Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1

M.L. Falchetti, Q.G. D'Alessandris, S. Pacioni, M. Buccarelli, L. Morgante, S. Giannetti, V. Lulli, M. Martini, L.M. Larocca, E. Vakana, L. Stancato, L. Ricci-Vitiani, R. Pallini

Research output: Contribution to journalArticle

Abstract

Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p <0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
Original languageEnglish
Pages (from-to)1331-1344
Number of pages14
JournalInternational Journal of Cancer
Volume144
Issue number6
DOIs
Publication statusPublished - 2019

Fingerprint

Glioblastoma
Endothelium
Growth
Brain
Neoplasms
Heterografts
Endothelial Cells
Students
Tropism
Epithelial-Mesenchymal Transition
Vascular Endothelium
Nuclear Family
Glioma
Vascular Endothelial Growth Factor A
Blood Vessels
Drive
Bevacizumab
plexin
Stem Cells
Monoclonal Antibodies

Keywords

  • antiangiogenic therapy
  • bevacizumab
  • brain infiltration
  • glioblastoma
  • PLXDC1
  • cell marker
  • cell receptor
  • Plexin Domain Containing 1 receptor
  • tumor marker
  • unclassified drug
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • astrocyte
  • blood brain barrier
  • cancer infiltration
  • cancer inhibition
  • cancer stem cell
  • cell invasion
  • controlled study
  • drug effect
  • epithelial mesenchymal transition
  • glioblastoma cell line
  • human
  • human cell
  • in vitro study
  • male
  • metastasis
  • nonhuman
  • nuclear magnetic resonance imaging
  • perivascular space
  • priority journal
  • rat
  • tropism
  • tumor growth
  • tumor xenograft
  • U87MG cell line
  • vascular endothelial cell

Cite this

Falchetti, M. L., D'Alessandris, Q. G., Pacioni, S., Buccarelli, M., Morgante, L., Giannetti, S., ... Pallini, R. (2019). Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. International Journal of Cancer, 144(6), 1331-1344. https://doi.org/10.1002/ijc.31983

Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. / Falchetti, M.L.; D'Alessandris, Q.G.; Pacioni, S.; Buccarelli, M.; Morgante, L.; Giannetti, S.; Lulli, V.; Martini, M.; Larocca, L.M.; Vakana, E.; Stancato, L.; Ricci-Vitiani, L.; Pallini, R.

In: International Journal of Cancer, Vol. 144, No. 6, 2019, p. 1331-1344.

Research output: Contribution to journalArticle

Falchetti, ML, D'Alessandris, QG, Pacioni, S, Buccarelli, M, Morgante, L, Giannetti, S, Lulli, V, Martini, M, Larocca, LM, Vakana, E, Stancato, L, Ricci-Vitiani, L & Pallini, R 2019, 'Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1', International Journal of Cancer, vol. 144, no. 6, pp. 1331-1344. https://doi.org/10.1002/ijc.31983
Falchetti ML, D'Alessandris QG, Pacioni S, Buccarelli M, Morgante L, Giannetti S et al. Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. International Journal of Cancer. 2019;144(6):1331-1344. https://doi.org/10.1002/ijc.31983
Falchetti, M.L. ; D'Alessandris, Q.G. ; Pacioni, S. ; Buccarelli, M. ; Morgante, L. ; Giannetti, S. ; Lulli, V. ; Martini, M. ; Larocca, L.M. ; Vakana, E. ; Stancato, L. ; Ricci-Vitiani, L. ; Pallini, R. / Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. In: International Journal of Cancer. 2019 ; Vol. 144, No. 6. pp. 1331-1344.
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title = "Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1",
abstract = "Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p <0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. {\circledC} 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
keywords = "antiangiogenic therapy, bevacizumab, brain infiltration, glioblastoma, PLXDC1, cell marker, cell receptor, Plexin Domain Containing 1 receptor, tumor marker, unclassified drug, animal experiment, animal model, animal tissue, Article, astrocyte, blood brain barrier, cancer infiltration, cancer inhibition, cancer stem cell, cell invasion, controlled study, drug effect, epithelial mesenchymal transition, glioblastoma cell line, human, human cell, in vitro study, male, metastasis, nonhuman, nuclear magnetic resonance imaging, perivascular space, priority journal, rat, tropism, tumor growth, tumor xenograft, U87MG cell line, vascular endothelial cell",
author = "M.L. Falchetti and Q.G. D'Alessandris and S. Pacioni and M. Buccarelli and L. Morgante and S. Giannetti and V. Lulli and M. Martini and L.M. Larocca and E. Vakana and L. Stancato and L. Ricci-Vitiani and R. Pallini",
note = "Export Date: 11 April 2019 CODEN: IJCNA Correspondence Address: Ricci-Vitiani, L.; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit{\`a}Italy; email: lriccivitiani@yahoo.it Chemicals/CAS: bevacizumab, 216974-75-3, 1438851-35-4 Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: Associazione Italiana per la Ricerca sul Cancro, IG 2014 15584, IG 2013 14574 Funding text 1: The authors wish to thank Alessandra Boe and Ramona Ilari for high qualified technical assistance in flow cytometry and molecular biology, respectively. The authors wish to thank Ramona Ilari for technical assistance. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro, AIRC (IG 2014 15584 to LRV and IG 2013 14574 to RP). References: Stupp, R., Hegi, M.E., Mason, W.P., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (2009) Lancet Oncol, 10, pp. 459-466; Semenza, G.L., HIF-1: using two hands to flip the angiogenic switch (2000) Cancer Metastasis Rev, 19, pp. 59-65; Calabrese, C., Poppleton, H., Kocak, M., A perivascular niche for brain tumor stem cells (2007) Cancer Cell, 11, pp. 69-82; Gilbertson, R.J., Rich, J.N., Making a tumour's bed: glioblastoma stem cells and the vascular niche (2007) Nature Rev Cancer, 7, pp. 733-736; Ricci-Vitiani, L., Pallini, R., Biffoni, M., Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells (2010) Nature, 468, pp. 824-828; Chinot, O.L., Wick, W., Mason, W., Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma (2014) N Engl J Med, 370, pp. 709-722; Taal, W., Oosterkamp, H.M., Walenkamp, A.M., Single agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial (2014) Lancet Oncol, 15, pp. 943-953; Wick, W., Gorlia, T., Bendszus, M., Lomustine and bevacizumab in progressive glioblastoma (2017) N Engl J Med, 377, pp. 1954-1963; de Groot, J.F., Fuller, G., Kumar, A.J., Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice (2010) Neuro Oncol, 12, pp. 233-242; Gomez-Manzano, C., Holash, J., Fueyo, J., VEGF trap induces antiglioma effect at different stages of disease (2008) Neuro Oncol, 10, pp. 940-945; P{\`a}ez-Ribes, M., Allen, E., Hudock, J., Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis (2009) Cancer Cell, 15, pp. 220-231; Chamberlain, M.C., Radiographic patterns of relapse in glioblastoma (2011) J Neurooncol, 101, pp. 319-323; Huveldt, D., Lewis-Tuffin, L.J., Carlson, B.L., Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion (2013) PLoS One, 8; Lucio-Eterovic, A.K., Piao, Y., de Groot, J.F., Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy (2009) Clin Cancer Res, 15, pp. 4589-4599; Norden, A.D., Drappatz, J., Wen, P.Y., Novel anti-angiogenic therapies for malignant gliomas (2008) Lancet Neurol, 7, pp. 1152-1160; Fischer, I., Cunliffe, C.H., Bollo, R.J., High-grade glioma before and after treatment with radiation and Avastin: initial observations (2008) Neuro Oncol, 10, pp. 700-708; Rose, S.D., Aghi, M.K., Mechanisms of evasion to antiangiogenic therapy in glioblastoma (2010) Clin Neurosurg, 57, pp. 123-128; Lu, K.V., Bergers, G., Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma (2013) CNS Oncol, 2, pp. 49-65; De Pascalis, I., Morgante, L., Pacioni, S., Endothelial trans-differentiation in glioblastoma recurring after radiotherapy (2018) Mod Pathol, 31, pp. 1361-1366. , https://doi.org/10.1038/s41379-018-0046-2; Moutal, A., Honnorat, J., Massoma, P., CRMP5 controls glioblastoma cell proliferation and survival through notch-dependent signaling (2015) Cancer Res, 75, pp. 3519-3528; Tate, C.M., Blosser, W., Wyss, L., LY2228820 dimesylate, a selective inhibitor of p38 mitogen-activated protein kinase, reduces angiogenic endothelial cord formation in vitro and in vivo (2013) J Biol Chem, 288, pp. 6743-6753; Gentleman, R.C., Carey, V.J., Bates, D.M., Bioconductor: open software development for computational biology and bioinformatics (2004) Genome Biol, 5, p. R80; Ritchie, M.E., Phipson, B., Wu, D., Limma powers differential expression analyses for RNA-sequencing and microarray studies (2015) Nucleic Acids Res, 43; Subramanian, A., Tamayo, P., Mootha, V.K., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles (2005) Proc Natl Acad Sci USA, 102, pp. 15545-15550; Martini, M., de Pascalis, I., D'Alessandris, Q.G., VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma (2018) BMC Cancer, 18, p. 553; Peterson, T.E., Kirkpatrick, N.D., Huang, Y., Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages (2016) Proc Natl Acad Sci USA, 113, pp. 4470-4475; Miller, T.E., Liau, B.B., Wallace, L.C., Transcription elongation factors represent in vivo cancer dependencies in glioblastoma (2017) Nature, 547, pp. 355-359; Beaty, R.M., Edwards, J.B., Boon, K., PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium (2007) J Neurooncol, 81, pp. 241-248; Carson-Walter, E.B., Hampton, J., Shue, E., Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis (2005) Clin Cancer Res, 11, pp. 7643-7650; Mathiisen, T.M., Lehre, K.P., Danbolt, N.C., The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction (2010) Glia, 58, pp. 1094-1103; Granholm, A.C., Curtis, M., Diamond, D.M., Development of an intact blood-brain barrier in brain tissue transplants is dependent on the site of transplantation (1996) Cell Transplant, 5, pp. 305-314; Wick, W., Chinot, O.L., Bendszus, M., Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma (2016) Neuro Oncol, 18, pp. 1434-1441; Nowosielski, M., Ellingson, B.M., Chinot, O.L., Radiologic progression of glioblastoma under therapy-an exploratory analysis of AVAglio (2018) Neuro Oncol, 20, pp. 557-566; Kunkel, P., Ulbricht, U., Bohlen, P., Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2 (2001) Cancer Res, 61, pp. 6624-6628; Otani, Y., Ichikawa, T., Kurozumi, K., Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion (2018) Oncogene, 37, pp. 777-786; Rubenstein, J.L., Kim, J., Ozawa, T., Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption (2000) Neoplasia, 2, pp. 306-314; Mesti, T., Savarin, P., Triba, M.N., Metabolic impact of anti-angiogenic agents on U87 glioma cells (2014) PLoS One, 9; Ono, T., Sasajima, T., Doi, Y., Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-beta, and/or bevacizumab for glioblastoma (2015) Nucl Med Biol, 42, pp. 598-607; Grossman, R., Brastianos, H., Blakeley, J.O., Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models (2014) J Neurooncol, 116, pp. 59-65; Saidi, A., Hagedorn, M., Allain, N., Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness (2009) Int J Cancer, 125, pp. 1054-1064; de Groot, J., Milano, V., Improving the prognosis for patients with glioblastoma: the rationale for targeting Src (2009) J Neurooncol, 95, pp. 151-163; Tsai, H.H., Niu, J., Munji, R., Oligodendrocyte precursors migrate along vasculature in the developing nervous system (2016) Science, 351, pp. 379-384; Griveau, A., Seano, G., Shelton, S.J., A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment (2018) Cancer Cell, 33, pp. 874-889; Piao, Y., Liang, J., Holmes, L.S., Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition (2013) Clin Cancer Res, 19, pp. 4392-4403; Urup, T., Staunstrup, L.M., Michaelsen, S.R., Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients (2017) BMC Cancer, 17, p. 278; Iwamoto, F.M., Abrey, L.E., Beal, K., Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma (2009) Neurology, 73, pp. 1200-1206; Delay, M., Jahangiri, A., Carbonell, W.S., Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy (2012) Clin Cancer Res, 18, pp. 2930-2942; Ricci-Vitiani, L., Pallini, R., Larocca, L.M., Mesenchymal differentiation of glioblastoma stem cells (2008) Cell Death Differ, 15, pp. 1491-1498; Wang, R., Chadalavada, K., Wilshire, J., Glioblastoma stem-like cells give rise to tumour endothelium (2010) Nature, 468, pp. 829-833; Miller, S.F., Summerhurst, K., R{\"u}nker, A.E., Expression of Plxdc2/TEM7R in the developing nervous system of the mouse (2007) Gene Expr Patterns, 7, pp. 635-644; Lee, H.K., Seo, I.A., Park, H.K., Identification of the basement membrane protein nidogen as a candidate ligand for tumor endothelial marker 7 in vitro and in vivo (2006) FEBS Lett, 580, pp. 2253-2257; Nanda, A., Buckhaults, P., Seaman, S., Identification of a binding partner for the endothelial cell surface proteins TEM7 and Tem7r (2004) cancer Res, 64, pp. 8507-8511; Zhang, Z.Z., Hua, R., Zhang, J.F., TEM7 (PLXDC1), a key prognostic predictor for resectable gastric cancer, promotes cancer cell migration and invasion (2015) Am J Cancer Res, 5, pp. 772-781; Bagley, R.G., Rouleau, C., Weber, W., Tumor endothelial marker 7 (TEM-7): a novel target for antiangiogenic therapy (2011) Microvasc Res, 82, pp. 253-262; Okamoto, S., Nitta, M., Maruyama, T., Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas (2016) Brain Tumor Pathol, 33, pp. 129-136; Stegmayr, C., Oliveira, D., Niemietz, N., Influence of bevacizumab on blood-brain barrier permeability and O-(2-18F-Fluoroethyl)-l-tyrosine uptake in rat gliomas (2017) J Nucl Med, 58, pp. 700-705",
year = "2019",
doi = "10.1002/ijc.31983",
language = "English",
volume = "144",
pages = "1331--1344",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1

