Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis

Filippo Calzolari; Irene Appolloni; Evelina Tutucci; Sara Caviglia; Marta Terrile; Giorgio Corte; Paolo Malatesta

doi:10.1593/neo.08814

Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis

Filippo Calzolari
, Irene Appolloni
, Evelina Tutucci
, Sara Caviglia
, Marta Terrile
, Giorgio Corte
, Paolo Malatesta^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B-addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.

Original language	English
Pages (from-to)	1373-1382
Number of pages	10
Journal	Neoplasia
Volume	10
Issue number	12
DOIs	https://doi.org/10.1593/neo.08814
Publication status	Published - 1 Jan 2008
Externally published	Yes

Funding

Abbreviations: IRES, internal ribosome entry site; GFP, green fluorescent protein; GFAP, glial fibrillary acidic protein Address all correspondence to: Paolo Malatesta, National Institute for Cancer Research (IST), IRCCS, Largo Rosanna Benzi 10, 16132 Genoa, Italy. E-mail: [email protected] 1This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) New Unit StartUp grant (In vivo screening for genes implicated in glioma formation and development of new animal models of glial tumors.) and by Fondazione Cassa di Risparmio di Genova grant (Basi molecolari e cellulari dei gliomi: individuazione di marcatori diagnostici e di nuovi bersagli terapeutici). 2This article refers to supplementary materials, which are designated by Table W1 and Figure W1 and are available online at www.neoplasia.com. 3Calzolari F. and Appolloni I. contributed equally to this work. Received 17 July 2008; Revised 11 September 2008; Accepted 12 September 2008 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.08814 Mice were handled in agreement with the guidelines conforming to the Italian current regulations regarding the protection of animals used for scientific purposes (D.lvo 27/01/1992, n. 116). Procedures were specifically approved by the Ethical Committee for Animal Experimentation of the National Institute of Cancer Research and by the Italian Ministry of Health. All experiments have been performed on the C57/Bl6 mouse strain.

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title = "Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis",

abstract = "Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B-addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.",

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AU - Calzolari, Filippo

AU - Appolloni, Irene

AU - Tutucci, Evelina

AU - Caviglia, Sara

AU - Terrile, Marta

AU - Corte, Giorgio

AU - Malatesta, Paolo

PY - 2008/1/1

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N2 - Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B-addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.

AB - Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B-addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.

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Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis

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