Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells

A. D'Alessio, G. Proietti, G. Lama, Flavia Biamonte, L. Lauriola, Umberto Moscato, A. Vescovi, Annunziato Mangiola, C. Angelucci, G. Sica

Research output: Contribution to journalArticle

Abstract

The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1a, HIF2a, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the "angiogenic switch" and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.
Original languageEnglish
Pages (from-to)78541-78556
Number of pages16
JournalOncotarget
Volume7
Issue number48
Publication statusPublished - 2016

Fingerprint

Neoplastic Stem Cells
Angiogenesis Inducing Agents
Glioblastoma
Endothelial Cells
Vascular Endothelial Growth Factor A
Immunohistochemistry
Autocrine Communication
Blood Vessels
Real-Time Polymerase Chain Reaction
Western Blotting
Cell Proliferation

Keywords

  • Angiogenesis
  • Cancer stem cells
  • Glioblastoma
  • Hypoxia
  • Peritumoral tissue

Cite this

D'Alessio, A., Proietti, G., Lama, G., Biamonte, F., Lauriola, L., Moscato, U., ... Sica, G. (2016). Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells. Oncotarget, 7(48), 78541-78556.

Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells. / D'Alessio, A.; Proietti, G.; Lama, G.; Biamonte, Flavia; Lauriola, L.; Moscato, Umberto; Vescovi, A.; Mangiola, Annunziato; Angelucci, C.; Sica, G.

In: Oncotarget, Vol. 7, No. 48, 2016, p. 78541-78556.

Research output: Contribution to journalArticle

D'Alessio, A, Proietti, G, Lama, G, Biamonte, F, Lauriola, L, Moscato, U, Vescovi, A, Mangiola, A, Angelucci, C & Sica, G 2016, 'Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells', Oncotarget, vol. 7, no. 48, pp. 78541-78556.
D'Alessio A, Proietti G, Lama G, Biamonte F, Lauriola L, Moscato U et al. Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells. Oncotarget. 2016;7(48):78541-78556.
D'Alessio, A. ; Proietti, G. ; Lama, G. ; Biamonte, Flavia ; Lauriola, L. ; Moscato, Umberto ; Vescovi, A. ; Mangiola, Annunziato ; Angelucci, C. ; Sica, G. / Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells. In: Oncotarget. 2016 ; Vol. 7, No. 48. pp. 78541-78556.
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title = "Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells",
abstract = "The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1a, HIF2a, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the {"}angiogenic switch{"} and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.",
keywords = "Angiogenesis, Cancer stem cells, Glioblastoma, Hypoxia, Peritumoral tissue",
author = "A. D'Alessio and G. Proietti and G. Lama and Flavia Biamonte and L. Lauriola and Umberto Moscato and A. Vescovi and Annunziato Mangiola and C. Angelucci and G. Sica",
note = "Cited By :2 Export Date: 27 March 2017 Correspondence Address: D'Alessio, A.; Institute of Histology and Embryology, A. Gemelli Faculty of Medicine, Catholic University of the Sacred HeartItaly; email: alessio.dalessio@unicatt.it Funding details: #14368 IG 2013, AIRC, Associazione Italiana per la Ricerca sul Cancro Funding text: We are grateful to Dr. Anna Colabianchi for technical support in immunoblotting analysis of HIFs. This work was supported from Italian Ministry for Education, University and Research (MIUR, 2010), FIRB Project RBAP10KJC5 and from the AIRC grant #14368 IG 2013. References: Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., Scheithauer, B.W., Kleihues, P., The 2007 WHO classification of tumours of the central nervous system (2007) Acta Neuropathol, 114, pp. 97-109; Ausprunk, D.H., Folkman, J., Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis (1977) Microvasc Res, 14, pp. 53-65; Holash, J., Maisonpierre, P.C., Compton, D., Boland, P., Alexander, C.R., Zagzag, D., Yancopoulos, G.D., Wiegand, S.J., Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF (1999) Science, 284, pp. 1994-1998; Kurz, H., Burri, P.H., Djonov, V.G., Angiogenesis and vascular remodeling by intussusception: from form to function (2003) News Physiol Sci, 18, pp. 65-70; Cao, Z., Bao, M., Miele, L., Sarkar, F.H., Wang, Z., Zhou, Q., Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: a systemic review and meta-analysis (2013) Eur J Cancer, 49, pp. 3914-3923; Maniotis, A.J., Folberg, R., Hess, A., Seftor, E.A., Gardner, L.M., Pe'er, J., Trent, J.M., Hendrix, M.J., Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry (1999) Am J Pathol, 155, pp. 739-752; Lama, G., Mangiola, A., Anile, C., Sabatino, G., De Bonis, P., Lauriola, L., Giannitelli, C., Maira, G., Activated ERK1/2 expression in glioblastoma multiforme and in peritumor tissue (2007) Int J Oncol, 38, pp. 1333-1342; Mangiola, A., Lama, G., Giannitelli, C., De Bonis, P., Anile, C., Lauriola, L., La Torre, G., Sica, G., Stem cell marker nestin and c-Jun NH2-terminal kinases in tumor and peritumor areas of glioblastoma multiforme: possible prognostic implications (2007) Clin Cancer Res, 13, pp. 6970-6977; Mangiola, A., Saulnier, N., De Bonis, P., Orteschi, D., Sica, G., Lama, G., Pettorini, B.L., Kovacs, G., Gene expression profile of glioblastoma peritumoral tissue: an ex vivo study (2013) PLoS One, 8; Lama, G., Mangiola, A., Proietti, G., Colabianchi, A., Angelucci, C., D'Alessio, A., De Bonis, P., Vescovi, A., Progenitor/Stem Cell Markers in Brain Adjacent to Glioblastoma: GD3 Ganglioside and NG2 Proteoglycan Expression (2016) J Neuropathol Exp Neurol; Sica, G., Lama, G., Anile, C., Geloso, M.C., La Torre, G., De Bonis, P., Maira, G., Mangiola, A., Assessment of angiogenesis by CD105 and nestin expression in peritumor tissue of glioblastoma (2011) Int J Oncol, 38, pp. 41-49; Ferrara, N., VEGF-A: a critical regulator of blood vessel growth (2009) Eur Cytokine Netw, 20, pp. 158-163; Senger, D.R., Galli, S.J., Dvorak, A.M., Perruzzi, C.A., Harvey, V.S., Dvorak, H.F., Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid (1983) Science, 219, pp. 983-985; Carmeliet, P., Dor, Y., Herbert, J.M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Moons, L., Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis (1998) Nature, 394, pp. 485-490; Semenza, G.L., Agani, F., Iyer, N., Kotch, L., Laughner, E., Leung, S., Yu, A., Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1 (1999) Ann N Y Acad Sci, 874, pp. 262-268; Eyler, C.E., Rich, J.N., Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis (2008) J Clin Oncol, 26, pp. 2839-2845; Fuchs, E., Tumbar, T., Guasch, G., Socializing with the neighbors: stem cells and their niche (2004) Cell, 116, pp. 769-778; Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H., Jones, D.L., Visvader, J., Wahl, G.M., Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells (2006) Cancer Res, 66, pp. 9339-9344; Glas, M., Rath, B.H., Simon, M., Reinartz, R., Schramme, A., Trageser, D., Eisenreich, R., Pietsch, T., Residual tumor cells are unique cellular targets in glioblastoma (2010) Ann Neurol, 68, pp. 264-269; Park, I., Tamai, G., Lee, M.C., Chuang, C.F., Chang, S.M., Berger, M.S., Nelson, S.J., Pirzkall, A., Patterns of recurrence analysis in newly diagnosed glioblastoma multiforme after three-dimensional conformal radiation therapy with respect to pre-radiation therapy magnetic resonance spectroscopic findings (2007) Int J Radiat Oncol Biol Phys, 69, pp. 381-389; Hochberg, F.H., Pruitt, A., Assumptions in the radiotherapy of glioblastoma (1980) Neurology, 30, pp. 907-911; Cenciarelli, C., Marei, H.E., Zonfrillo, M., Pierimarchi, P., Paldino, E., Casalbore, P., Felsani, A., Mangiola, A., PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment (2014) Mol Cancer, 13, p. 247; Bao, S., Wu, Q., Sathornsumetee, S., Hao, Y., Li, Z., Hjelmeland, A.B., Shi, Q., Rich, J.N., Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor (2006) Cancer Res, 66, pp. 7843-7848; Folkins, C., Shaked, Y., Man, S., Tang, T., Lee, C.R., Zhu, Z., Hoffman, R.M., Kerbel, R.S., Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1 (2009) Cancer Res, 69, pp. 7243-7251; Zhu, T.S., Costello, M.A., Talsma, C.E., Flack, C.G., Crowley, J.G., Hamm, L.L., He, X., Fan, X., Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stemlike cells (2011) Cancer Res, 71, pp. 6061-6072; Oka, N., Soeda, A., Inagaki, A., Onodera, M., Maruyama, H., Hara, A., Kunisada, T., Iwama, T., VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells (2007) Biochem Biophys Res Commun, 360, pp. 553-559; Steiner, H.H., Karcher, S., Mueller, M.M., Nalbantis, E., Kunze, S., Herold-Mende, C., Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels (2004) J Neurooncol, 66, pp. 129-138; Bonnet, D., Dick, J.E., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell (1997) Nat Med, 3, pp. 730-737; Ward, R.J., Dirks, P.B., Cancer stem cells: at the headwaters of tumor development (2007) Annu Rev Pathol, 2, pp. 175-189; Chen, J., Li, Y., Yu, T.S., McKay, R.M., Burns, D.K., Kernie, S.G., Parada, L.F., A restricted cell population propagates glioblastoma growth after chemotherapy (2012) Nature, 488, pp. 522-526; Peterson, T.E., Kirkpatrick, N.D., Huang, Y., Farrar, C.T., Marijt, K.A., Kloepper, J., Datta, M., Snuderl, M., Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages (2016) Proc Natl Acad Sci U S A; 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year = "2016",
language = "English",
volume = "7",
pages = "78541--78556",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "48",

}

TY - JOUR

T1 - Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells

AU - D'Alessio, A.

AU - Proietti, G.

AU - Lama, G.

AU - Biamonte, Flavia

AU - Lauriola, L.

AU - Moscato, Umberto

AU - Vescovi, A.

AU - Mangiola, Annunziato

AU - Angelucci, C.

AU - Sica, G.

N1 - Cited By :2 Export Date: 27 March 2017 Correspondence Address: D'Alessio, A.; Institute of Histology and Embryology, A. Gemelli Faculty of Medicine, Catholic University of the Sacred HeartItaly; email: alessio.dalessio@unicatt.it Funding details: #14368 IG 2013, AIRC, Associazione Italiana per la Ricerca sul Cancro Funding text: We are grateful to Dr. Anna Colabianchi for technical support in immunoblotting analysis of HIFs. This work was supported from Italian Ministry for Education, University and Research (MIUR, 2010), FIRB Project RBAP10KJC5 and from the AIRC grant #14368 IG 2013. References: Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., Scheithauer, B.W., Kleihues, P., The 2007 WHO classification of tumours of the central nervous system (2007) Acta Neuropathol, 114, pp. 97-109; Ausprunk, D.H., Folkman, J., Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis (1977) Microvasc Res, 14, pp. 53-65; Holash, J., Maisonpierre, P.C., Compton, D., Boland, P., Alexander, C.R., Zagzag, D., Yancopoulos, G.D., Wiegand, S.J., Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF (1999) Science, 284, pp. 1994-1998; Kurz, H., Burri, P.H., Djonov, V.G., Angiogenesis and vascular remodeling by intussusception: from form to function (2003) News Physiol Sci, 18, pp. 65-70; Cao, Z., Bao, M., Miele, L., Sarkar, F.H., Wang, Z., Zhou, Q., Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: a systemic review and meta-analysis (2013) Eur J Cancer, 49, pp. 3914-3923; Maniotis, A.J., Folberg, R., Hess, A., Seftor, E.A., Gardner, L.M., Pe'er, J., Trent, J.M., Hendrix, M.J., Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry (1999) Am J Pathol, 155, pp. 739-752; Lama, G., Mangiola, A., Anile, C., Sabatino, G., De Bonis, P., Lauriola, L., Giannitelli, C., Maira, G., Activated ERK1/2 expression in glioblastoma multiforme and in peritumor tissue (2007) Int J Oncol, 38, pp. 1333-1342; Mangiola, A., Lama, G., Giannitelli, C., De Bonis, P., Anile, C., Lauriola, L., La Torre, G., Sica, G., Stem cell marker nestin and c-Jun NH2-terminal kinases in tumor and peritumor areas of glioblastoma multiforme: possible prognostic implications (2007) Clin Cancer Res, 13, pp. 6970-6977; Mangiola, A., Saulnier, N., De Bonis, P., Orteschi, D., Sica, G., Lama, G., Pettorini, B.L., Kovacs, G., Gene expression profile of glioblastoma peritumoral tissue: an ex vivo study (2013) PLoS One, 8; Lama, G., Mangiola, A., Proietti, G., Colabianchi, A., Angelucci, C., D'Alessio, A., De Bonis, P., Vescovi, A., Progenitor/Stem Cell Markers in Brain Adjacent to Glioblastoma: GD3 Ganglioside and NG2 Proteoglycan Expression (2016) J Neuropathol Exp Neurol; Sica, G., Lama, G., Anile, C., Geloso, M.C., La Torre, G., De Bonis, P., Maira, G., Mangiola, A., Assessment of angiogenesis by CD105 and nestin expression in peritumor tissue of glioblastoma (2011) Int J Oncol, 38, pp. 41-49; Ferrara, N., VEGF-A: a critical regulator of blood vessel growth (2009) Eur Cytokine Netw, 20, pp. 158-163; Senger, D.R., Galli, S.J., Dvorak, A.M., Perruzzi, C.A., Harvey, V.S., Dvorak, H.F., Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid (1983) Science, 219, pp. 983-985; Carmeliet, P., Dor, Y., Herbert, J.M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Moons, L., Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis (1998) Nature, 394, pp. 485-490; Semenza, G.L., Agani, F., Iyer, N., Kotch, L., Laughner, E., Leung, S., Yu, A., Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1 (1999) Ann N Y Acad Sci, 874, pp. 262-268; Eyler, C.E., Rich, J.N., Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis (2008) J Clin Oncol, 26, pp. 2839-2845; Fuchs, E., Tumbar, T., Guasch, G., Socializing with the neighbors: stem cells and their niche (2004) Cell, 116, pp. 769-778; Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H., Jones, D.L., Visvader, J., Wahl, G.M., Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells (2006) Cancer Res, 66, pp. 9339-9344; Glas, M., Rath, B.H., Simon, M., Reinartz, R., Schramme, A., Trageser, D., Eisenreich, R., Pietsch, T., Residual tumor cells are unique cellular targets in glioblastoma (2010) Ann Neurol, 68, pp. 264-269; Park, I., Tamai, G., Lee, M.C., Chuang, C.F., Chang, S.M., Berger, M.S., Nelson, S.J., Pirzkall, A., Patterns of recurrence analysis in newly diagnosed glioblastoma multiforme after three-dimensional conformal radiation therapy with respect to pre-radiation therapy magnetic resonance spectroscopic findings (2007) Int J Radiat Oncol Biol Phys, 69, pp. 381-389; Hochberg, F.H., Pruitt, A., Assumptions in the radiotherapy of glioblastoma (1980) Neurology, 30, pp. 907-911; 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PY - 2016

Y1 - 2016

N2 - The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1a, HIF2a, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the "angiogenic switch" and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.

AB - The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1a, HIF2a, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the "angiogenic switch" and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.

KW - Angiogenesis

KW - Cancer stem cells

KW - Glioblastoma

KW - Hypoxia

KW - Peritumoral tissue

M3 - Article

VL - 7

SP - 78541

EP - 78556

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 48

ER -