transforming-growth-factor-beta and Central-Nervous-System-Neoplasms

Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC-TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells). At the signaling level, we outline the role of important mediators, like the gasotransmitter nitric oxide and different types of reactive oxygen species and the systems producing them. Finally, we briefly discuss the current antiangiogenic therapies used against brain and CNS tumors and the potential of new pharmacological interventions that target the EC-TC interaction.

Topics: Animals; Brain; Brain Neoplasms; Cell Communication; Central Nervous System; Central Nervous System Neoplasms; Endothelial Cells; Gap Junctions; Glioblastoma; Humans; Neovascularization, Pathologic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells.

Topics: Animals; Cell Transformation, Neoplastic; Central Nervous System Neoplasms; Humans; Neurogenesis; Neurons; Stem Cells; Transforming Growth Factor beta

The transforming growth factor-beta (TGF-beta) family of polypeptides includes three structurally and functionally related mammalian isoforms that influence cell proliferation, differentiation, and extracellular matrix production. Recent identification of these isoforms in the embryonic murine central nervous system suggests that these factors may regulate proliferation and differentiation of meningeal and neuroepithelial cells during development. Predominant expression of TGF-beta 1 in the leptomeninges compared with the brain of the murine and human central nervous system implicates this isoform in regulation of that mesodermal tissue. Thus, defective TGF-beta regulation may contribute to neoplastic transformation. Failure to activate latent TGF-beta s may contribute to the loss of autocrine regulation seen in meningiomas. Expression of TGF-beta 2 and TGF-beta 3 primarily in embryonic murine radial glia and adult human astrocytes suggests other roles for these isoforms, including glioblast differentiation and guidance of neuroblast migration. Although inhibitory to "normal" astrocyte proliferation, TGF-beta s demonstrate autocrine growth stimulation in vitro among hyperdiploid malignant gliomas, medulloblastomas, primitive neuroectodermal tumors, and anaplastic ependymomas. Hence, synthesis and release of active TGF-beta s by malignant brain tumors may create aberrant stimulatory autocrine loops. The mechanism of TGF-beta-induced growth stimulation is poorly understood. Future studies will likely clarify and identify additional roles for the TGF-beta isoforms in neuro-embryogenesis and neoplasia.

Topics: Animals; Cell Differentiation; Cell Division; Central Nervous System; Central Nervous System Neoplasms; Humans; Nervous System; Nervous System Neoplasms; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme.. Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 mug per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years.. Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor beta(2) (TGF-beta(2)). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-beta(2) expression within the tumors and positively correlated with clinical survival (P = 0.047).. Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-beta(2) expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell-based vaccines.

Topics: Adult; Aged; Cancer Vaccines; Central Nervous System; Central Nervous System Neoplasms; Cohort Studies; Dendritic Cells; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Male; Middle Aged; Peptides; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta2; Treatment Outcome

Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown.. The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.. CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia.. These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials.

Topics: Animals; Antigens, Neoplasm; Brain Neoplasms; CD8-Positive T-Lymphocytes; Central Nervous System Neoplasms; Female; Humans; Immune Tolerance; Melanoma, Experimental; Mice; Microglia; T-Lymphocytes, Cytotoxic; Transforming Growth Factor beta; Vaccination

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis Regulatory Proteins; beta Catenin; Central Nervous System Neoplasms; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation, Neoplastic; Hemangioma, Cavernous, Central Nervous System; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sulindac; Transforming Growth Factor beta

A human glioblastoma multiforme cell line (U87) and its derived-spheroids were irradiated either using a conventional irradiation (CIR) or a CK-like irradiation (IIR) in which the 8 Gy was delivered intermittently over a period of 40 minutes. The ability of glioma cells to migrate into a matrigel matrix was evaluated on days 1-8 from irradiation. Irradiation with CK-driven IIR significantly increased the invasion potential of U87 cells in a matrigel-based assay. In contrast to CIR, IIR was associated with increased levels of TGF-β at four days (Real time PCR), β1-integrin at 4-5 days (real-time PCR and western blot) and no elevation in phosphorylated AKT at days 4 and 5 (western blot). Our data suggests that glioma cell invasion as well as elevations of TGF-β and β1-integrin are associated with IIR and not CIR.

Topics: Cell Line, Tumor; Cell Movement; Central Nervous System Neoplasms; Collagen; Drug Combinations; Glioblastoma; Glioma; Humans; Integrin beta1; Laminin; Neoplasm Invasiveness; Oncogene Protein v-akt; Phosphorylation; Proteoglycans; Radiosurgery; Transforming Growth Factor beta; Up-Regulation

Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3(+) Treg and higher levels of TGF-beta1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-beta production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the anti-tumor immune response.

Topics: Animals; Cell Line, Tumor; Central Nervous System Neoplasms; Dendritic Cells; Flow Cytometry; Forkhead Transcription Factors; Glioma; Histocytochemistry; Kaplan-Meier Estimate; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Cytokines can influence the interactions between members of the integrin cell adhesion receptor family and the extracellular matrix thereby potentially affecting cell function and promoting cell adhesion, growth and migration of malignant astrocytoma tumor cells. As malignant astrocytoma cells synthesize TGF-beta1 in vivo, we analysed the effects of TGF-beta1 on signaling events associated with integrin receptor ligation, focusing on the effects on paxillin, a phosphorylated adaptor protein, that acts as a scaffold for signaling molecules recruited to focal adhesions. TGF-beta1-stimulation of primary astrocytes and serum-starved U-251MG malignant astrocytoma cells attached to fibronectin induced a substantial increase in the levels of paxillin protein (fivefold increase at 2.0 ng/ml) in a dose- and time-dependent manner compared to the levels observed on plating onto fibronectin in the absence of stimulation. In the astrocytoma cells, this resulted in an increase in the pool of tyrosine-phosphorylated paxillin, although it did not appear to alter the extent of phosphorylation of the paxillin molecules. In contrast, in primary astrocytes the protein levels were upregulated in the absence of a parallel increase in phosphorylation. The TGF-beta1-stimulated increase in paxillin levels required ligation of the fibronectin receptor, as it was not induced when the cells were plated onto vitronectin, collagen or laminin. The increase in the pool of paxillin on TGF-beta1 stimulation of the fibronectin-plated astrocytoma cells was associated with an increase in translation, but was not associated with an increase in the steady-state levels of paxillin mRNA. Stimulation with TGF-beta1 on a fibronectin substrate increased subsequent attachment and spreading of U-251MG cells onto fibronectin and, to a lesser extent, vitronectin, but not collagen. Our results indicate that physiologic levels of TGF-beta1 stimulate the expression of paxillin protein at the level of translation through a process that requires engagement of the fibronectin receptor, and promotes attachment and spreading of malignant astrocytoma cells on fibronectin.

Topics: Animals; Astrocytoma; Blotting, Western; Cell Adhesion; Cell Size; Central Nervous System Neoplasms; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Extracellular Matrix; Fibronectins; Half-Life; Humans; Microscopy, Fluorescence; Paxillin; Phosphoproteins; Phosphorylation; Protein Biosynthesis; Pseudopodia; Rats; Receptors, Fibronectin; RNA, Messenger; Substrate Specificity; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Up-Regulation