Search Results (370)

Recent advances have highlighted the multifaceted roles of the lymphatic vasculature in immune cell trafficking, immunomodulation, nutrient transport, and fluid homeostasis. Beyond these physiological functions, lymphatic vessels are critically involved in pathologies such as cancer metastasis and lymphedema, rendering their structural and functional regulation of major interest. Emerging evidence suggests that limited proteolysis is a key regulatory mechanism for lymphatic vascular function. In dyslipidemic conditions, dysregulated calpain activity impairs lymphatic trafficking and destabilizes regulatory T cells, partly via the limited proteolysis of mitogen-activated kinase kinase kinase 1 and inhibitor of κBα. In addition, a disintegrin and metalloprotease with thrombospondin motifs-3-mediated proteolytic activation of vascular endothelial growth factor-C has been implicated in both developmental and tumor-associated lymphangiogenesis. Proteolytic shedding of lymphatic vessel endothelial hyaluronan receptor-1 by a disintegrin and metalloprotease 17 promotes lymphangiogenesis, whereas cleavage by membrane-type 1 matrix metalloproteinase inhibits it. This review is structured around two core aspects—lymphatic inflammation and lymphangiogenesis—and highlights recent findings on how limited proteolysis regulates each of these processes. It also discusses the therapeutic potential of targeting these proteolytic machineries and currently unexplored research questions, such as how intercellular junctions of lymphatic endothelial cells are controlled. Full article

Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic agents. To address this limitation, bioreductive drugs have been developed that become selectively activated in hypoxic environments, providing targeted cytotoxic effects within oxygen-deprived tumor regions. Additionally, the rapid growth of tumors often results in disorganized and inefficient vasculature, further impairing the delivery of oxygen and therapeutic agents. This review explores the molecular mechanisms by which hypoxia disrupts DNA repair and contributes to treatment resistance. It also presents emerging therapeutic strategies aimed at targeting the hypoxic tumor microenvironment to improve treatment efficacy and patient outcomes. Full article

Canine histiocytic sarcoma (HS) is a rare tumor with a poor prognosis. Rapid tumor growth often causes central hypoxia and starvation, impacting tumor progression. In the present study, HS cells were cultured under hypoxia and starvation for 1 and 3 days, simulating intermediate and central tumor zones, respectively. Cells were counted at each time point, followed by RNAseq analysis. Only hypoxia significantly reduced the cell number (p < 0.05). Short-term hypoxia altered 1645 differentially expressed genes (DEGs). Upregulated genes belonged to vasculature development, and downregulated genes to cell cycle processes. Short-term starvation affected 157 genes, mainly involving responses to stimuli. Prolonged hypoxia and starvation induced 1301 and 836 DEGs, respectively. Prolonged hypoxia upregulated genes mainly involved in immune responses, response to stimulus, adhesion, and angiogenesis. Prolonged starvation upregulated genes associated with signaling, adhesion, circulatory system development, and response to stimulus. Lipid metabolism and cell cycle pathways were downregulated under prolonged hypoxia and starvation, respectively. KEGG “pathways in cancer” were enriched under all conditions (adjusted p-values < 0.05). These findings indicate that hypoxia and starvation significantly alter the expression of genes involved in tumor progression. Further studies, namely post-translational analyses, are needed to elucidate the functional impact of these changes and identify potential therapeutic targets. Full article

