastoma and NHA cells activated the PI3K-Akt, ERK, and p38 MAPK pathways (Fig.…”

Extracellular Matrix Microenvironment in Glioma Progression

“…CD44 serves as a surface receptor for ECM molecules such as HA and CSPGs (Ranuncolo et al 2002). CD44 receptor is overexpressed in glioma cells in vitro (Wiranowska et al 2000, Yu et al 2010) and found in vivo at the leading edge of glioma at the brain-tumor interface (Wiranowska et al 2006). The HA-CD44 interaction and CD44 shedding from the cell surface were found to be associated with glioma cell motility, migration, and infiltration into the normal brain parenchyma (Annabi et al 2005).…”