Identification of Molecular Pathways Facilitating Glioma Cell Invasion In Situ (original) (raw)
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2021
ABSTRACTBrain tumor cells thrive by adapting to the signals in their microenvironment. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Using multiple tissue analysis approaches to identify and measure immune cell infiltration and extracellular matrix deposition in brain tumors, we show that low-grade glioma is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade glioma exhibits abundant immune cell infiltration and activation, as well as extensive collagen deposition. Spatial analysis shows that most T-cells are sequestered in perivascular nests, but macrophages penetrate deep into tumor cell rich regions. High-grade gliomas exhibi...
Molecular and Microenvironmental Determinants of Glioma Stem-Like Cell Survival and invasion
Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults with a 5-year survival rate of 5% despite intensive research efforts. The poor prognosis is due, in part, to aggressive invasion into the surrounding brain parenchyma. Invasion is a complex process mediated by cell-intrinsic pathways, extrinsic microenvironmental cues, and biophysical cues from the peritumoral stromal matrix. Recent data have attributed GBM invasion to the glioma stem-like cell (GSC) subpopulation. GSCs are slowly dividing, highly invasive, therapy resistant, and are considered to give rise to tumor recurrence. GSCs are localized in a heterogeneous cellular niche, and cross talk between stromal cells and GSCs cultivates a fertile environment that promotes GSC invasion. Pro-migratory soluble factors from endothelial cells, astrocytes, macrophages, microglia, and non-stem-like tumor cells can stimulate peritumoral invasion of GSCs. Therefore, therapeutic efforts designed to target the invasive GSCs may enhance patient survival. In this review, we summarize the current understanding of extrinsic pathways and major stromal and immune players facilitating GSC maintenance and survival.
Role of Microenvironment in Glioma Invasion: What We Learned from In Vitro Models
International Journal of Molecular Sciences, 2018
The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an oversimplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used.
Biological mechanisms of glioma invasion and potential therapeutic targets
Journal of neuro-oncology, 2001
The current understanding of glioma biology reveals targets for anti-invasive therapy which include manipulations of extracellular matrix and receptors, growth factors and cytokines, proteases, cytoskeletal components, oncogenes and tumor suppressor genes. A better understanding of the complex regulation and the signalling molecules involved in glioma invasion is still needed in order to design new and effective treatment modalities towards invasive tumor cells. Representative and valid in vitro experimental systems and animal models of gliomas are necessary for the characterization of the invasive phenotype and further development of anti-invasive therapy. In the future, it will probably be important to move from comparative genomic modelling through protein characterization based on advanced proteomic techniques to analyse tissue samples, where the aim for gliomas should be to compare invaded and non-invaded tissue. This will hopefully render promising new therapeutic targets for ...
Tumor Cell Invasion in Glioblastoma
International Journal of Molecular Sciences
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms fo...
Host cell recruitment by gliomas
European Journal of Cancer Supplements, 2008
Background: Glioblastoma multiforme (GBM) is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites.
Biomaterials, 2013
Glioblastoma is an aggressive brain tumor characterized by its high propensity for local invasion, formation of secondary foci within the brain, as well as areas of necrosis. This study aims to (i) provide a technical approach to reproduce features of the disease in vitro and (ii) characterize the tumor/host brain tissue interaction at the molecular level. Human engineered neural tissue (ENT) obtained from pluripotent stem cells was generated and co-cultured with human glioblastoma-initiating cells. Within two weeks, glioblastoma cells invaded the nervous tissue. This invasion displayed features of the disease in vivo: a primary tumor mass, diffuse migration of invading single cells into the nervous tissue, secondary foci, as well as peritumoral cell death. Through comparative molecular analyses, this model allowed the identification of more than 100 genes that are specifically induced and up-regulated by the nervous tissue/tumor interaction. Notably the type I interferon response, extracellular matrix-related genes were most highly represented and showed a significant correlation with patient survival. In conclusion, glioblastoma development within a nervous tissue can be engineered in vitro, providing a relevant model to study the disease and allows the identification of clinically-relevant genes induced by the tumor/host tissue interaction.
