RESUMO
PURPOSE OF REVIEW: This review provides an overview of recent updates in understanding the mechanisms by which glioblastoma cells interact with their cellular and molecular partners within the microenvironment. RECENT FINDINGS: We have now a better knowledge of the cell populations involved in Glioblastoma (GBM) invasion. Recent works discovered the role of new molecular players in GBM invasion, and, most importantly, better models are emerging which better recapitulate GBM invasion. SUMMARY: Invasive properties of glioblastoma make complete surgical resection impossible and highly invasive cells are responsible for tumor recurrence. In this review, we focus on recent updates describing how invasive cells progress in the surrounding tissue along brain structures. We also provide an overview of the current knowledge on key cells and molecular players within the microenvironment that contribute to the invasive process. VIDEO ABSTRACT.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Animais , Humanos , Invasividade Neoplásica , Microambiente TumoralRESUMO
Phosphatase of regenerating liver 2 (also known as PTP4A2) has been linked to cancer progression. Still, its exact role in glioblastoma (GBM), the most aggressive type of primary brain tumor, remains elusive. In this study, we report that pharmacologic treatment using JMS-053, a pan-phosphatase of regenerating liver inhibitor, inhibits GBM cell viability and spheroid growth. We also show that PTP4A2 is associated with a poor prognosis in gliomas, and its expression correlates with GBM aggressiveness. Using a GBM orthotopic xenograft model, we show that PTP4A2 overexpression promotes tumor growth and reduces mouse survival. Furthermore, PTP4A2 deletion leads to increased apoptosis and proinflammatory signals. Using a syngeneic GBM model, we show that depletion of PTP4A2 reduces tumor growth and induces a shift in the tumor microenvironment (TME) toward an immunosuppressive state. In vitro assays show that cell proliferation is not affected in PTP4A2-deficient or -overexpressing cells, highlighting the importance of the microenvironment in PTP4A2 functions. Collectively, our results indicate that PTP4A2 promotes GBM growth in response to microenvironmental pressure and support the rationale for targeting PTP4A2 as a therapeutic strategy against GBM. SIGNIFICANCE: High levels of PTP4A2 are associated with poor outcomes in patients with glioma and in mouse models. PTP4A2 depletion increases apoptosis and proinflammatory signals in GBM xenograft models, significantly impacts tumor growth, and rewires the TME in an immunocompetent host. PTP4A2 effects in GBM are dependent on the presence of the TME.
Assuntos
Neoplasias Encefálicas , Progressão da Doença , Glioblastoma , Microambiente Tumoral , Glioblastoma/patologia , Glioblastoma/genética , Animais , Humanos , Camundongos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células , Apoptose , Macrófagos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.