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Integrin Alpha 6: Anchors Away for Glioma Stem Cells

2010; Elsevier BV; Volume: 6; Issue: 5 Linguagem: Inglês

10.1016/j.stem.2010.04.003

1934-5909

Nina S. Corsini, Ana Martin‐Villalba,

Cell Adhesion Molecules Research

The laminin receptor Integrin α6β1 anchors adult neural stem cells to the niche vasculature. In this issue of Cell Stem Cell, Lathia et al., 2010Lathia J.D. Gallagher J. Heddleston J.M. Wang J. Eyler C.E. MacSwords J. Wu Q. Vasanji A. McLendon R.E. Hjelmeland A.B. Rich J.N. Cell Stem Cell. 2010; 6 (this issue): 421-432Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar show that glioblastoma stem cells highly express integrin α6 and that their interaction with laminin on endothelial cells directly regulates their tumorigenic capacity. The laminin receptor Integrin α6β1 anchors adult neural stem cells to the niche vasculature. In this issue of Cell Stem Cell, Lathia et al., 2010Lathia J.D. Gallagher J. Heddleston J.M. Wang J. Eyler C.E. MacSwords J. Wu Q. Vasanji A. McLendon R.E. Hjelmeland A.B. Rich J.N. Cell Stem Cell. 2010; 6 (this issue): 421-432Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar show that glioblastoma stem cells highly express integrin α6 and that their interaction with laminin on endothelial cells directly regulates their tumorigenic capacity. Glioblastoma multiforme (GBM) is the most frequent and malignant primary brain tumor. Despite advances in radiotherapy, chemotherapy and aggressive surgical resection treatments, the prognosis remains dismal. After diagnosis, patients have a mean survival of 15 months and a 2 year survival rate of ∼ 25%. New directions for development of cancer therapies have emerged with the idea that malignant tumors harbor a small subpopulation of cells that are responsible for tumor propagation and that share common features with their tissue stem cell counterparts. These features refer to their ability to grow under stem cell selective conditions, their multilineage differentiation potential, and their extensive self-renewal, as indicated by their ability to form tumors after single and serial transplantation. Targeting these glioma stem cells (GSCs) thus has the potential to reduce tumor relapse and improve chances of finding a final cure. The difficult task of targeting GSCs starts with the identification of this subpopulation within the tumor bulk. Research on specific GSC markers has been guided by previously acknowledged markers of their neuronal stem cell counterparts (NSCs). This is how CD133 and CD15 came to the forefront as markers for GSCs. CD133+ or CD15+ cells isolated from GBM tumors fulfill the GSC's criteria; however, expression of these markers is not consistently found in every malignant brain tumor. Moreover, in a recent study, patient-derived CD133 negative cells gave rise to tumors in nude rats, findings that suggest that CD133 expression is not uniquely informative for all GSC populations (Wang et al., 2008Wang J. Sakariassen P.O. Tsinkalovsky O. Immervoll H. Boe S.O. Svendsen A. Prestegarden L. Rosland G. Thorsen F. Stuhr L. et al.Int. J. Cancer. 2008; 122: 761-768Crossref PubMed Scopus (453) Google Scholar). Thus, identifying additional GSC markers is an important goal in cancer stem cell research. In this issue of Cell Stem Cell, Lathia et al., 2010Lathia J.D. Gallagher J. Heddleston J.M. Wang J. Eyler C.E. MacSwords J. Wu Q. Vasanji A. McLendon R.E. Hjelmeland A.B. Rich J.N. Cell Stem Cell. 2010; 6 (this issue): 421-432Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar now add integrin α6 to the battery of known GSC markers. Looking at the overlap of CD133+ and integrin α6+ populations, the authors find that integrin α6 expression enriches for GSCs in tumors that lack CD133 expression and that combining CD133 and integrin α6 expression results in a higher enrichment of GSCs than CD133 expression alone. In addition to advancing our ability to identify GSCs, the findings also point to the potential of targeting integrin