CXCR4/CXCR7-CXCL11/CXCL12 AXIS PROMOTES MALIGNANT PHENOTYPE IN PUTATIVE STEM CELLS FROM HUMAN MENINGIOMAS
Creators: name: SOLARI, AGNESE
Publisher: name: Universit� degli studi di Genova
Year: 2019

description: Meningioma is the most frequent primary tumor of the central nervous system. The
greatest percentage of meningiomas is benign tumors (WHO grade I). However,
although surgical and radiotherapy techniques have significantly improved over the
years, some meningiomas, independently from the grading, are refractory to
multimodality therapies, and recur and/or undergo malignant transformation,
representing an unsolved therapeutic challenge. Therefore, beside histopathologic
benign appearance, biologically aggressive meningiomas need to be molecularly
characterized, to identify novel therapeutic targets.
In malignant tumors, recurrence is mainly ascribed to the presence of cancer stem
cells (CSCs) which are expression of tumor cell heterogeneity, and sustain
tumorigenesis, metastasization and drug resistance.
CSCs are characterized by stem cell marker expression, self-renewal, and ability to
differentiate into tumor-specific cell types. Recently, CSCs and their functional role
have been also studied in benign tumors, including meningioma. A range of genes
and proteins have been proposed to identify meningioma stem-like cells, among
them CD105, a transmembrane glycoprotein, involved in angiogenesis and in the
progression of a variety of tumors. Stemness, as well as cancer cell aggressive
behavior, is a cell property strictly linked to tumor microenvironment: reciprocal
interactions between growth factors, cytokines and chemokines released by both
CSCs and other cell types forming the niche, modulate each other to sustain tumor
growth. Chemokine signaling, and the CXCL11/CXCL12-CXCR4/CXCR7 system in
particular, drives cell proliferation and migration in several solid tumors. On these
premises, this study is focused on the isolation and characterization of stem-like
cells from post-surgical samples of human meningiomas, delving deeply into the
role of this subpopulation in meningioma aggressive behavior. Moreover, we
analyzed the contribution of CXCR4-7 receptors in the regulation of their biological
properties. Twenty-eight primary cell cultures have been obtained from 35
meningiomas, and maintained in stem cell-permissive culture conditions to enrich
in CSCs. Putative meningioma stem cells rapidly grow, form meningospheres and
express stem markers, such as Sox2, NANOG, CD133 and Oct-4. Conversely, CD105
was not differentially expressed between stem-like cells and their ?non-stem?
counterpart, cells grown in serum-containing medium. Moreover, stem-like cells
displayed high migratory capacity and in vitro angiogenic activity, supporting their
malignant phenotype. Meningioma stem-like cells displayed a distinct chemokinereceptor
profile from ?non-stem? cell population, and selectively respond to in vitro
CXCL11 and CXCL12 stimulation enhancing proliferation, migration and vascular
mimicry. Pharmacological inhibition of individual CXCR4 or CXCR7 significantly
impaired CXCL12- and CXCL11-induced proliferation, chemotaxis and vessel-like
structure formation, therefore suggesting that these activities are mediated by both
receptors. We speculated that these receptors act as heterodimers, formed upon
ligand activation and that the blockade of one of them results in a complete
inhibition of biological effects.
Overall our results, collected from a large number of meningioma cell cultures
derived from different patients, allow the identification of a tumor subpopulation
endowed with comm
on stem cell-like features, and suggest that both CXCR4 and
CXCR7 signaling sustains meningioma stem cell phenotype. Prospectively, the
isolation and culture of stem-like cells directly from the meningioma tissues will
allow to test new therapeutic compounds to block meningioma growth and
invasiveness, in particular for those tumors showing an unpredictable aggressive
behavior. In this context, we propose that the CXCR4-7 chemokinergic system might
represent a relevant pharmacological target.