Nitric oxide (NO), the first gaseous molecule identified as a signaling mediator, plays a pivotal role in numerous physiological processes including cardiovascular regulation, immune response, and neurotransmission. Synthesized from L-arginine by nitric oxide synthase (NOS), NO exerts both protective and cytotoxic effects depending on its local concentration. At low levels, NO supports tumor growth by mitigating oxidative stress, while at high concentrations, it induces apoptosis through mechanisms such as p53 activation, cytochrome c release, and peroxynitrite formation. These dual properties position NO as a complex but promising agent in cancer therapy. Recent studies have highlighted the potential of NO in enhancing the efficacy of photodynamic therapy (PDT), where it synergizes with reactive oxygen species (ROS) to induce cytotoxic effects in tumor cells. Despite its promise, challenges such as rapid diffusion and limited tumor accumulation hinder NO’s therapeutic utility. This has spurred the development of NO donors and nanotechnology-based delivery systems to enable controlled, site-specific release. Moreover, NO has been shown to counteract multidrug resistance, improve tumor perfusion by dilating vasculature, and potentiate ROS-based therapies like PDT and radiotherapy. However, an emerging concern is NO’s role in promoting proliferation and migration of non-targeted “bystander” tumor cells following PDT-induced stress, primarily through iNOS upregulation. This feedback loop can contribute to tumor aggressiveness and metastasis, underscoring the need for a deeper understanding of NO’s molecular actions. While iNOS inhibitors show preclinical promise in various inflammatory and neoplastic conditions, no such agents have reached clinical approval, due to the complexity and context-dependent effects of NO. Future research should focus on refining NO delivery systems, developing selective iNOS inhibitors, and elucidating NO’s dual role in cancer biology to fully harness its therapeutic potential in PDT and beyond. Full article

Background: The use of photon-counting detector computed tomography (PCD-CT) has improved image quality in cardiac, pulmonary, and musculoskeletal imaging. Abdominal imaging research, especially about the use of PCD-CT in hepatocellular carcinoma (HCC), is sparse. Objectives: We aimed to compare the image quality of tumors, the liver parenchyma, and the vasculature in patients with HCC using PCD-CT reconstructions at different slice thicknesses and kernels to identify the most appropriate settings for the clinical routine. Methods: CT exams from twenty adult patients with HCC performed with a clinically approved, first-generation PCD-CT scanner (Naeotom Alpha^®, Siemens Healthineers), were retrospectively reviewed. For each patient, images were reconstructed at four different sharp kernels, designed for abdominal imaging (Br40; Br44; Br48; Br56) and at three slice thicknesses (0.4 mm; 1 mm; 3 mm). The reconstruction with the Br40 kernel at 3 mm (Br40_{3 mm}) was used as a clinical reference. Three readers independently assessed the image quality of different anatomical abdominal structures and hypervascular HCC lesions using a five-point Likert scale. In addition, image sharpness was assessed using line-density profiles. Results: Compared with the clinical reference, the Br44_{1 mm} and Br48_{1 mm} reconstructions were rated superior for the assessment of the hepatic vasculature (median difference +0.67 [+0.33 to +1.33], p < 0.001 and +1.00 [+0.67 to +1.67], p < 0.001). Reconstructions for Br40_{1 mm} (+0.33 [−0.67 to +1.00], p < 0.001), and Br44_{3 mm} (+0.0 [0.0 to +1.00], p = 0.030) were scored superior for overall image quality. The noise demonstrated a continuous increase when using sharper kernels and thinner slices than Br40_{3 mm} (p < 0.001), leading to a decrease in contrast-to-noise ratio. Although there was a trend toward increased image sharpness using the slope analysis with higher kernels, this was not significantly different compared with the reference standard. Conclusion: PCD-CT reconstruction Br40_{1 mm} was the most suitable setting for overall image quality, while reconstructions with sharper kernels (Br44_{1 mm} and Br48_{1 mm}) can be considered for the assessment of the hepatic vasculature in patients with HCC. Full article