α6 for antiglioblastoma therapy. Lathia and colleagues examined integrin α6 expression in biopsy samples from glioblastoma patients and found that integrin α6+ cells were localized in close proximity to the tumor vasculature and often coexpressed the stem cell markers CD133 and nestin. The authors next found that patient-derived GSCs propagated as xenografts had elevated levels of integrin α6 expression relative to bulk glioma cells and that integrin α6 and CD133 expressing GSC populations largely overlapped as determined with FACS analysis and immunostaining of tumorspheres generated from GSCs. To investigate the tumorigenic potential of integrin α6+ cells relative to CD133 expression, Lathia et al. studied self-renewal ability of FACS-sorted tumor populations that are single positive for integrin α6 and CD133 and double positive for both markers. Integrin α6+ cells exhibited a high proliferation rate as well as a high tumorsphere-building capacity both in the absence and presence of CD133 expression. Xenotransplantation of integrin α6+ cells in the brains of immunocompromised mice resulted in a higher incidence of secondary tumor formation and a reduced survival than what was obtained with Integrin α6− cells. Altogether, these findings establish integrin α6 as a novel GSC marker and also suggest that integrin α6 expression can be useful for identifying GSCS in tumors with low or little CD133 expression. To address the functional role of integrin α6 expression in GSCs, the authors reduced integrin α6 expression using siRNA or a blocking antibody that abolishes the laminin-integrin α6 interaction. Interestingly, this not only reduced proliferation and tumorsphere-building capacity of GSCs but also resulted in a strong increase in cell death. Accordingly, when GSCs expressing siRNA against integrin α6 or GSCs treated with integrin α6 blocking antibody were injected into the brains of immunocompromised mice, these mice survived significantly longer than mice with an intact integrin α6-laminin interaction. Consequently, blocking integrin α6 signaling could be a promising therapeutic strategy. The present findings raise questions of whether integrin α6 expression on GSCs has functional implications for tumor behavior. Integrins regulate stem-cell adhesion to the extracellular matrix (ECM). ECM proteins contain binding sites for cell-adhesion molecules and growth factors, which make them the ideal platform to establish stable morphogen gradients and enable molecular cross talk (Hynes, 2009Hynes R.O. Science. 2009; 326: 1216-1219Crossref PubMed Scopus (1972) Google Scholar). Laminin contains multiple EGF-like domains, which might bind to EGF receptors and enable their crosstalk with integrin α6β1 (Panayotou et al., 1989Panayotou G. End P. Aumailley M. Timpl R. Engel J. Cell. 1989; 56: 93-101Abstract Full Text PDF PubMed Scopus (247) Google Scholar). The integrin α6-laminin interaction was recently reported to play an important role in the subventricular zone (SVZ) of the lateral ventricles in the adult brain (Shen et al., 2008Shen Q. Wang Y. Kokovay E. Lin G. Chuang S.M. Goderie S.K. Roysam B. Temple S. Cell Stem Cell. 2008; 3: 289-300Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar). This neurogenic zone contains an extensive, superficial network of vasculature that acts as a niche for neural stem and progenitor cells (Mirzadeh et al., 2008Mirzadeh Z. Merkle F.T. Soriano-Navarro M. Garcia-Verdugo J.M. Alvarez-Buylla A. Cell Stem Cell. 2008; 3: 265-278Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar, Shen et al., 2008Shen Q. Wang Y. Kokovay E. Lin G. Chuang S.M. Goderie S.K. Roysam B. Temple S. Cell Stem Cell. 2008; 3: 289-300Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar, Tavazoie et al., 2008Tavazoie M. Veken L. Silva-Vargas V. Louissaint M. Colonna L. Zaidi B. Garcia-Verdugo J.M. Doetsch F. Cell Stem Cell. 2008; 3: 279-288Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar). In these studies, the SVZ stem cells (B-type cells), and their progeny, the