CD44 adhesion molecule and neuro-glial proteoglycan NG2 as invasive markers of glioma

Abstract

Glioma invasion into the CNS involves the interaction of tumor cells with the host's cells and extracellular matrix (ECM) molecules. In this study, the expression of ECM-associated and cell-associated proteins such as the transmembrane CD44 adhesion molecule and neuro-glial proteoglycan 2 (NG2), a member of the chondroitin sulfate proteoglycan family, were evaluated during glioma progression, in vitro and in vivo, using a model of a highly invasive and aggressive intracerebral mouse G-26 glioma. We found a marked increase in CD44 and NG2 expression in brain tissue containing glioma. The glioma levels of these proteins gradually increased over time to reach 3-15 times the levels in the contralateral control. NG2 and CD44 expression paralleled progression of the glioma, being higher on days 14 and 21 than on day 2 post-glioma implant. In addition, when invading glioma crossed the midline in the advanced tumor stage, levels of each of these proteins in the contralateral tissue were elevated, but were still significantly lower than in the ipsilateral, tumor-bearing hemisphere. Immunohistochemistry of advanced stage G-26 glioma (day 21) showed CD44 expression to be most prominent at the front of the glioma invasion line, sharply separated from normal brain parenchyma which expressed glial fibrillary acidic protein (GFAP). However, single CD44 positive cells that escaped the tumor mass penetrated between the astrocytes that encased the tumor at its periphery. In contrast, NG2 was expressed on nearly all glioma cells within the tumor mass but less so at the leading edge of the tumor. The NG2 positive cells were clearly demarcated and morphologically distinguishable from GFAP positive cells and only sporadic, small groups of NG2 positive cells were seen in the GFAP positive zone of the neuropil. Taken together, these data show that during glioma progression in the brain, the level and pattern of glioma-associated molecules such as CD44 and NG2 may aid in tracing and targeting the invading glioma cells.

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).…”

Roles of NG2 glial cells in diseases of the central nervous system

“…Molecular interactions allow NG2 proteoglycan to contribute to critical processes such as cell proliferation, glioma vasculature, cell motility and cell survival. Moreover, several reports have correlated the expression of NG2 proteoglycan with the degree of malignancy of the glioma [55][56][57][58][59][60] .…”

Proteoglycans in normal physiology and carcinogenesis

“…Экспрессия CD44 заметно увеличивается при про-грессировании глиомы [76]. Вероятно, гиалуроновая кислота усиливает инвазию клеток глиомы в модельной системе in vitro именно через молекулярный механизм, включающий в себя взаимодействие гиалуроновой кислоты с CD44 [77].…”