Transarterial chemoembolization (TACE) is a well-established treatment for intermediate-stage hepatocellular carcinoma (HCC), shown through randomized trials to improve survival compared to supportive care in patients with large, unresectable tumors who are not candidates for liver transplantation or local ablation. As the most commonly used transarterial intervention, TACE is also employed to downstage advanced HCC, allowing certain patients to become eligible for orthotopic liver transplantation under the Milan criteria. Despite its widespread use, variability in therapeutic outcomes highlights the need for improved procedural guidance. Recent advancements in intra-arterial contrast-enhanced ultrasound (IA CEUS) offer new opportunities to enhance TACE precision with real-time imaging that provides superior visualization of tumor vasculature and chemoembolic agent distribution. This review explores the role of IA CEUS in refining TACE for HCC, emphasizing its potential to increase intraprocedural accuracy and reduce the risk of incomplete tumor embolization. The enhanced spatial resolution of IA CEUS enables real-time tracking of embolic agent dispersion within tumor vessels, which could improve therapeutic efficacy by ensuring complete tumor targeting and minimizing non-target embolization. Additionally, IA CEUS may decrease procedural complications by allowing dynamic adjustment of embolic delivery based on real-time imaging feedback. By reviewing existing evidence on IA CEUS applications in TACE, this article highlights the modality’s potential to transform treatment protocols, improve outcomes, and expand the patient population eligible for TACE. Full article

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

Background: Bone marrow (BM)-derived myeloid–lymphatic endothelial cell progenitors (M-LECPs) promote formation of tumor lymphatics that are responsible for metastasis to lymph nodes. The regenerative capacity of BM progenitors to other lineages is mediated through cell fusion, a process that delivers a pro-mitotic message directly to division-restricted cells. This suggested that M-LECPs might use a similar mechanism to induce division of lymphatic endothelial cells (LECs). Methods: To test this hypothesis, we determined expression of fusogenic markers in M-LECP produced in vitro and recruited to human or mouse tumors in vivo as well as quantified their fusion with LECs in both settings. Fusion in vivo was determined in female chimera mice grafted with male BM that have been implanted with MDA-MB-231 or EMT6 breast tumors. Co-staining for Y-chromosome and LEC-specific markers allowed us to quantify tumor lymphatic vessels fused with BM progenitors. Results: We found that both tumor-recruited and in-vitro-produced M-LECPs expressed multiple fusogenic regulators and possessed a significant fusogenic activity towards cultured and vessel-lining LECs. Y-chromosomes, a marker of fusion, were detected in nearly half of tumor lymphatics and were associated with mitotic division, vessel formation, and node metastasis. Both in vitro and in vivo assays showed dependency of fusion on Th2 and Toll-like receptor-4 (TLR4) pathways. Conclusions: This novel mechanism of tumor lymphatic formation triggered by fusion with BM myeloid–lymphatic progenitors suggests a variety of new targets for inhibition of metastatic spread. Full article

The apelinergic system exerts multiple biological activities in human pathologies, including cancer. Overactivation of apelin/APJ, which has been detected in many malignant tumors, and the strong correlation with progression-free and overall survival, suggested the role of an oncogene for the apelin gene. Emerging evidence sheds new light on the effects of apelin on cellular functions and homeostasis in cancer cells and supports a direct role for this pathway on different hallmarks of cancer: “sustaining proliferative signaling”, “resisting cell death”, “activating invasion and metastasis”, “inducing/accessing vasculature”, “reprogramming cellular metabolism”, “avoiding immune destruction” and “tumor-promoting inflammation”, and “enabling replicative immortality”. This article reviews the currently available literature on the intracellular processes regulated by apelin/APJ, focusing on those pathways correlated with tumor development and progression. Furthermore, the association between the activity of the apelinergic axis and the resistance of cancer cells to oncologic treatments (chemotherapy, immunotherapy, radiation) suggests apelin/APJ as a possible target to potentiate traditional therapies, as well as to develop diagnostic and prognostic applications. This issue will be also covered in the review. 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

The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect”, which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies. Full article

Introduction: Curative treatment of HCC can be achieved by liver transplantation. In the framework of transplantation, add-on transarterial chemoembolization (TACE) can be performed as bridging therapy for local tumor control. The association between TACE and an increased incidence of hepatic arterial complications after transplantation has been investigated in multiple research items; however, the exact association remains unclear. The aim of this report was to explore the role of pre-transplantation TACE and pre-existing vascular celiac pathologies on the occurrence of postoperative hepatic arterial complications. Methods: This retrospective single-center study included all patients who underwent liver transplantation between 2008 and 2020. Arterial complication was defined as any postoperative occlusion, stenosis >50%, dissection or aneurysm on cross-sectional imaging. Results: This study encompasses 109 patients after transplantation, of which 80 underwent TACE prior to transplantation. The overall incidence of postoperative arterial complications did not differ between the groups (TACE 8/80 vs. control 6/29, p = 0.19). Further analysis showed no significant differences in the occurrence of specific complications (Occlusion: TACE 9/80 vs. control 3/29, p = 0.56; Stenosis: TACE 4/80 vs. control 5/29, p = 0.05; Dissection: TACE 1/80 vs. control 1/29; p = 0.46). Furthermore, linear regression analysis for preoperative TACE therapy, anatomic variants and pre-existing pathologies of the hepatic vasculature showed no association with postoperative arterial complications. Conclusions: Preoperative TACE therapy showed no influence on the incidence of post-transplant arterial complications in patients after liver transplantation. Furthermore, preoperative TACE therapy as well as anatomic variants and pre-existing arterial pathologies of the celiac axis could not be identified as risk factors for complications at the arterial anastomotic site after transplantation. Full article

Endobronchial ultrasound (EBUS) has evolved beyond conventional applications in mediastinal staging and central pulmonary tumor diagnosis. It encompasses the assessment of pulmonary vasculature in patients with thoracic malignancies. EBUS can visualize major vessels and allow assessment of pulmonary embolism, differential diagnosis of endovascular lesions, and T staging. Additionally, EBUS-guided transvascular needle aspiration (TVNA) has proven valuable for sampling lesions behind vessels and diagnosing conditions such as pulmonary artery sarcoma and tumor embolism, with low complication rates reported. The PubMed and SCOPUS databases were searched up to November 2024 for articles in the English language reporting the use of EBUS for pulmonary vasculature assessment. References were also searched for relevant articles. The integration of EBUS with other modalities enhances staging and diagnostic capabilities in thoracic malignancies. Despite promising findings, limitations include suboptimal image quality and challenges in extensively assessing all the vasculature. Safety concerns, particularly with transvascular biopsy, remain minimal with expert handling, although further studies are needed to assess specific risks like hematogenous tumor seeding. EBUS continues to evolve, suggesting its potential to become the cornerstone in advanced thoracic diagnostics and treatment planning. This review systematically explores the feasibility, safety, and diagnostic utility of EBUS in pulmonary vasculature assessment, highlighting its potential as an indispensable tool in thoracic diagnostics and treatment planning. Full article

This research describes the development and thorough characterization of a novel, versatile, and biocompatible hybrid nanocarrier of the NO-releasing agent NOC-18, with a specific focus on optimizing the purification process. In this study, we focused on the sustained release of NO using biocompatible and diagnostic hybrid magnetic nanoparticles (hMNPs) containing cerium-doped maghemite (CM) NPs, embedded within human serum albumin (HSA) protein. A comprehensive study was conducted using electron paramagnetic resonance (EPR) alongside the Griess assay to evaluate NO release from the chosen NO donor, NOC-18, and to assess the limitations of the molecule under various reaction conditions, identifying the optimal conditions for binding NOC-18 with minimal NO loss. Two types of particles were designed: In-hMNPs, where NOC-18 is encapsulated within the particles, and Out-hMNPs, where NOC-18 is attached onto the surface. Our results demonstrated that In-hMNPs provided a sustained and prolonged release of NO (half-life, 50 h) compared to the rapid release for the Out-hMNPs, likely due to the strong bonds formed with cerium, which helped to stabilize the NO molecules. These results represent a promising approach to designing a dual-function agent that combines contrast properties for tumor MRI with the possibility of increasing the permeability of tumor vasculature. The employment of this dual-function agent in combination with nanotherapeutics could improve the latter’s efficacy by facilitating their access to the tumor. Full article