highly proliferative transit-amplifying cells (TACs; C-type cells) were reported to be in direct or close contact to the vasculature and to express integrin α6. In contrast, the more differentiated neuroblasts (A-type cells) were more distally located and downregulated integrin α6 expression (Figure 1). The SVZ niche vasculature is surrounded by branched structures of extracellular matrix rich in laminin, also known as fractones. In the SVZ, blocking the laminin-integrin α6β1 interaction caused stem cells to lose contact and move away from the vascular niche (Shen et al., 2008Shen Q. Wang Y. Kokovay E. Lin G. Chuang S.M. Goderie S.K. Roysam B. Temple S. Cell Stem Cell. 2008; 3: 289-300Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar), suggesting that the integrin α6-laminin interaction is functionally important for maintaining niche integrity and regulating exit from the niche. In the present study, Lathia et al. identify integrin α6 as a hallmark of GSCs. Integrin α6 is also expressed outside of the nervous system by tissue stem cells including epidermal and mammary stem cells and was identified as part of a "stemness" signature common to embryonic and hematopoietic stem cells (Fortunel et al., 2003Fortunel N.O. Otu H.H. Ng H.H. Chen J. Mu X. Chevassut T. Li X. Joseph M. Bailey C. Hatzfeld J.A. et al.Science. 2003; 302: 393Crossref PubMed Google Scholar). The paradox behavior of NSCs and GSCs toward the same instructive molecule probably highlights the aberrant lineage relationship of GSCs. Accordingly, whereas NSCs are regarded as a relatively quiescent population, Lathia et al. show that integrin α6-labeled GSCs consistently expressed the mitotic marker phosphohistone-3. Similarly, CD133 expression in human neural stem cells, as well as in colon cancer and melanoma cells, correlated with an enrichment of cells in G2-M phase of the cell cycle (Sun et al., 2009Sun Y. Kong W. Falk A. Hu J. Zhou L. Pollard S. Smith A. PLoS ONE. 2009; 4: e5498Crossref PubMed Scopus (106) Google Scholar). Therefore, the observed correlation between CD15, CD133, and integrin α6 expression with malignancy might indicate an increased presence of cycling transient-amplifying cells within the tumor stem cell compartment; however, whether these markers identify dormant glioma stem cells remains unclear. Similarly, expression of CD133 increases upon exposure to ischemic conditions or with the onset of angiogenesis, suggesting that it might rather be a marker of tumor progression than a GSC marker (Griguer et al., 2008Griguer C.E. Oliva C.R. Gobin E. Marcorelles P. Benos D.J. Lancaster Jr., J.R. Gillespie G.Y. PLoS ONE. 2008; 3: e3655Crossref PubMed Scopus (190) Google Scholar, Wang et al., 2008Wang J. Sakariassen P.O. Tsinkalovsky O. Immervoll H. Boe S.O. Svendsen A. Prestegarden L. Rosland G. Thorsen F. Stuhr L. et al.Int. J. Cancer. 2008; 122: 761-768Crossref PubMed Scopus (453) Google Scholar). The presence of potential dormant stem cells in the integrin α6− population would explain the reported tumor formation ability of both integrin α6+ and integrin α6− cells. Further comprehensive characterization of the tumor stem cell compartment, as the one reported in this issue, shall clarify whether we are still missing the dormant GSCs. Integrin Alpha 6 Regulates Glioblastoma Stem CellsLathia et al.Cell Stem CellMay 07, 2010In BriefCancer stem cells (CSCs) are a subpopulation of tumor cells suggested to be critical for tumor maintenance, metastasis, and therapeutic resistance. Prospective identification and targeting of CSCs are therefore priorities for the development of novel therapeutic paradigms. Although CSC enrichment has been achieved with cell surface proteins including CD133 (Prominin-1), the roles of current CSC markers in tumor maintenance remain unclear. We examined the glioblastoma stem cell (GSC) perivascular microenvironment in patient specimens to identify enrichment markers with a functional significance and identified integrin α6 as a candidate. Full-Text PDF Open Archive