Search Results (25)

Glioblastoma (GBM, isocitrate dehydrogenase wild-type) is the most common primary malignant brain tumor in adults and is associated with a severely low survival rate. Treatments offer mere palliation and are ineffective, due, in part, to a lack of understanding of the intricate mechanisms underlying the disease, including the contribution of the tumor microenvironment (TME). Current GBM models continue to face challenges as they lack the critical components and properties required. To address this limitation, we developed innovative and practical three-dimensional (3D) GBM models with structural and mechanical biomimicry and tunability. These models allowed for more accurate emulation of the extracellular matrix (ECM) and vasculature characteristics of the native GBM TME. Additionally, 3D bioprinting was utilized to integrate these complexities, employing a hydrogel composite to mimic the native environment that is known to contribute to tumor cell growth. First, we examined the changes in physical properties that resulted from adjoining hydrogels at diverse concentrations using Fourier-Transform Infrared Spectroscopy (FTIR), compression testing, scanning electron microscopy (SEM), rheological analysis, and degradation analysis. Subsequently, we refined and optimized the embedded bioprinting processes. The resulting 3D GBM models were structurally reliable and reproducible, featuring integrated inner channels and possessing tunable properties to emulate the characteristics of the GBM ECM. Biocompatibility testing was performed via live/dead and AlamarBlue analyses using GBM cells (both commercial cell lines and patient-derived cell lines) encapsulated in the constructs, along with immunohistochemistry staining to understand how ECM properties altered the functions of GBM cells. The observed behavior of GBM cells indicated greater functionality in softer matrices, while the incorporation of hyaluronic acid (HA) into the gelatin methacryloyl (gelMA) matrix enhanced its biomimicry of the native GBM TME. The findings underscore the critical role of TME components, particularly ECM properties, in influencing GBM survival, proliferation, and molecular expression, laying the groundwork for further mechanistic studies. Additionally, the outcomes validate the potential of leveraging 3D bioprinting for GBM modeling, providing a fully controllable environment to explore specific pathways and therapeutic targets that are challenging to study in conventional model systems. Full article

Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient’s genetic signatures, represent an effective game changer? Full article

Glioblastoma multiforme (GBM) is the most severe form of brain cancer in adults, characterized by its complex vascular network that contributes to resistance to conventional therapies. Thermal therapies, such as magnetic hyperthermia (MHT), emerge as promising alternatives, using heat to selectively target tumor cells while minimizing damage to healthy tissues. The organ-on-a-chip can replicate this complex vascular network of GBM, allowing for detailed investigations of heat dissipation in MHT, while computational simulations refine treatment parameters. In this in silico study, tumor-on-a-chip models were used to optimize MHT therapy by comparing heat dissipation in normal and abnormal vascular networks, considering geometries, flow rates, and concentrations of magnetic nanoparticles (MNPs). In the high vascular complexity model, the maximum velocity was 19 times lower than in the normal vasculature model and 4 times lower than in the low-complexity tumor model, highlighting the influence of vascular complexity on velocity and temperature distribution. The MHT simulation showed greater heat intensity in the central region, with a flow rate of 1 µL/min and 0.5 mg/mL of MNPs being the best conditions to achieve the therapeutic temperature. The complex vasculature model had the lowest heat dissipation, reaching 44.15 °C, compared to 42.01 °C in the low-complexity model and 37.80 °C in the normal model. These results show that greater vascular complexity improves heat retention, making it essential to consider this heterogeneity to optimize MHT treatment. Therefore, for an efficient MHT process, it is necessary to simulate ideal blood flow and MNP conditions to ensure heat retention at the tumor site, considering its irregular vascularization and heat dissipation for effective destruction. Full article

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy. Full article

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study’s objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer. Full article

Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM cell lines were lentivirally transduced with either ALDH1A3 (ox) or an empty vector (ev). The angiogenesis phenotype was studied in indirect and direct co-culture of endothelial cells (ECs) with oxGBM cells (oxGBMs) and in an angiogenesis model in vivo. Angiogenesis array was performed in oxGBMs. RT²-PCR, Western blot, and double-immunofluorescence staining were performed to confirm the expression of targets identified from the array. A significantly activated angiogenesis phenotype was observed in ECs indirectly and directly co-cultured with oxGBMs and in vivo. Overexpression of ALDH1A3 (oxALDH1A3) led to a marked upregulation of PAI-1 and IL-8 mRNA and protein and a consequential increased release of both proteins. Moreover, oxALDH1A3-induced angiogenesis was abolished by the treatment of the specific inhibitors, respectively, of PAI-1 and IL-8 receptors, CXCR1/2. This study defined ALDH1A3 as a novel angiogenesis promoter. oxALDH1A3 in GBM cells stimulated EC angiogenesis via paracrine upregulation of PAI-1 and IL-8, suggesting ALDH1A3-PAI-1/IL-8 as a novel signaling for future anti-angiogenesis therapy in GBM. Full article

Despite in vivo malignancy, ependymoma lacks cell culture models, thus limiting therapy development. Here, we used a tunable three-dimensional (3D) culture system to approximate the ependymoma microenvironment for recapitulating a patient’s tumor in vitro. Our data showed that the inclusion of VEGF in serum-free, mixed neural and endothelial cell culture media supported the in vitro growth of all four ependymoma patient samples. The growth was driven by Nestin and Ki67 double-positive cells in a putative cancer stem cell niche, which was manifested as rosette-looking clusters in 2D and spheroids in 3D. The effects of extracellular matrix (ECM) such as collagen or Matrigel superseded that of the media conditions, with Matrigel resulting in the greater enrichment of Nestin-positive cells. When mixed with endothelial cells, the 3D co-culture models developed capillary networks resembling the in vivo ependymoma vasculature. The transcriptomic analysis of two patient cases demonstrated the separation of in vitro cultures by individual patients, with one patient’s culture samples closely clustered with the primary tumor tissue. While VEGF was found to be necessary for preserving the transcriptomic features of in vitro cultures, the presence of endothelial cells shifted the gene’s expression patterns, especially genes associated with ECM remodeling. The homeobox genes were mostly affected in the 3D in vitro models compared to the primary tumor tissue and between different 3D formats. These findings provide a basis for understanding the ependymoma microenvironment and enabling the further development of patient-derived in vitro ependymoma models for personalized medicine. Full article

Background: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. Methods: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0–2+) groups. The association between PSMA and VEGF expression was evaluated using Chi² analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. Results: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009–2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups—16.1 and 10.8 months, respectively (p = 0.02). Conclusion: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival. Full article

Laser interstitial thermal therapy (LITT) is an emerging clinical treatment for deep brain tumors, which is safe, minimally invasive, and effective. This paper established a three-dimensional model based on the LITT heat transfer model, including brain tissue, laser fiber, and straight tube vessels. Combining the PID control equation, diffuse approximation equation, Pennes heat transfer equation, and Murray’s law, the effect of micro-vessel radius and distance between vessels and fiber on the ablation temperature field during laser ablation was investigated by using COMSOL finite element software. The results showed that at a constant distance of 1 mm between the vessel and the fiber, the vessels with a radius of 0.1–0.2 mm could be completely coagulated, the vessels with a radius of 0.3–0.6 mm had cooling and directional effects on temperature distribution and thermal damage, and the vessels with a radius of 0.7–1.0 mm had cooling effects on the ablation temperature. When the vessel-fiber spacing was raised by 2 mm, 0.3–0.4 mm, vasculature had a directional influence on the temperature field; when the vessel-fiber spacing was raised by 3 mm, only 0.3 mm vessels had a directional effect on the temperature field. The range of temperature field impacted by blood flow diminishes as the distance between the optical fiber and the blood artery grows. The ablation zone eventually tends to be left and right symmetrical. In this study, we simulated the LITT ablation temperature field model influenced by tiny vessels based on PID control. We initially classified the vessels, which provided some guidance for accurate prediction and helped the accuracy of preoperative planning. Full article

Medulloblastoma (MB) is a heterogeneous disease in which survival is highly affected by the underlying subgroup-specific characteristics. Although the current treatment modalities have increased the overall survival rates of MB up to 70–80%, MB remains a major cause of cancer-related mortality among children. This indicates that novel therapeutic approaches against MB are needed. New promising treatment options comprise the targeting of cells and components of the tumor microenvironment (TME). The TME of MB consists of an intricate multicellular network of tumor cells, progenitor cells, astrocytes, neurons, supporting stromal cells, microglia, immune cells, extracellular matrix components, and vasculature systems. In this review, we will discuss all the different components of the MB TME and their role in MB initiation, progression, metastasis, and relapse. Additionally, we briefly introduce the effect that age plays on the TME of brain malignancies and discuss the MB subgroup-specific differences in TME components and how all of these variations could affect the progression of MB. Finally, we highlight the TME-directed treatments, in which we will focus on therapies that are being evaluated in clinical trials. Full article

Immunotherapies with immune checkpoint inhibitors or adoptive cell transfer have become powerful tools to treat cancer. These treatments act via overcoming or alleviating tumor-induced immunosuppression, thereby enabling effective tumor clearance. Glioblastoma (GBM) represents the most aggressive, primary brain tumor that remains refractory to the benefits of immunotherapy. The immunosuppressive immune tumor microenvironment (TME), genetic and cellular heterogeneity, and disorganized vasculature hinder drug delivery and block effector immune cell trafficking and activation, consequently rendering immunotherapy ineffective. Within the TME, the mutual interactions between tumor, immune and endothelial cells result in the generation of positive feedback loops, which intensify immunosuppression and support tumor progression. We focus here on the role of aberrant tumor vasculature and how it can mediate hypoxia and immunosuppression. We discuss how immune cells use immunosuppressive signaling for tumor progression and contribute to the development of resistance to immunotherapy. Finally, we assess how a positive feedback loop between vascular normalization and immune cells, including myeloid cells, could be targeted by combinatorial therapies with immune checkpoint blockers and sensitize the tumor to immunotherapy. Full article

Cutaneous melanoma is one of the most aggressive and deadliest cancers in human beings due to its invasiveness and other factors. Histopathological analysis is crucial for a proper diagnosis. Optical tissue clearing is a novel field that allows 3D image acquisition of large-scale biological tissues. Optical clearing and immunolabeling for 3D fluorescence imaging has yet to be extensively applied to melanoma. In the present manuscript, we establish, for the first time, an optical clearing and immunostaining procedure for human melanoma and human cell line-derived melanoma xenograft models using the CUBIC (clear, unobstructed brain imaging cocktails) technique. We have successfully cleared the samples and achieved 3D volumetric visualization of the tumor microenvironment, vasculature, and cell populations. Full article

Glioblastomas (GBMs) are high-grade malignancies with a poor prognosis. The current standard of care for GBM is maximal surgical resection followed by radiotherapy and chemotherapy. Despite all these treatments, the overall survival is still limited, with a median of 15 months. For patients harboring inoperable GBM, due to the anatomical location of the tumor or poor general condition of the patient, the life expectancy is even worse. The challenge of managing GBM is therefore to improve the local control especially for non-surgical patients. Interstitial photodynamic therapy (iPDT) is a minimally invasive treatment relying on the interaction of light, a photosensitizer and oxygen. In the case of brain tumors, iPDT consists of introducing one or several optical fibers in the tumor area, without large craniotomy, to illuminate the photosensitized tumor cells. It induces necrosis and/or apoptosis of the tumor cells, and it can destruct the tumor vasculature and produces an acute inflammatory response that attracts leukocytes. Interstitial PDT has already been applied in the treatment of brain tumors with very promising results. However, no standardized procedure has emerged from previous studies. Herein, we propose a standardized and reproducible workflow for the clinical application of iPDT to GBM. This workflow, which involves intraoperative imaging, a dedicated treatment planning system (TPS) and robotic assistance for the implantation of stereotactic optical fibers, represents a key step in the deployment of iPDT for the treatment of GBM. This end-to-end procedure has been validated on a phantom in real operating room conditions. The thorough description of a fully integrated iPDT workflow is an essential step forward to a clinical trial to evaluate iPDT in the treatment of GBM. Full article

Angiogenesis, a complex, multistep process of forming new blood vessels, plays crucial role in normal development, embryogenesis, and wound healing. Malignant tumors characterized by increased proliferation also require new vasculature to provide an adequate supply of oxygen and nutrients for developing tumor. Gliomas are among the most frequent primary tumors of the central nervous system (CNS), characterized by increased new vessel formation. The processes of neoangiogenesis, necessary for glioma development, are mediated by numerous growth factors, cytokines, chemokines and other proteins. In contrast to other solid tumors, some biological conditions, such as the blood–brain barrier and the unique interplay between immune microenvironment and tumor, represent significant challenges in glioma therapy. Therefore, the objective of the study was to present the role of various proangiogenic factors in glioma angiogenesis as well as the differences between normal and tumoral angiogenesis. Another goal was to present novel therapeutic options in oncology approaches. We performed a thorough search via the PubMed database. In this paper we describe various proangiogenic factors in glioma vasculature development. The presented paper also reviews various antiangiogenic factors necessary in maintaining equilibrium between pro- and antiangiogenic processes. Furthermore, we present some novel possibilities of antiangiogenic therapy in this type of tumors. Full article

The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood–brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability. Full article