Glioma Invasiveness Responds Variably to Irradiation in a Co-Culture Model

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, United States
International Journal of Radiation OncologyBiologyPhysics (Impact Factor: 4.26). 11/2007; 69(3):880-6. DOI: 10.1016/j.ijrobp.2007.06.052
Source: PubMed


We developed a co-culture system to quantitate the growth and invasion of human malignant gliomas into a background of confluent normal human astrocytes, then used this assay to assess independently the effects of irradiating both cell types on glioma invasion.
Enhanced green fluorescent protein (EGFP)-labeled immortalized human astrocytes, human malignant glioma cells, or transformed human astrocytes were focally plated onto a confluent layer of normal human astrocytes, and the invasiveness of EGFP-labeled cells was scored after 96 h. To address the consequences of irradiation on glioma invasion, the invasiveness of irradiated glioma cell lines and irradiated astrocytic backgrounds was assessed. Fluorescence-activated cell sorting was used to quantitate the total number of EGFP-labeled cells.
Growth in the co-culture assay consistently reflected transformation states of the plated cells. Immortalized, but untransformed human astrocytes failed even to establish growth on confluent normal human astrocytes. In contrast, all malignant human glioma cell lines and transformed human astrocytes demonstrated various degrees of infiltration into the astrocytic bed. Irradiation failed to alter the invasiveness of U87, A172, and U373. A 1-Gy dose slightly reduced the invasiveness of U251 MG by 75% (p < 0.05 by one-way analysis of variance and post hoc Neuman-Keuls), without reducing total cell numbers. Independently irradiating the human astrocytic bed did not alter the invasiveness of nonirradiated U251, whereas the matrix metalloproteinase (MMP) inhibitor GM6001 reduced U251 invasiveness in the co-culture assay.
Growth in the co-culture assay reflects the transformation status and provides a useful in vitro model for assessing invasiveness. Human glioma invasiveness in the co-culture model responds variably to single low-dose fractions. MMP activity promotes invasiveness in the co-culture model. Reduced invasiveness in irradiated U251 appears to be mediated by MMP-independent mechanisms.

5 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Matrix metalloproteases (MMPs) are key players in the progression and metastasis of cancer. MMPs cleave extracellular matrix components and in this way promote tumor growth, invasion and vascularization. MMPs also affect tumor progression by regulating availability and activity of growth factors, inflammatory cytokines and chemokines. Accordingly, several MMPs have been found to serve as prognostic indicators in solid tumors. Usually the increased levels of MMPs in patients' tumor tissue or serum/plasma are associated with poor outcome. Interestingly, recent results show that certain MMPs also serve as tumor suppressors. Objective: This review discusses the latest view on MMPs as diagnostic and prognostic indicators in cancer patients. Methods: Studies with clinical samples of 70 or more patients are included in particular. In addition, the possible roles of MMPs in future molecular diagnostics and in the evaluation of therapeutic responses are discussed. Conclusion: MMP-9 in particular has shown prognostic value in various types of tumor, and its measurement in circulation, urine or tumor tissue might help in clinical surveillance of otherwise problematic patient cases. There is upcoming new knowledge on MMPs in therapy response evaluation, in which MMPs might be useful together with CT scans and other clinically more established prognostic factors. Certain MMPs have a dual role in terms of cancer-modulating properties and thus it is essential to evaluate their expression and function in tumor cells and host environment to select validated therapy targets but spare MMP antitargets.
    Expert Opinion on Medical Diagnostics 09/2008; 2(9):1025-39. DOI:10.1517/17530059.2.9.1025
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased expression of the proteoglycan, versican is strongly associated with poor outcome for many different cancers. Depending on the cancer type, versican is expressed by either the cancer cells themselves or by stromal cells surrounding the tumor. Versican plays diverse roles in cell adhesion, proliferation, migration and angiogenesis, all features of invasion and metastasis. These wide ranging functions have been attributed to the central glycosaminoglycan-binding region of versican, and to the N-(G1) and C-(G3) terminal globular domains which collectively interact with a large number of extracellular matrix and cell surface structural components. Here we review the recently identified mechanisms responsible for the regulation of versican expression and the biological roles that versican plays in cancer invasion and metastasis. The regulation of versican expression may represent one mechanism whereby cancer cells alter their surrounding microenvironment to facilitate the malignant growth and invasion of several tumor types. A greater understanding of the regulation of versican expression may contribute to the development of therapeutic methods to inhibit versican function and tumor invasion.
    CANCER AND METASTASIS REVIEW 02/2009; 28(1-2):233-45. DOI:10.1007/s10555-009-9182-y · 7.23 Impact Factor
  • Saha ·

    International Journal of Oncology 03/2009; 34(4). DOI:10.3892/ijo_00000231 · 3.03 Impact Factor
Show more