title: Modulation of invasive properties of CD133+ glioblastoma stem cells: a role for MT1-MMP in bioactive lysophospholipid signaling.
abstract: Future breakthroughs in cancer therapy must accompany targeted agents that will neutralize cancer stem cells response to circulating growth factors. Since the brain tissue microenvironmental niche is a prerequisite for expression of the stem cell marker CD133 antigen in brain tumors, we investigated the invasion mechanisms specific to CD133(+) U87 glioblastoma cells in response to lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two circulating bioactive lysophospholipids and potent inducers of cancer. A CD133(+) U87 glioma cell population was isolated from parental U87 glioblastoma cells using magnetic cell sorting technology. The CD133(+)-enriched cell population grew as neurospheres and showed enhanced maximal response to both LPA (approximately 5.0-fold) and S1P (approximately 2.5-fold) at 1 microM when compared to parental U87 cells. The increased response to LPA in CD133(+) cells, reflected by increased levels of phosphorylated ERK, was found independent of the cooperative functions of the membrane-type-1 matrix metalloproteinase (MT1-MMP), while this cooperativity was essential to the S1P response. Quantitative RT-PCR was performed and we found higher gene expression levels of the S1P receptors S1P1 and S1P2, and of the LPA receptor LPA1 in CD133(+) cells than in their parental U87 cells. These increased levels reflected those observed from in vivo experimental U87 tumor implants. Our data suggest that the CD133(+) cell subpopulation evokes most of the lysophospholipid response within brain tumors through a combined regulation of S1P/LPA cell surface receptors signaling and by MT1-MMP. The emergence of lead compounds targeting the stem cell niche and S1P/LPA signaling in CD133(+) cancer cells is warranted.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada.
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Lachambre
authors.forename: Karine
authors.initials: K
authors.lastname: Plouffe
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau