Angiogenesis is a complex physiological process. In recent years, the immune regulation of angiogenesis has received increasing attention, and innate immune cells, which are centred on macrophages, are thought to play important roles in vascular neogenesis and development. Various innate immune cells can act on the vasculature through a variety of mechanisms, with commonalities as well as differences and synergistic effects, which are crucial for the progression of vascular lesions. In recent years, monotherapy with antiangiogenic drugs has encountered therapeutic bottlenecks because of the short-term effect of 'vascular normalization'. The combination treatment of antiangiogenic therapy and immunotherapy breaks the traditional treatment pattern. While it has a remarkable curative effect and survival benefits, it also faces many challenges. This review focuses on innate immune cells and mainly introduces the regulatory mechanisms of monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils in vascular lesions. The purpose of this paper was to elucidate the underlying mechanisms of angiogenesis and development and the current research status of innate immune cells in regulating vascular lesions in different states. This review provides a theoretical basis for addressing aberrant angiogenesis in disease processes or finding new antiangiogenic immune targets in inflammation and tumor.

Melanoma is a highly invasive and metastatic malignant skin tumor. Recently, immunogenic cell death (ICD) has attracted great attention as a promising approach to immunotherapy. However, efficiently and comprehensively activating ICD throughout the dense tumor tissue is a key challenge. Herein, we designed a NIR II light-driven asymmetric nanomotor drug delivery system (Sor@CS-ZIF-8@MO1) to achieve deep penetration into the tumor tissue. By combining photothermal therapy (PTT) and chemodynamic therapy (CDT) to synergistically induce ICD, the immunotherapeutic efficacy against melanoma is enhanced. The research results showed that Sor@CS-ZIF-8@MO1 exhibited good photothermal performance and motor-driven performance, and was able to effectively penetrate 3D tumor cell spheroids deeply. Sor@CS-ZIF-8@MO1 targeted tumor tissues through mannose and controllably released sorafenib under the low pH conditions in tumor tissues and photothermal stimulation, thereby promoting tumor tissue angiogenesis to improve its hypoxic microenvironment and effectively enhancing the CDT effect induced by Cu+/2+. This could synergistically enhance the ICD of tumor cells with the PTT. Meanwhile, the tumor-associated antigens released by ICD, together with ovalbumin and mannose, stimulated immune response, reshaped the tumor immune microenvironment, enhanced tumor immunity, and ultimately effectively inhibited the growth and metastasis of melanoma tumors. In this work, a nanomotor delivery system that integrates multiple modalities and is capable of deeply penetrating tumor tissues to efficiently and comprehensively induce immunogenic cell death (ICD) has been designed, providing a new strategy to address the problem of insufficient induction of ICD in melanoma immunotherapy.

Hypoxia is an established hallmark of tumorigenesis. HIF-1α activation may be the prime driver of adaptive regulation of tumor cells reacting to hypoxic conditions of the tumor microenvironment. Here, we report a novel regulatory mechanism in charge of the fundamental stability of HIF-1α in solid tumor. Under hypoxic conditions, the checkpoint kinase CHK2 binds to HIF-1α and inhibits its ubiquitination, which is highly likely due to phosphorylation of a threonine residue (Thr645), a formerly uncharacterized site within the inhibitory domain. Meanwhile, HIF-1α phosphorylation induced by CHK2 promotes complex formation between HIF-1-α and the deubiquitination enzyme USP7, increasing stability under hypoxic conditions. This novel modification of the crosstalk between phosphorylation and ubiquitination of HIF-1α mediated by CHK2 enriches the post-translational modification spectrum of HIF-1α, thus offering novel insights into potential anti-angiogenesis therapies.

Previous studies have shown the potential of bevacizumab-based ADCs in tumor vascular normalization and chemotherapy synergies. Here, in order to improve the tumor treatment efficiency of ADC and further avoid drug resistance, we introduced the previously discovered photodynamic therapy group PDT into bevacizumab, which has high reactive oxygen generation efficiency and deep tissue penetration ability, and has surprising imaging effect on solid tumors. At the same time, doxorubicin, a chemotherapy drug molecule with strong cytotoxicity, has also been introduced to construct novel multifunctional integrated antibody-drug conjugates, Bevacizumab-DOX-PDT. It is proved that novel ADCs have the antigen-antibody binding ability similar to bevacizumab, while also possess strong antitumor activity and vascular normalization activity. In addition, it also showed great tracer ability for transplanted tumors. In summary, the novel ADC showed a surprising vascular normalization-chemotherapy-photodynamic synergistic therapeutic effect, which further enriched the expansion of vascular normalization in the field of new drug discovery.

Metastasis, the leading cause of cancer-related deaths, underscores the critical need to understand its regulatory mechanisms to improve prevention and treatment strategies for late-stage tumors. Hematogenous dissemination is a key route of metastasis. However, as the gatekeeper of vessels, the role of pericytes in hematogenous metastasis remains largely unknown. In this review, we comprehensively explore the contributions of pericytes throughout the metastatic cascade, particularly their functions that extend beyond influencing tumor angiogenesis. Pericytes should not be perceived as passive bystanders, but rather as active participants in various stages of the metastatic cascade. Pericytes-targeted therapy may provide novel insights for preventing and treating advanced-stage tumor.

Tumor angiogenesis facilitates cancer progression by supporting tumor growth and metastasis. MicroRNA-155 (miR-155) plays a pivotal role in regulating angiogenesis through both direct effects on tumor and endothelial cells and indirect modulation via exosomal communication. This review highlights miR-155's pro-angiogenic influence on endothelial cell behavior and tumor microenvironment remodeling. Additionally, exosomal miR-155 enhances intercellular communication, promoting vascularization in several cancers. Emerging therapeutic strategies include miR-155 inhibition using antagomirs, exosome-mediated delivery systems, and modulation of pathways such as JAK2/STAT3 and TGF-β/SMAD2. Targeting miR-155 represents a promising approach to hinder tumor angiogenesis and improve cancer therapy outcomes.

Many cancer therapies fail in clinical trials despite showing potent efficacy in preclinical studies. One of the key reasons is the adopted preclinical models cannot recapitulate the complex tumor microenvironment (TME) and reflect the heterogeneity and patient specificity in human cancer. Cancer-on-a-chip (CoC) microphysiological systems can closely mimic the complex anatomical features and microenvironment interactions in an actual tumor, enabling more accurate disease modeling and therapy testing. This review article concisely summarizes and highlights the state-of-the-art progresses in CoC development for modeling critical TME compartments including the tumor vasculature, stromal and immune niche, as well as its applications in therapying screening. Current dilemma in cancer therapy development demonstrates that future preclinical models should reflect patient specific pathophysiology and heterogeneity with high accuracy and enable high-throughput screening for anticancer drug discovery and development. Therefore, CoC should be evolved as well. We explore future directions and discuss the pathway to develop the next generation of CoC models for precision cancer medicine, such as patient-derived chip, organoids-on-a-chip, and multi-organs-on-a-chip with high fidelity. We also discuss how the integration of sensors and microenvironmental control modules can provide a more comprehensive investigation of disease mechanisms and therapies. Next, we outline the roadmap of future standardization and translation of CoC technology toward real-world applications in pharmaceutical development and clinical settings for precision cancer medicine and the practical challenges and ethical concerns. Finally, we overview how applying advanced artificial intelligence tools and computational models could exploit CoC-derived data and augment the analytical ability of CoC.

Multiple members of the caveolae-associated protein (Cavin) family are implicated in angiogenesis. However, the specific role of CAVIN3 in pathological angiogenesis within the eye remains unclear. The present study demonstrated that CAVIN3 knockdown in endothelial cells (ECs) promoted vascular normalization in ocular pathological neovascularization. Elevated CAVIN3 expression was observed in the ECs of retinal pigment epithelium/choroid complexes from patients with neovascular age-related macular degeneration and fibrovascular membranes from patients with proliferative diabetic retinopathy. Additionally, upregulated Cavin3 expression was detected in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) mouse models. In both OIR and CNV mice, Cavin3 knockdown inhibited pathological neovascularization. Cavin3 deficiency further disrupted EC proliferation and vascular sprouting, thereby promoting vascular normalization by partially restoring microenvironmental hypoxia and reestablishing pericyte-EC interactions. Mechanistically, we demonstrated that zinc finger E-box-binding homeobox 1 (ZEB1) regulated CAVIN3 transcription in ECs under hypoxic conditions. CAVIN3 deficiency modulated pathological vascularization by inhibiting ERK phosphorylation, which downregulated jagged 1 (JAG1) expression. Conclusively, this study elucidated the protective role of endothelial CAVIN3 deficiency in pathological neovascularization models, addressing a gap in understanding the regulatory role of Cavins in angiogenesis. These findings suggested a therapeutic direction for ocular neovascular diseases.

MicroRNAs (miRs) have emerged as pivotal regulators in the development and progression of colorectal cancer (CRC), and MicroRNA-206 (miR-206) has garnered attention as a potentially influential factor. However, the specific biological functions and complete mechanistic understanding of miR-206 in CRC remain largely uncharacterized. This study aims to bridge this research gap by providing a comprehensive analysis of miR-206's role in CRC. An exploration of the molecular mechanisms regulated by miR-206, its intricate interplay with target genes, and its significant impact on cellular processes highlights its potential utility as both a diagnostic marker and a therapeutic target. The significance of this research lies in potentially enabling the development of innovative therapeutic approaches, ultimately aiming to improve prognosis and survival rates in CRC patients by elucidating the functions of miR-206. Critical pathways, such as c-Met and PTEN/AKT, play crucial roles within the regulatory network of miR-206 in CRC and impact various cellular processes involved in CRC pathogenesis, metastasis, and treatment response. Understanding the complex interactions between miR-206 and key signaling pathways like c-Met and PTEN/AKT is crucial for understanding the underlying mechanisms driving CRC initiation and progression. This knowledge can inform the development of targeted therapeutic interventions, potentially leading to improved patient outcomes and advances in CRC management.

Antiangiogenic medications for cancer treatment have generally failed in showing substantial benefits in terms of prolonging life on their own; their effects are noticeable only when combined with chemotherapy. Moreover, treatments based on prolonged antiangiogenics administration have demonstrated to be ineffective in stopping tumor progression. In this scenario, nanotherapeutics can address certain issues linked to existing antiangiogenic treatments. More specifically, they can provide the ability to target the tumor's blood vessels to enhance drug accumulation and manage release, ultimately decreasing undesired side effects. Additionally, they enable the administration of multiple angiogenesis inhibitors at the same time as chemotherapy. Key reports in this field include the design of polymeric nanoparticles, inorganic nanoparticles, vesicles, and hydrogels for loading antiangiogenic substances like endostatin and interleukin-12. Furthermore, nanoformulations have been proposed to efficiently control relevant pro-angiogenic pathways such as VEGF, Tie2/Angiopoietin-1, HIF-1α/HIF-2α, and TGF-β, providing powerful approaches to block tumor growth and metastasis. In this article, we outline a selection of nanoformulations for antiangiogenic treatments for cancer that have been developed in the past ten years.

Abnormal tumor blood vessels can significantly promote the malignant progression of tumors, prompting researchers to focus on drugs that normalize these vessels for clinical treatment. The combination of the Qi-tonifying drug Astragali Radix and the blood-activating drug Curcumae Rhizoma, referred to as AC, exhibited significant anti-tumor metastasis effects. However, the association between the anti-tumor metastasis effect of AC and its potential role in regulating tumor vascular remodeling warrants further exploration.

This study aimed to elucidate the mechanism through which AC induces tumor blood vessel normalization in colon cancer (CC).

The potential active components of AC were identified through UPLC-MS/MS. An orthotopic transplantation model of CC was established in BALB/c mice using the CT26-Lucifer cell line, and the effects of AC were evaluated using IVIS imaging, hematoxylin and eosin (H&E) staining, and immunohistochemistry. Network pharmacology and molecular biology analyses were employed to identify the potential direct targets of AC. Subsequently, RT-PCR and Western blotting techniques were utilized to validate the findings obtained from network pharmacology. Furthermore, ELISA and other methodologies were used to investigate glycolysis-related indicators, along with immunofluorescence technology to demonstrate changes in vascular leakage and perfusion characteristics associated with blood vessel normalization.

We identified HIF-1α as a potential direct target of AC. This interaction influences the glycolytic processes in both tumor cells and tumor-associated endothelial cells (TECs) by directly binding to HIF-1α and modulating its nuclear translocation, thereby determining the integrity of TEC junctions. Mechanistically, AC directly regulates the key enzyme PFKFB3 in glycolysis by modulating HIF-1α expression and inhibiting its nuclear translocation. This action reduces tumor glycolytic flux, decreases the internalization of VE-cad, and influences the expression of downstream matrix metalloproteinases (MMPs), thereby strengthening the adherens and tight junctions between TECs and restoring vascular integrity.

This study presents novel findings that AC can regulate glycolysis through the inhibition of HIF-1α nuclear translocation, thereby promoting the normalization of tumor blood vessels and effectively inhibiting tumor metastasis. These results suggested that AC may serve as an effective therapeutic agent for normalizing tumor blood vessels.

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery. Therefore, there is an urgent need to develop new methods for the treatment of this condition. Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions. They have low immunogenicity, good stability, high delivery efficiency, and the ability to cross the blood-brain barrier. These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke. The rapid development of nanotechnology has advanced the application of engineered exosomes, which can effectively improve targeting ability, enhance therapeutic efficacy, and minimize the dosages needed. Advances in technology have also driven clinical translational research on exosomes. In this review, we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke, including their anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects. However, it is worth noting that, despite their significant therapeutic potential, there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes. Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke. Ultimately, our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

Hypoxia in the tumor environment leads to an activation of genotypes that favors the tumor, promoting angiogenesis, epithelial-mesenchymal transition, cell invasion, and metastasis. It is considered a prognostic factor related to the progression and aggressiveness of Head and Neck Cancer (HNC). Hypoxia-inducible factor (HIF) is the main gene activated by hypoxia and has been associated with tumor advancement. Thus, this work aims to evaluate the performance of the compounds Acriflavine, Resveratrol, Topotecan, and RNA interference (siRNA) as HIF inhibitors as well as a therapeutic approach. Molecular docking results have suggested that the evaluated compounds present potential interactions with HIF-1α and HIF-2α. In vitro analysis, they demonstrated that treatments with Acriflavine and Topotecan caused a decrease in the gene expression of HIFs in the HN13 cell line (carcinoma of the oral cavity). Furthermore, treatments performed with siRNAs effectively inhibited gene expression of HIFs in HN13 and FaDu (carcinoma of the pharynx) cell lines. Considering the role of hypoxia and HIFs in tumor aggressiveness; the present study shows the potential of the evaluated compounds as a therapeutic use for the prevention of tumor progression in head and neck cancer.

Organoids provide 3D structures that replicate native tissues in biomedical research. The development of vascular networks within organoids enables oxygen and nutrient delivery while facilitating metabolic waste removal, which supports organoid growth and maturation. Recent studies demonstrate that vascularized organoid models offer insights into tissue interactions and promote tissue regeneration. However, the current limitations in establishing functional vascular networks affect organoid growth, viability, and clinical translation potential. This review examines the development of vascularized organoids, including the mechanisms of angiogenesis and vasculogenesis, construction strategies, and biomedical applications. The approaches are categorized into in vivo and in vitro methods, with analysis of their specific advantages and limitations. The review also discusses emerging techniques such as bioprinting and gene editing for improving vascularization and functional integration in organoid-based therapies. Current developments in organoid vascularization indicate potential applications in modeling human diseases and developing therapeutic strategies, contributing to advances in translational research.

Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is linked to elevated global incidence and mortality rates. Elucidating the intricate molecular pathways that drive the progression of HCC is imperative for devising targeted and effective therapeutic interventions. RNA-binding proteins (RBPs) serve as pivotal regulators of post-transcriptional processes, influencing various cellular functions. This review endeavors to provide a comprehensive analysis of the expression, function, and potential implications of RBPs in HCC. We discuss the classification and diverse roles of RBPs, with a particular focus on key RBPs implicated in HCC and their association with disease progression. Additionally, we explore the mechanisms by which RBPs contribute to HCC, including their impact on gene expression, cell proliferation, cell metastasis, angiogenesis, signaling pathways, and post-transcriptional modifications. Importantly, we examine the potential of RBPs as therapeutic targets and prognostic biomarkers, offering insights into their relevance in HCC treatment. Finally, we outline future research directions, emphasizing the need for further investigation into the functional mechanisms of RBPs and their clinical translation for personalized HCC therapy. This comprehensive review highlights the pivotal role of RBPs in HCC and their potential as novel therapeutic avenues to improve patient outcomes.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Local injection of the drug-loaded hydrogel at the surgery site is promising for postoperative breast cancer. However, the postoperative changes in the tumor microenvironment, such as inflammation, abnormal angiogenesis and hypoxia, inhibit drug perfusion and contribute to breast cancer recurrence (BCR). Normalizing the abnormal blood vessels can effectively improve perfusion and reduce hypoxia. Here, we encapsulated gemcitabine (GEM) in a PLGA-PEG-PLGA hydrogel (GEM-hydrogel) for local treatment of postoperative breast cancer. The GEM-hydrogel can be injected into the surgery cavity allowing sustained release of the drug. Meanwhile, traditional Chinese medicine (TCM) Shexiang Baoxin Pill (SBP) was given to normalize the blood vessels to enhance drug perfusion. The results suggest that the combination of SBP enhances the therapeutic efficiency of the GEM-hydrogel, inhibiting tumor recurrence. Mechanism studies reveal that SBP works by promoting PDGFB expression in macrophages, subsequently recruiting pericytes, and normalizing blood vessels, finally alleviating hypoxia. This study demonstrates that the combination of TCM and chemotherapeutics is promising for suppressing postoperative tumor recurrence.

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in patients with metastatic colorectal cancer (mCRC) characterized by high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). However, most patients experience intrinsic or acquired resistance. The need for treatment for patients with MSI-H/dMMR mCRC remains unmet. Here, we report the case of a patient with dMMR mCRC who achieved a durable therapeutic benefit from the combination of ICI and angiogenesis inhibitor after ICI failure.

A 40-year-old Chinese woman diagnosed with cT4N2M1b mCRC characterized by dMMR attributed to MLH-1 and PMS-2 deficiency, along with KRAS mutation. Primarily, the patient was treated with a combination of Chinese medicine and XELOX and underwent disease progression. Due to dMMR status, this patient then received single-agent camrelizumab. Unfortunately, disease progression was observed after two cycles of treatment. Subsequently, she received camrelizumab combined with bevacizumab. After treatment, the patient achieved a complete response, and the disease was sustainably controlled with a progression-free survival (PFS) of 3 years and counting.

This report demonstrates that the combination of ICI and anti-angiogenesis therapy can induce a powerful and durable antitumor response in patients with ICI-resistant MSI-H/dMMR mCRC, which is worthy of further research.

Head and neck tumors represent a prevalent category of oral and maxillofacial malignancies, posing significant therapeutic and prognostic challenges due to their complex anatomical structure, tumor heterogeneity, and resistance to conventional therapies. Recent studies have highlighted the strong association between tumor progression and neoangiogenesis, with the angiopoietin (ANG) family playing a central role in this process. Comprising ANG1, ANG2, ANG3, and ANG4, these factors regulate multiple signaling pathways that promote cellular growth, differentiation, and proliferation, thereby driving angiogenesis and accelerating tumor growth and metastasis. Therefore, a comprehensive investigation of the ANG family's role in head and neck tumors may offer critical insights into tumorigenesis mechanisms and unveil novel therapeutic targets. Such research has the potential to improve treatment outcomes and enhance the quality of life for patients.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They are associated with various biological processes related to tumors. Among the numerous miRNAs, miR-29 has garnered attention for its role in regulating tumor angiogenesis. In numerous human tumors, miR-29 has been demonstrated to negatively correlate with the capacity for angiogenesis and the degree of malignancy, as well as with the expression levels of pro-angiogenic factors such as vascular endothelial growth factor vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and matrix metalloproteinase (MMP)-2. Multiple studies, utilizing techniques like dual-luciferase reporter assays, have confirmed that miR-29 directly targets the 3'-untranslated region (UTR) of mRNAs for VEGF, PDGF, and MMP-2. Extensive investigations involving tumor cell lines and animal models have shown that the overexpression of miR-29, achieved through miRNA transfection or the introduction of miRNA mimics, effectively inhibits angiogenesis by upregulating these pro-angiogenic factors. Conversely, downregulation of miR-29 using specific inhibitors promotes angiogenesis. While small molecule inhibitors and antibodies targeting VEGF constitute a primary strategy in anti-angiogenesis therapies, miR-29's ability to target multiple pro-angiogenic molecules positions it as a promising candidate for future therapeutic interventions, especially with ongoing advancements in nucleic acid drug design and delivery systems.

Cholangiocarcinoma (CCA) presents a therapeutic challenge due to its aggressiveness and poor survival rates. This study introduces an approach using tissue inhibitor of metalloproteinase 2 (TIMP2)-enriched bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo) encapsulated in chitosan hydrogels (CS), intending to provide novel insight into the CCA treatment.

BMSC-Exo was characterized by using TEM, nanoparticle tracking analysis, and western blotting. Role of TIMP2 in CCA was explored using bioinformatics analysis. Therapeutic efficacy and mechanisms of BMSC-Exo/CS in CCA were assessed through cell viability tests and colony formation assays. Angiogenic and Wnt/β-catenin signaling pathways-related key factors were detected through RT-qPCR or western blotting.

BMSC-Exo displayed typical cup-shaped morphology and was positive for exosomal markers CD9 and TSG101, but negative for endoplasmic reticulum marker Calnexin, with a diameter of 124.6 nm. BMSC-Exo combined with CS showed synergistic anti-proliferative effects in CCA cells. High-expression TIMP2 samples indicated a better prognosis of CCA patients, and BMSC-Exo/CS increased the TIMP2 expression in CCA cells. Mechanistically, BMSC-Exo/CS TIMP2 overexpression inhibited key factors related to angiogenesis (VEGFA and VEGFR2) and Wnt/β-catenin pathway (β-catenin and c-Myc), thereby reducing CCA cell viability. Notably, these inhibitory effects were reversed by a Wnt signaling agonist (BML-284).

The study validates the therapeutic potential of BMSC-Exo/CS TIMP2 in CCA treatment. This innovative approach targets angiogenesis and Wnt/β-catenin signaling, providing a new avenue for more effective and comprehensive CCA therapies.

The still young and developing space age, characterized by lunar and Martian exploration and the vision of extraterrestrial settlements, presents a unique environment to study the impact of microgravity (µg) on human physiology and disease development. Cancer research is currently a key focus of international space science, as µg fundamentally impacts cellular processes like differentiation, adhesion, migration, proliferation, survival, cell death, or growth of cancer cells as well as the cytoskeleton and the extracellular matrix (ECM). By creating three-dimensional (3D) tumor models in a µg-environment, like multicellular spheroids (MCS), researchers can expedite drug discovery and development, reducing the need for animal testing. This concise review analyses the latest knowledge on the influence of µg on cancer cells and MCS formation. We will focus on cells from brain tumors, lung, breast, thyroid, prostate, gastrointestinal, and skin cancer exposed to real (r-) and simulated (s-) µg-conditions.

The tumor microenvironment (TME) contains tumor cells, surrounding cells, and secreted factors. It provides a favorable environment for the maintenance of cancer stem cells (CSCs), the spread of cancer cells to metastatic sites, angiogenesis, and apoptosis, as well as the growth, proliferation, invasion, and drug resistance of cancer cells. Cancer cells rely on the activation of oncogenes, inactivation of tumor suppressors, and the support of a normal stroma for their growth, proliferation, and survival, all of which are provided by the TME. The TME is characterized by the presence of various cells, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), CD8 + cytotoxic T cells (CTLs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), endothelial cells, adipocytes, and neuroendocrine (NE) cells. The high expression of inflammatory cytokines, angiogenic factors, and anti-apoptotic factors, as well as drug resistance mechanisms in the TME, contributes to the poor therapeutic efficacy of anticancer drugs and tumor progression. Hence, this review describes the mechanisms through which the TME is involved in apoptosis, angiogenesis, metastasis, and drug resistance in tumor cells.

Endothelial cell adhesion and migration are crucial to various biological processes, including vascular development. The identification of factors that modulate vascular development through these cell functions has emerged as a prominent focus in cardiovascular research. Crip2 is known to play a crucial role in cardiac development, yet its involvement in vascular development and the underlying mechanism remains elusive. In this study, we revealed that Crip2 is expressed predominantly in the vascular system, particularly in the posterior cardinal vein and caudal vein plexus intersegmental vein. Upon Crip2 loss, the posterior cardinal vein plexus and caudal vein plexus are hypoplastic, and endothelial cells exhibit aberrant aggregation. In human umbilical vein endothelial cells (HUVECs), CRIP2 interacts with the cytoskeleton proteins KRT8 and VIM. The absence of CRIP2 negatively regulates their expression, thereby fine-tuning cytoskeleton formation, resulting in a hyperadhesive phenotype. Moreover, CRIP2 deficiency perturbs the VEGFA/CDC42 signaling pathway, which in turn diminishes the migrating capacity of HUVECs. Furthermore, the loss of CRIP2 impairs cell proliferation by affecting its interaction with SRF through PDE10A/cAMP and PDGF/JAK/STAT/SRF signaling. Collectively, our findings delineate a crucial role for CRIP2 in controlling the migration, adhesion and proliferation of endothelial cells, thereby contributing to vascular development in zebrafish. These insights may provide a deeper understanding of the etiology of cardiovascular disorders.

Immunotherapy plays an important role in the treatment of bladder cancer (BLCA), with outcomes influenced by the tumor microenvironment (TME). Angiogenesis, a hallmark of cancer progression, shapes the TME and impacts immunotherapy efficacy. However, its specific role in BLCA remains underexplored.

We analyzed 268 angiogenesis-related genes (ARGs) across ten gene sets using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Through unsupervised clustering, we identified ARG-based subtypes and developed an ARG scoring system to quantify angiogenesis activity. The ARG score was correlated with clinical outcomes, immune cell infiltration, and immunotherapy response. Functional validation was performed using in vitro assays.

Two distinct ARG clusters exhibited significant differences in immune profiles, clinical outcomes, and functional characteristics. Patients in the high ARG cluster had poorer survival but showed enhanced responsiveness to immune checkpoint inhibitors (ICIs). The novel ARG score demonstrated strong predictive power for immunotherapy efficacy and survival outcomes.

ARG expression patterns profoundly impact the TME, clinical outcomes, and immunotherapy response in BLCA. The ARG score is a novel biomarker for stratifying patients and optimizing treatment strategies. These findings may contribute to clarifying the characteristics of TME and enable the exploration of more potent immunotherapy strategies.

Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat-containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1-associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.

The P2X7 receptor, a key player in purinergic signaling, is a crucial factor in modulating the response of cancer cells to radiotherapy. The aim of this study was to elucidate the molecular mechanisms by which P2X7 receptor activation contributes to radioresistance in different cancer types. P2X7 receptor signaling influences cellular processes such as DNA damage repair and inflammatory responses, thereby improving tumor survival after radiation exposure. Activation of the P2X7 receptor leads to changes in the tumor microenvironment and promotes an adaptive response that enables cancer cells to resist therapeutic interventions. Therefore, targeting the P2X7 receptor could represent a new therapeutic strategy against cancer. By linking molecular insights with therapeutic implications, this research highlights the P2X7 receptor as a promising target for overcoming radioresistance in cancer therapy and paves the way for novel combination approaches that could significantly improve patient outcomes.

Breast cancers (BCs) are frequently linked to an immunosuppressive microenvironment that facilitates tumor evasion of anti-cancer immunity. The cells that suppress the immune system such as regulatory B cells (Bregs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), play a crucial role in immune resistance. Also, tumor progression and immune evasion of cancers are facilitated by cytokines and factors released by tumor cells or immunosuppressive cells. Targeting these regulatory cells therapeutically, whether through elimination, inactivation, or reprogramming, has resulted in hopeful anti-tumor reactions. Yet, the substantial diversity and adaptability of these cells, both in terms of appearance and function, as well as their variation over time and depending on where they are in the body, have posed significant challenges for using them as reliable biomarkers and creating focused therapies that could target their creation, growth, and various tumor-promoting roles. The immunotherapy approaches in BC and their effectiveness in treating certain subtypes are still in their initial phases. In this review, we thoroughly outlined the characteristics, roles, and possible treatment options for these immune-suppressing cells in the tumor environment.

New triazoloquinazoline derivatives were synthesized to explore their cytotoxic activity on various cancer cell lines, prompted by the need for effective anticancer agents.

All synthesized compounds were confirmed by spectroscopic methods and tested in vitro for their inhibitory activities against hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and prostate cancer (PC3) cell lines. Ten compounds were tested in vitro to explore their inhibitory activity against the VEGFR-2. Additionally, various studies were investigated for the most active compound 6, including cell cycle analysis, apoptotic activity assessment, effect on gene expression, safety profiling, molecular docking, MD simulation, and ADMET analysis.

Compounds 3a, 3c, and 6 exhibited higher cytotoxic activity against MCF-7 than doxorubicin. Compound 6 was most potent, arresting the cell cycle at G1 phase and showing proapoptotic action. It significantly inhibited VEGFR-2 and altered gene expression, promoting BAX, P21, and P53 while downregulating BCL-2. Docking and MD simulations indicated stable interaction with VEGFR-2, safety, and ADMET profiles suggested favorable drug-likeness and safety.

Compound 6 has shown promising anticancer potential, particularly against breast cancer, but further research is needed to confirm these findings and address long-term safety.

The clinical management of ischemic disease and cancer is complex, with disruptions in local vascular function and tumor angiogenesis contributing to blood stasis, which complicates treatment strategies. Salvia miltiorrhiza, a natural product, is known to restore vascular structure and function. However, its specific roles in concurrently addressing ischemic disease and cancer within the same organism remain poorly understood.

This study aimed to explore the material basis, pharmacological effects, and underlying mechanisms of Salvia miltiorrhiza extract (SME) in promoting blood flow recovery in ischemic hindlimbs and inducing tumor vascular normalization.

The pharmacological effects of SME were evaluated in a mouse model combining ischemic hindlimbs and tumors. Mice were administered low (SME-L) or high (SME-H) doses of SME daily, and the gastrocnemius muscle mass and tumor vascular structure were assessed. Laser Doppler perfusion imaging (LDPI) was used to monitor hindlimb blood flow recovery and tumor vascular perfusion. The pharmacokinetics of the key bioactive constituents in SME were characterized by liquid chromatography-mass spectrometry (LC-MS). Interactions between SME's active compounds and predicted targets were investigated using molecular docking, microscale thermophoresis (MST), and luciferase reporter assays. The synergistic effects of the primary components, Tanshinone I (Tan I) and Salvianolic acid A (Sal A), were analyzed through tube formation assays, enzyme-linked immunosorbent assays (ELISA), immunofluorescence staining, and western blot.

Phytochemical profiling revealed that SME contains several active compounds, including Danshensu, Sal A, Sal B, Tan IIA, and Tan I. SME treatment reduced the frequency of necrotic toes, increased muscle mass, and alleviated hypoxia in the gastrocnemius muscle. SME significantly improved tumor vascular perfusion and notably enhanced pericyte coverage and basement membrane integrity. Pharmacokinetic analysis identified Tan I and Sal A as the key bioactive components that promote vascular normalization. Tan I inhibited FoxO1, preventing endothelial cell activation induced by angiopoietin 2 (Ang2), while Sal A bound to Ang2, facilitating Tie2 activation mediated by Ang1. Both in vitro and in vivo results demonstrated that the combination of Tan I and Sal A exerted a synergistic therapeutic effect on correcting abnormal blood vessels in ischemic hindlimbs and tumors.

Our study innovatively revealed a reliable mouse model wherein the Ang2/Tie2 signaling cascade disrupted the endothelial homeostasis to aggravate the progression of hindlimb ischemia and tumor angiogenesis. This balance can be rescued by the combination therapy of Tan I and Sal A that were both from SME, leading to the occurrence of vascular normalization.

Circular RNAs (circRNAs) are formed by splicing of precursor RNAs and covalently linked at the 5' and 3' ends. Dysregulated circRNAs are closely related to the epithelial-mesenchymal transition (EMT) of gastrointestinal malignancies. CircRNAs, including circRNA_0008717, circGOT1, circ-DOCK5, circVPS33B, circPVT1, circMET, circ-OXCT1, circ_67835, circRTN4, circ_0087502, circFNDC38, circ_PTEN1, circPGPEP1, and circ-E-Cad are involved in the EMT process of gastrointestinal malignancies through a variety of mechanisms, such as regulating EMT-inducing transcription factors, signaling pathways, and tumor microenvironments. Gastrointestinal (GI) malignancies are common malignant tumors worldwide, and the heterogeneity and easy metastasis of gastrointestinal malignancies limit the effectiveness of medical treatments. Therefore, investigating the molecular mechanisms involved in the pathogenesis of gastrointestinal malignancies is essential for clinical treatment. This article summarizes the biological roles and molecular mechanism of circRNAs in EMT of gastrointestinal malignancies, providing a theoretical basis for applying EMT-related circRNAs in targeted therapy.

Angiogenesis is one of the important factors related to tumorigenesis, invasion, and metastasis. Cancer-secreted exosomes are essential mediators of intercellular cross-talk and participate in angiogenesis and metastasis. Unveiling the mechanism of angiogenesis is an important way to develop anti-angiogenesis therapeutic strategies to against cancer progression.

miR-1825 expression and relationship with microvascular density were validated in colorectal cancer (CRC) by in situ hybridization (ISH) staining and immunohistochemistry (IHC). Sequential differential centrifugation, transmission electron microscopy, and western blotting analysis were used to extract and characterize exosomes. The effort of exosomal miR-1825 on endothelial cells was examined by transwell assay, wound healing assay, tube formation assay, and aortic ring assay. The relationship of miR-1825, ING1 and the downstream pathway were analyzed by western blot, RT-PCR, Immunofluorescence, and dual-luciferase reporter system analysis.

Exosomal miR-1825 is associated with angiogenesis in CRC and is enriched in exosomes extracted from the serum of CRC patients. The CRC-secreted exosomal miR-1825 can be transferred into vascular endothelial cells, promoting endothelial cell migration and tube formation in vitro, and facilitating angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal miR-1825 regulates angiogenesis and tumor metastasis by suppressing inhibitor of growth family member 1 (ING1) and activating the TGF-β/Smad2/Smad3 signaling pathway in the recipient HUVECs.

Our study demonstrated the CRC-secreted exosomal miR-1825 could be transferred to vascular endothelial cells, subsequently leads to the inhibition of ING1 and the activation of the TGF-β/Smad2/Smad3 signaling pathway, thereby promoting angiogenesis and liver metastasis in CRC. Exosomal miR-1825 is thus a potential diagnostic and therapeutic target for CRC patients.

Tumor blood vessels are tortuous and dilated, contributing to the aberrant tumor microenvironment. CD93 is a newly reported transmembrane receptor, mainly expressed in tumor endothelial cells, that has demonstrated prognostic value in some cancer types. However, the role of CD93 in the vasculature of colorectal cancer (CRC) tissues and its prognostic significance remain unknown. It is therefore necessary to explore the effect of CD93 in patients with CRC.

We detected the expression of CD93 in human CRC tissues using immunohistochemistry. We then examined the correlation between CD93 expression and clinicopathological factors in cancer tissues from 134 patients with CRC.

CD93 expression levels were higher in CRC vessels than in vessels in adjacent normal tissues. Upregulation of CD93 was associated with tumor site and microsatellite instability. CD93 protein expression was positively related to macrophage infiltration in CRC. High expression of CD93 may indicate normalization of the tumor vasculature and was associated with better overall survival.

CD93 was highly expressed in CRC vessels and correlated with infiltration of immune cells. Our findings reveal that vascular normalization and patient prognosis can be predicted by detecting CD93 expression in CRC tumor tissues.

Angiogenesis, the process of new blood vessel formation, involves endothelial cell proliferation and migration, accompanied by the remodeling of the extracellular matrix (ECM). Type IV collagen, a major ECM component, plays a critical role in vascular basement membrane regeneration, influencing cell polarity, migration, and survival. This study examines the regulatory role of Notch signaling, mediated by Notch3, in type IV collagen expression using TIG-1 fibroblasts and a co-culture angiogenesis model with human umbilical vein endothelial cells (HUVECs). Using small interfering RNA (siRNA) to suppress Notch3 expression, we observed a significant reduction in COL4A1 gene expression, which encodes the α1 chain of type IV collagen. Conversely, transient expression of the Notch3 intracellular domain (NICD3) activated Notch signaling, resulting in increased COL4A1 expression. In the co-culture model, pre-treatment of TIG-1 cells with Notch signaling inhibitors, including siNotch3 and DAPT, decreased the number of α1(IV)-positive TIG-1 fibroblasts adjacent to HUVECs. This reduction highlights the essential role of Notch3-mediated signaling in promoting type IV collagen expression during angiogenesis. Our findings suggest that Notch signaling regulates type IV collagen expression levels, supporting basement membrane formation and vascular maturation. These results provide insight into the molecular mechanisms of angiogenesis, potentially contributing to therapeutic strategies targeting vascular-related pathologies.

Breast cancer, with its diverse subtypes like ER-positive, HER-2-positive, and triple-negative, presents complex challenges demanding personalized treatment approaches. The intricate interplay of genetic, environmental, and lifestyle factors underscores its status as a primary contributor to cancer-related fatalities in women globally. Understanding the molecular drivers specific to each subtype is crucial for developing effective therapies. In this landscape, connective tissue growth factor (CTGF), also referred to as cellular communication network factor 2 (CCN2), emerges as a significant player. CTGF regulates critical biological activities like cell growth, invasion, and migration, impacting breast cancer development and progression. It modulates breast tumor microenvironment by promoting angiogenesis, activating cancer-associated fibroblasts (CAFs), and inducing inflammation. The activity of CTGF depends on several factors including oxygen levels, hormone signals, and growth factors and differs according to the type of breast cancer. CTGF can regulate breast cancer cells by activating various signaling pathways and modulating the transcription of other genes that are involved in tumor development and metastasis including S100A4, glucose transporter 3 (GLUT3), and vascular endothelial growth factor (VEGF). The matricellular protein can be considered a potential therapeutic target, as it can promote tumor growth and confer drug resistance in breast cancer. Numerous tactics, including neutralizing antibodies, antisense oligonucleotides, natural compounds, recombinant proteins, and short hairpin RNAs have been suggested to block its function. This review highlights the structure of CTGF, regulation of its expression, and current knowledge of its oncogenic role in breast cancer, as well as focusing on potential therapeutic strategies for targeting CTGF in breast cancer.

Tumors grow by receiving oxygen and nutrients from the surrounding blood vessels, leading to rapid angiogenesis. This results in functionally and structurally abnormal vasculature characterized by high permeability and irregular blood flow, causing hypoxia within the tumor microenvironment (TME). Hypoxia exacerbates the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), further perpetuating abnormal vessel formation. This environment compromises the efficacy of radiotherapy, immunotherapy, and chemotherapy. In this study, we developed a pH-sensitive liposome (PSL) system, termed OD_PSL@AKB, to co-deliver oxygen (OD) and razuprotafib (AKB-9778) to tumors. This system rapidly responds to the acidic TME to alleviate hypoxia and inhibit VEGF secretion, restoring VE-cadherin expression in hypoxic endothelial cell/cancer cell cocultures. Our findings highlight the potential of OD_PSL@AKB in normalizing tumor vasculature and improving therapeutic efficacy.

Gastric cancer (GC) is one of the most common tumors; one of the reasons for its poor prognosis is that GC cells can resist normal cell death process and therefore develop distant metastasis. Cuproptosis is a novel type of cell death and a limited number of studies have been conducted on the relationship between cuproptosis-related genes (CRGs) in GC. The purpose of the present study was to establish a prognostic model of CRGs and provide directions for the diagnosis and treatment of GC. Transcriptome and clinical data of patients with GC were collected from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Single sample gene set enrichment analysis (GSEA) and the randomized forest method were used to establish the prognostic model. Kaplan-Meier survival curve, receiver operating characteristics diagram and a nomogram were used to evaluate the reliability of the model. GSEA and gene set variation analysis (GSVA) were used to examine enrichment pathways between high and low risk groups. Finally, immunohistochemical analysis was used to examine ephrin 4 (EFNA4) expression in GC samples and determine the prognosis of patients with GC based on the expression pattern of EFNA4. A group of 7 predictive models (RTKN2, INO80B, EFNA4, ELF2, MUSTN, KRTAP4, and ARHGEF40) was established which were correlated with CRGs. This model can be used as an independent prognostic factor to predict the prognosis of patients with GC. GSEA and GSVA results indicated that high risk patients with GC were mainly associated with the enrichment of ANGIOGENESIS and TGF_BETA_SIGNALING pathways. Finally, EFNA4 expression in GC was significantly higher than that in normal tissues, and patients with GC and high EFNA4 expression exhibited improved prognosis. In conclusion, the prognosis model based on CRGs could be used as the basis for predicting the potential prognosis of patients with GC and provide new insights for the treatment of GC.