Elevated invasive potential of glioblastoma stem cells
Biochemical and Biophysical Research Communications, 2011
Glioblastomas (GBMs) are the most lethal and common types of primary brain tumors. The hallmark of GBMs is their highly infiltrative nature. The cellular and molecular mechanisms underlying the aggressive cancer invasion in GBMs are poorly understood. GBM displays remarkable cellular heterogeneity and hierarchy containing self-renewing glioblastoma stem cells (GSCs). Whether GSCs are more invasive than non-stem tumor cells and contribute to the invasive phenotype in GBMs has not been determined. Here we provide experimental evidence supporting that GSCs derived from GBM surgical specimens or xenografts display greater invasive potential in vitro and in vivo than matched non-stem tumor cells. Furthermore, we identified several invasion-associated proteins that were differentially expressed in GSCs relative to non-stem tumor cells. One of such proteins is L1CAM, a cell surface molecule shown to be critical to maintain GSC tumorigenic potential in our previous study. Immunohistochemical staining showed that L1CAM is highly expressed in a population of cancer cells in the invasive fronts of primary GBMs. Collectively, these data demonstrate the invasive nature of GSCs, suggesting that disrupting GSCs through a specific target such as L1CAM may reduce GBM cancer invasion and tumor recurrence.► Glioblastoma stem cells (GSCs) display elevated invasive capacity in vitro. ► GSCs are more invasive than matched non-stem tumor cells in vivo. ► GSCs increase expression of invasion-associated proteins including L1CAM. ► L1CAM is highly expressed in GSCs and the invasive fronts of glioblastomas.
Cancer stem cell contribution to glioblastoma invasiveness
Stem Cell Research & Therapy, 2013
Cancer stem cells and neural stem cells: common features with diff erent purposes Parallels between neurogenesis and the processes contributing to brain tumor formation exist. Neural stem cells (NSCs) are quiescent cells able to self-renew and generate partially committed, highly proliferative progenitors that subsequently undergo complete diff erentiation into one of the three lineages composing the brain. A recognized hallmark of neural stem/progenitor cells is their ability to migrate, an essential process for recovery after brain injury [1]. Th e same role exerted by NSCs in the physiological context has been proposed to be played in glioblastoma (GBM) by a rare fraction of self-renewing, multipotent tumor-initiating cells called cancer stem cells (CSCs), responsible for tumor progression, maintenance, and recurrence [2,3]. Th is subpopulation has shown intrinsic resistance to therapy, being able to repopulate the tumor after treatment [4]. Recently, many studies have ascribed to CSCs the infi ltrative property of GBM. Cancer stem cells and invasive cells: two sides of the same coin? Th e clinically distinct feature of GBM lies within its infi ltrative potential, rendering complete tumor resection nearly impossible. Tumor infi ltration is an extremely com plex program that requires the steady supply of extra cellular cues, abrogation of cell-cell interactions, and extracellular matrix (ECM) remodeling. Invading GBM cells are particularly resistant to current therapies and are often localized within the neurovascular niche, two features in common with CSCs [5]. Recent experimental data started to suggest that CSCs are responsible for GBM invasiveness. Cells enriched for the putative stem cell marker CD133 display greater migratory and invasive potential in vitro and in vivo when compared with matched CD133-negative tumor cells derived from human primary GBMs, GBM xenografts [4], and brain tumor cell lines [6-9]. We and others reported a marked upregulation of proteins involved in the processes of migration and invasion in GBM CSCs, such as diff erent types of matrix metalloproteinases, or diff erent members of both ADAMs (a disintegrin and metallo proteinases) and ADAMTS (ADAM with thrombo spondin motifs) families [4,6-8,10]. Th erefore, the highly migrating and invasive ability of GBM CSCs may be due to increased expression of proinvasive genes. Based on the findings that the GBM CSCs are more infiltrative than their diff rentiated descendants, a novel strategy has also been proposed to isolate and enrich CSCs from the whole tumor population by exploiting the tumor cell heterogeneity of invasiveness [11]. Cells at the leading edge of the tumor have been found to be positive for putative stem cell markers such as Abstract Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. Its invasive nature currently represents the most challenging hurdle to surgical resection. The mechanism adopted by GBM cells to carry out their invasive strategy is an intricate program that recalls what takes place in embryonic cells during development and in carcinoma cells during metastasis formation, the so-called epithelial-to-mesenchymal transition. GBM cells undergo a series of molecular and conformational changes shifting the tumor toward mesenchymal traits, including extracellular matrix remodeling, cytoskeletal re-patterning, and stemlike trait acquisition. A deeper understanding of the mechanisms driving the whole infi ltrative process represents the fi rst step toward successful treatment of this pathology. Here, we review recent fi ndings demonstrating the invasive nature of GBM cancer stem cells, together with novel candidate molecules associated with both cancer stem cell biology and GBM invasion, like doublecortin and microRNAs. These fi ndings may aff ect the design of eff ective therapies currently not considered for GBM invasive progression.
Cellular Host Responses to Gliomas
PLoS ONE, 2012
Background: Glioblastoma multiforme (GBM) is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites.