Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

Cancers, Journal Year: 2024, Volume and Issue: 16(17), P. 2975 - 2975

Published: Aug. 27, 2024

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing formation new vasculature (antiangiogenic treatments) or destroying formed tumor (vascular disrupting agents) show promise. This study summarizes existing knowledge regarding processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses activation redundant proangiogenic pathways, heightened cell invasion metastasis, induced hypoxia, creation vascular mimicry channels, regulation immune microenvironment. Subsequently, we explore potential strategies overcome this resistance, such as combining other methods, personalizing treatments for each patient, focusing on therapeutic targets, incorporating immunotherapy, utilizing drug delivery systems based nanoparticles. Additionally, would like discuss limitations methods future directions enhance beneficial effects patients GBM. Therefore, review aims research outcome GBM provide a more promising opportunity thoroughly exploring mechanisms investigating novel strategies.

Language: Английский

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The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 18, 2025

The mechanical properties of the tumor microenvironment (TME) undergo significant changes during growth, primarily driven by alterations in extracellular (ECM) stiffness and viscoelasticity. These not only promote progression but also hinder therapeutic efficacy impairing drug delivery activating mechanotransduction pathways that regulate crucial cellular processes such as migration, proliferation, resistance to therapy. In this review, we examine mechanisms through which cells sense transmit signals maintain homeostasis biomechanically altered TME. We explore current computational modelling strategies for pathways, highlighting need developing models incorporate additional components mechanosignaling machinery. Furthermore, review available methods measuring tumors clinical settings aiming at restoring TME blocking deregulated pathways. Finally, propose proper characterization a deeper understanding landscape TME, both tissue levels, are essential account influence forces on treatment efficacy.

Language: Английский

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Cancer-associated fibroblasts, tumor and radiotherapy: interactions in the tumor micro-environment

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Dec. 19, 2024

Abstract Cancer-associated fibroblasts (CAFs) represent a group of genotypically non-malignant stromal cells in the tumor micro-environment (TME) solid tumors that encompasses up to 80% volume. Even though phenotypic diversity and plasticity CAFs complicates research, it is well-established can affect many aspects progression, including growth, invasion therapy resistance. Although anti-tumorigenic properties have been reported, majority research demonstrates pro-tumorigenic role for via (in)direct signaling cancer cells, immunomodulation extracellular matrix (ECM) remodeling. Following harsh therapeutic approaches such as radio- and/or chemotherapy, do not die but rather become senescent. Upon conversion towards senescence, characteristics are preserved or even amplified. Senescent continue promote cell resistance, modulate ECM, stimulate epithelial-to-mesenchymal transition (EMT) induce immunosuppression. Consequently, play significant survival, relapse potentially malignant transformation surviving following therapy. Modulating CAF functioning TME therefore critical area research. Proposed strategies enhance efficacy include reverting senescent quiescent phenotype selectively targeting (non-)senescent CAFs. In this review, we discuss before during therapy, with strong focus on radiotherapy. future, should be taken into account when designing treatment plans new approaches.

Language: Английский

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Sonopermeation combined with stroma normalization enables complete cure using nano-immunotherapy in murine breast tumors

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113722 - 113722

Published: April 1, 2025

Nano-immunotherapy shows great promise in improving patient outcomes, as seen advanced triple-negative breast cancer, but it does not cure the disease, with median survival under two years. Therefore, understanding resistance mechanisms and developing strategies to enhance its effectiveness cancer is crucial. A key mechanism pronounced desmoplasia tumor microenvironment, which leads dysfunction of blood vessels thus, hypoperfusion, limited drug delivery hypoxia. Ultrasound sonopermeation agents that normalize stroma have been employed separately restore vascular abnormalities tumors some success. Here, we performed vivo studies murine, orthotopic models explore if combination ultrasound a normalization can synergistically improve perfusion efficacy nano-immunotherapy. We found proposed combinatorial treatment drastically reduce primary growth many cases were no longer measurable. Overall showed all mice received survived rechallenge experiments revealed survivors obtained immunological memory. Employing elastography contrast enhanced along proteomics analysis, flow cytometry immunofluorescene staining, reduced stiffness normal levels, restoring oxygenation. Furthermore, increased infiltration activity immune cells altered levels immunosupportive chemokines. Finally, using machine learning identified stiffness, CD8+ T M2-type macrophages strong predictors response.

Language: Английский

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Shear Stress and Microbubble‐Mediated Modulation of Endothelial Cell Immunobiology

Small Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Cellular immunotherapy remains hindered in the context of solid tumors due to immunosuppressive microenvironment, which key endothelial cell adhesion molecules (CAM) are suppressed. Microbubble‐mediated focused ultrasound is being explored for targeted and can exert local shear stress upon neighboring cells. However, fluid microbubble‐induced modulation immunobiology not well understood. Herein, influence both types on human vein (HUVEC) brain (HBEC‐5i) CAM expression secretion over 90 cytokines using acoustically coupled microscopy examined. Fluid flow results time‐dependent expression, where ICAM‐1 peaked at 4 h (1.98‐fold, p < 0.001, HUVEC) 24 (1.56‐fold, HBEC‐5i). While some chemokines significantly enhanced (up 16.2‐fold; 0.001) from (e.g., IL‐8, MCP‐1, MCP‐3), others differentially expressed CCL5, CXCL‐16, SDF‐1). Under ultrasound, increased (≈1.4‐fold, 0.01) resulted significant large‐magnitude ( 0.05) differential 20 cytokines, most have immune‐activating function within a subset those induced by shear‐flow. regulates secretome toward an immune recruitment paradigm, thus may reinforce tumor cellular efforts.

Language: Английский

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In-silico tool based on Boolean networks and meshless simulations for prediction of reaction and transport mechanisms in the systemic administration of chemotherapeutic drugs

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0315194 - e0315194

Published: Feb. 7, 2025

Using in-house computational tools, this work focuses on investigating how the combination of electric field magnitude (E), bloodstream velocity (λinl) and pharmaco-kinetic profile (PK) impacts reaction transport mechanisms drug (RTMs) arising in electro-chemotherapeutic treatments. The first step implies retrieving ratios between extracellular, free intracellular, bound intracellular concentrations from numerical simulations, employing a meshless code developed, calibrated validated previous work. Subsequently, Boolean model is developed to determine presence, interaction rates RTMs based comparison spatio-temporal evolution concentration ratios, being main contribution present comprehension phenomena involved systemic administration chemotherapeutic drugs cancer tumors. Different combinations E (0 kV/m, 46 70 kV/m), λinl (1x10-4m/s, 1x10-3m/s, 1x10-2m/s) PK (One-short tri-exponential, mono-exponential) are examined. In general, results show that both presence relative importance can differ PKs for given λinl. Additionally, PK, radial uniformity transmembrane rate aversively affected by increase λinl, whereas homogeneity association/dissociation monotonously only E. Regarding axial rate, benefited and, lower extent, reduction

Language: Английский

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Targeting VEGF signaling for tumor microenvironment remodeling and metastasis inhibition: Therapeutic strategies and insights

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 186, P. 118023 - 118023

Published: April 2, 2025

Language: Английский

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Cancer nanomedicine from a clinician-scientist perspective: Lessons and prospects

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113731 - 113731

Published: April 1, 2025

Language: Английский

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Spatial tertiary lymphoid structures imply response to anti‐PD‐1 plus anlotinib in advanced non‐small cell lung cancer

Immunology, Journal Year: 2024, Volume and Issue: 173(3), P. 536 - 551

Published: July 30, 2024

Despite breakthroughs of immunotherapy synergistically combined with blockade vascular endothelial growth factor receptor, several patients advanced non-small cell lung cancer (NSCLC) experience non-response or followed relapse. Organized lymphoid aggregates, termed tertiary structures (TLSs), are found to be associated improved response immunotherapy. Here, we explore the landscapes TLSs in tumour tissues from a real-world retrospective study. Our investigation showed that median follow-up 11.2 months, ORR was 28.6% (18/63, 95% CI 17.9-41.3) and PFS 6.1 (95% 5.5-6.6) months NSCLC treated PD-1 anlotinib. By multiplex immunofluorescence (mIF) analysis, spatially, more high CD20+ B-cell ratio were higher ORR. High density intratumoral CD8+ T cells better PFS. The numbers distance within 20 μm 20-50 between responders than non-responders. But had significantly rather inflamed immunophenotyping occupied proportions Besides, non-responders temporal cell-in-cell responders, which could protect inner T-cell attacks. Taken together, landscape proximity architecture may imply superior responses anlotinib for cancer.

Language: Английский

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Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Nov. 27, 2024

Pancreatic cancer remains one of the most lethal malignancies, with limited treatment options and poor prognosis. A common characteristic among pancreatic patients is biomechanically altered tumor microenvironment (TME), which others responsible for elevated mechanical stresses in interior. Although significant research has elucidated effect stress on cell proliferation migration, it not yet been investigated how could affect drug sensitivity. Here, we demonstrated that triggers autophagy activation, correlated increased resistance to oxaliplatin cells. Our results demonstrate inhibition using hydroxychloroquine (HCQ) enhanced oxaliplatin-induced apoptotic death cells exposed stress. The combined HCQ losartan, a known modulator abnormalities tumors, synergistically therapeutic efficacy murine models. Furthermore, our study revealed use losartan alleviate levels restore blood vessel integrity beyond its role modulation. These findings underscore potential co-targeting as promising strategy overcome increase chemotherapy efficacy. Inhibiting mechanically induced improves especially when losartan. This combination, only increases oxaliplatin's potency but also integrity.

Language: Английский

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