AU - Falchetti, M.L.

AU - D'Alessandris, Q.G.

AU - Pacioni, S.

AU - Buccarelli, M.

AU - Morgante, L.

AU - Giannetti, S.

AU - Lulli, V.

AU - Martini, M.

AU - Larocca, L.M.

AU - Vakana, E.

AU - Stancato, L.

AU - Ricci-Vitiani, L.

AU - Pallini, R.

N1 - Export Date: 11 April 2019 CODEN: IJCNA Correspondence Address: Ricci-Vitiani, L.; Department of Oncology and Molecular Medicine, Istituto Superiore di SanitàItaly; email: lriccivitiani@yahoo.it Chemicals/CAS: bevacizumab, 216974-75-3, 1438851-35-4 Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: Associazione Italiana per la Ricerca sul Cancro, IG 2014 15584, IG 2013 14574 Funding text 1: The authors wish to thank Alessandra Boe and Ramona Ilari for high qualified technical assistance in flow cytometry and molecular biology, respectively. The authors wish to thank Ramona Ilari for technical assistance. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro, AIRC (IG 2014 15584 to LRV and IG 2013 14574 to RP). References: Stupp, R., Hegi, M.E., Mason, W.P., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (2009) Lancet Oncol, 10, pp. 459-466; Semenza, G.L., HIF-1: using two hands to flip the angiogenic switch (2000) Cancer Metastasis Rev, 19, pp. 59-65; Calabrese, C., Poppleton, H., Kocak, M., A perivascular niche for brain tumor stem cells (2007) Cancer Cell, 11, pp. 69-82; Gilbertson, R.J., Rich, J.N., Making a tumour's bed: glioblastoma stem cells and the vascular niche (2007) Nature Rev Cancer, 7, pp. 733-736; Ricci-Vitiani, L., Pallini, R., Biffoni, M., Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells (2010) Nature, 468, pp. 824-828; Chinot, O.L., Wick, W., Mason, W., Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma (2014) N Engl J Med, 370, pp. 709-722; Taal, W., Oosterkamp, H.M., Walenkamp, A.M., Single agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial (2014) Lancet Oncol, 15, pp. 943-953; Wick, W., Gorlia, T., Bendszus, M., Lomustine and bevacizumab in progressive glioblastoma (2017) N Engl J Med, 377, pp. 1954-1963; de Groot, J.F., Fuller, G., Kumar, A.J., Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice (2010) Neuro Oncol, 12, pp. 233-242; Gomez-Manzano, C., Holash, J., Fueyo, J., VEGF trap induces antiglioma effect at different stages of disease (2008) Neuro Oncol, 10, pp. 940-945; Pàez-Ribes, M., Allen, E., Hudock, J., Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis (2009) Cancer Cell, 15, pp. 220-231; Chamberlain, M.C., Radiographic patterns of relapse in glioblastoma (2011) J Neurooncol, 101, pp. 319-323; Huveldt, D., Lewis-Tuffin, L.J., Carlson, B.L., Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion (2013) PLoS One, 8; Lucio-Eterovic, A.K., Piao, Y., de Groot, J.F., Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy (2009) Clin Cancer Res, 15, pp. 4589-4599; Norden, A.D., Drappatz, J., Wen, P.Y., Novel anti-angiogenic therapies for malignant gliomas (2008) Lancet Neurol, 7, pp. 1152-1160; Fischer, I., Cunliffe, C.H., Bollo, R.J., High-grade glioma before and after treatment with radiation and Avastin: initial observations (2008) Neuro Oncol, 10, pp. 700-708; Rose, S.D., Aghi, M.K., Mechanisms of evasion to antiangiogenic therapy in glioblastoma (2010) Clin Neurosurg, 57, pp. 123-128; Lu, K.V., Bergers, G., Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma (2013) CNS Oncol, 2, pp. 49-65; De Pascalis, I., Morgante, L., Pacioni, S., Endothelial trans-differentiation in glioblastoma recurring after radiotherapy (2018) Mod Pathol, 31, pp. 1361-1366. , https://doi.org/10.1038/s41379-018-0046-2; Moutal, A., Honnorat, J., Massoma, P., CRMP5 controls glioblastoma cell proliferation and survival through notch-dependent signaling (2015) Cancer Res, 75, pp. 3519-3528; Tate, C.M., Blosser, W., Wyss, L., LY2228820 dimesylate, a selective inhibitor of p38 mitogen-activated protein kinase, reduces angiogenic endothelial cord formation in vitro and in vivo (2013) J Biol Chem, 288, pp. 6743-6753; Gentleman, R.C., Carey, V.J., Bates, D.M., Bioconductor: open software development for computational biology and bioinformatics (2004) Genome Biol, 5, p. R80; Ritchie, M.E., Phipson, B., Wu, D., Limma powers differential expression analyses for RNA-sequencing and microarray studies (2015) Nucleic Acids Res, 43; Subramanian, A., Tamayo, P., Mootha, V.K., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles (2005) Proc Natl Acad Sci USA, 102, pp. 15545-15550; Martini, M., de Pascalis, I., D'Alessandris, Q.G., VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma (2018) BMC Cancer, 18, p. 553; Peterson, T.E., Kirkpatrick, N.D., Huang, Y., Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages (2016) Proc Natl Acad Sci USA, 113, pp. 4470-4475; Miller, T.E., Liau, B.B., Wallace, L.C., Transcription elongation factors represent in vivo cancer dependencies in glioblastoma (2017) Nature, 547, pp. 355-359; Beaty, R.M., Edwards, J.B., Boon, K., PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium (2007) J Neurooncol, 81, pp. 241-248; Carson-Walter, E.B., Hampton, J., Shue, E., Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis (2005) Clin Cancer Res, 11, pp. 7643-7650; Mathiisen, T.M., Lehre, K.P., Danbolt, N.C., The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction (2010) Glia, 58, pp. 1094-1103; Granholm, A.C., Curtis, M., Diamond, D.M., Development of an intact blood-brain barrier in brain tissue transplants is dependent on the site of transplantation (1996) Cell Transplant, 5, pp. 305-314; Wick, W., Chinot, O.L., Bendszus, M., Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma (2016) Neuro Oncol, 18, pp. 1434-1441; Nowosielski, M., Ellingson, B.M., Chinot, O.L., Radiologic progression of glioblastoma under therapy-an exploratory analysis of AVAglio (2018) Neuro Oncol, 20, pp. 557-566; Kunkel, P., Ulbricht, U., Bohlen, P., Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2 (2001) Cancer Res, 61, pp. 6624-6628; Otani, Y., Ichikawa, T., Kurozumi, K., Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion (2018) Oncogene, 37, pp. 777-786; Rubenstein, J.L., Kim, J., Ozawa, T., Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption (2000) Neoplasia, 2, pp. 306-314; Mesti, T., Savarin, P., Triba, M.N., Metabolic impact of anti-angiogenic agents on U87 glioma cells (2014) PLoS One, 9; Ono, T., Sasajima, T., Doi, Y., Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-beta, and/or bevacizumab for glioblastoma (2015) Nucl Med Biol, 42, pp. 598-607; Grossman, R., Brastianos, H., Blakeley, J.O., Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models (2014) J Neurooncol, 116, pp. 59-65; Saidi, A., Hagedorn, M., Allain, N., Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness (2009) Int J Cancer, 125, pp. 1054-1064; de Groot, J., Milano, V., Improving the prognosis for patients with glioblastoma: the rationale for targeting Src (2009) J Neurooncol, 95, pp. 151-163; Tsai, H.H., Niu, J., Munji, R., Oligodendrocyte precursors migrate along vasculature in the developing nervous system (2016) Science, 351, pp. 379-384; Griveau, A., Seano, G., Shelton, S.J., A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment (2018) Cancer Cell, 33, pp. 874-889; Piao, Y., Liang, J., Holmes, L.S., Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition (2013) Clin Cancer Res, 19, pp. 4392-4403; Urup, T., Staunstrup, L.M., Michaelsen, S.R., Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients (2017) BMC Cancer, 17, p. 278; 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PY - 2019

Y1 - 2019

N2 - Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p <0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

AB - Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p <0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

KW - antiangiogenic therapy

KW - bevacizumab

KW - brain infiltration

KW - glioblastoma

KW - PLXDC1

KW - cell marker

KW - cell receptor

KW - Plexin Domain Containing 1 receptor

KW - tumor marker

KW - unclassified drug

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - astrocyte

KW - blood brain barrier

KW - cancer infiltration

KW - cancer inhibition

KW - cancer stem cell

KW - cell invasion

KW - controlled study

KW - drug effect

KW - epithelial mesenchymal transition

KW - glioblastoma cell line

KW - human

KW - human cell

KW - in vitro study

KW - male

KW - metastasis

KW - nonhuman

KW - nuclear magnetic resonance imaging

KW - perivascular space

KW - priority journal

KW - rat

KW - tropism

KW - tumor growth

KW - tumor xenograft

KW - U87MG cell line

KW - vascular endothelial cell

U2 - 10.1002/ijc.31983

DO - 10.1002/ijc.31983

M3 - Article

VL - 144

SP - 1331

EP - 1344

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -