Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 3, 2024

Abstract Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role maintaining homeostasis among various tissues and organs. They are tasked with serious of responsibilities, including regulation lymph absorption transport, orchestration immune surveillance responses. vessel development undergoes series sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into highly specialized lymphatic networks. Lymphangiogenesis, as defined by new vessels sprouting from preexisting vessels/embryonic veins, is main developmental mechanism underlying formation expansion networks an embryo. However, abnormal lymphangiogenesis could be observed many pathological conditions has close relationship progression diseases. Mechanistic studies have revealed set lymphangiogenic factors cascades that may serve potential targets for regulating lymphangiogenesis, further modulate Actually, increasing number clinical trials demonstrated promising interventions showed feasibility currently available treatments future translation. Targeting promoters or inhibitors not only directly regulates but improves efficacy diverse treatments. In conclusion, we present comprehensive overview physiological functions, describe critical involvement multiple Moreover, summarize targeting therapeutic values providing novel perspectives treatment strategy

Язык: Английский

---

A Randomized Double-Blind Phase 2 Clinical Trial Treating Cervical Intraepithelial Neoplasia 2/3 with PepCan orCandida

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 19, 2025

ABSTRACT PURPOSE A non-surgical alternative for treating cervical intraepithelial neoplasia (CIN) 2/3 is an unmet need due to a risk of incompetency. METHODS PepCan consists four human papillomavirus (HPV) type 16 E6 peptides and Candida skin testing reagent (adjuvant). In this randomized, double-blind Phase 2 study, women with biopsy-confirmed CIN2/3 were treated or at one ratio. Four intradermal injections given every 3 weeks, observation visits 6 12 months post-vaccination. Quadrant biopsies performed the 12-month visit, those whose lesions regressed no CIN considered be complete responders. Regression rates each treatment group compared that historical placebo group. RESULTS With intention-to-treat analysis, (n=39) showed 30.8% efficacy (95% confidence interval [CI], 17 47.6; p =0.25) while (n=42) demonstrated 47.6% CI, 32 63.6; <0.001). Likewise, per-protocol (n=24) 45.8% 25.6 67.2; =0.08) (n=29) 62.1% 42.3 79.3; There was difference between . No dose-limiting toxicity observed. HPV-specific T cell responses elicited in both groups. Vaccine-induced CD4 CD8 cells present cervix regardless histological response. Single-cell RNA-seq revealed increased expression granzymes, CCR5, EOMES CD8-positive responder, non-responders. Six cytokines (CCL4, CCL5, interleukin-9, lymphotoxin-α, platelet-derived growth factor-ββ, tumor factor-β1) significantly decreased recipients responders suggesting may possibly exert its anti-tumor effects through these systemic mediators. CONCLUSIONS effective inducing regression. treatments are safe. should evaluated trial as potential new CIN2/3.

Язык: Английский

---

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment

Hepatology, Год журнала: 2024, Номер 80(1), С. 69 - 86

Опубликована: Фев. 20, 2024

Background and Aims: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in lymph microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled adaptation remodeling of cells microenvironment. Approach Results: Here, we applied single-cell RNA sequencing primary tumor lesions paired metastases from revealed significantly reduced intertumor heterogeneity syntropic lipid after nodes, which was verified by pan-cancer analysis, highlighting essential role metabolism nodes. Metabolomics vivo CRISPR/Cas9 screening identified PPARγ as crucial regulator fueling nodes through oleic acid-PPARγ-fatty acid–binding protein 4 positive feedback loop upregulating fatty acid uptake oxidation. Patient-derived organoids animal models have demonstrated that blocking this impairs proliferation superior systemic inhibition PPARγ-regulated also contributes immune-suppressive niche producing kynurenine found be associated relapse, microenvironment, poor immune checkpoint blockade response. Conclusions: Our results reveal demonstrate promising therapeutic target relieving burden reducing further progression.

Язык: Английский

---

Lymphangiogenesis in gastric cancer: function and mechanism

European journal of medical research, Год журнала: 2023, Номер 28(1)

Опубликована: Окт. 7, 2023

Abstract Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, associated with patient's poor prognosis. There is increasing evidence that the lymphatic system may play a crucial role regulating tumor immune response limiting since more prominent diffusion. Lymphangiogenesis takes place embryonic development, wound healing, variety of pathological conditions, including tumors. Tumor cells microenvironment generate growth factors (such as factor VEGF-C/D), which can promote lymphangiogenesis, thereby inducing diffusion cells. Nevertheless, current research on gastric relatively scattered lacks comprehensive understanding. Therefore, this review, we aim provide detailed perspective molecules signal transduction pathways regulate lymphogenesis, new insights for diagnosis treatment cancer.

Язык: Английский

---

Prolyl 4-hydroxylase subunit beta (P4HB) could serve as a prognostic and radiosensitivity biomarker for prostate cancer patients

European journal of medical research, Год журнала: 2023, Номер 28(1)

Опубликована: Июль 22, 2023

Prolyl 4-hydroxylase subunit beta (P4HB) has been reported as a suppressor in ferroptosis. However, no known empirical research focused on exploring relationships between P4HB and prostate cancer (PCa). In this research, we initially examine the function of PCa by thorough analysis numerous databases proliferation experiment. We analyzed correlations expression with prognosis, clinical features, mutation genes, tumor heterogeneity, stemness, immune microenvironment cells using multiple vitro experiment R 3.6.3 software its suitable packages. was significantly upregulated tissues compared to normal closely related biochemical recurrence-free survival. terms correlations, found that higher older age, Gleason score, advanced T stage residual tumor. Surprisingly, had highly diagnostic accuracy radiotherapy resistance (AUC 0.938). TGF signaling pathway dorso ventral axis formation were group low-expression P4HB. For positively EREG.EXPss RNAss, but negatively associated ENHss DNAss statistical significance. MATH, ploidy microsatellite instability. overall assessment TME, observed all parameters, including B cells, CD4+ CD8+ neutrophils, macrophages, dendritic stromal score ESTIMATE score. Spearman showed TIDE experiment, RT-qPCR western blot three siRNAs effective knockdown expression. Furthermore, downregulation significant influence cell six lines, LNCap, C4-2, C4-2B, PC3, DU145 22RV1 cells. study, might serve prognostic biomarker predict for patients. Downregulation could inhibit

Язык: Английский

---

Relationship between clonal evolution and drug resistance in bladder cancer: A genomic research review

Pharmacological Research, Год журнала: 2024, Номер 206, С. 107302 - 107302

Опубликована: Июль 13, 2024

Bladder cancer stands as a prevalent global malignancy, exhibiting notable sex-based variations in both incidence and prognosis. Despite substantial strides therapeutic approaches, the formidable challenge of drug resistance persists. The genomic landscape bladder cancer, characterized by intricate clonal heterogeneity, emerges pivotal determinant fostering this resistance. Clonal evolution, encapsulating dynamic transformations within subpopulations tumor cells over time, is implicated emergence drug-resistant traits. Within review, we illuminate contemporary insights into role evolution elucidating its influence driver initiation, disease progression, obstacle therapy

Язык: Английский

---

Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Regulatory Mechanisms, Functions, and Therapeutic Implications

Cancers, Год журнала: 2024, Номер 16(20), С. 3542 - 3542

Опубликована: Окт. 20, 2024

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope treating iCCA. However, several issues remain, including the identification of reliable biomarkers response to ICIs immune-based combinations. Tumor microenvironment (TIME) these hepatobiliary tumors has been evaluated is under assessment this setting order boost efficacy convert immunologically "cold" "hot" tumors. Herein, review TIME ICCA its critical function immunotherapy. Moreover, paper also discusses potential avenues future research, novel targets emerging treatment plans aimed increase effectiveness survival rates iCCA patients.

Язык: Английский

---

⁶⁴Cu Radiolabeled PDGFRβ-Targeting Affibody for PET Imaging in Pancreatic Cancer

Molecular Pharmaceutics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 16, 2025

Pancreatic cancer is a malignant solid tumor that contains significant number of cancer-associated fibroblasts (CAFs). Clinical trials have confirmed CAF-targeted radionuclide therapy can suppress growth and extend the survival patients; therefore, quantifying CAFs by molecular imaging CAF biomarkers helpful for assessing disease progression therapeutic responses pancreatic cancer. In our previous study, we found platelet-derived factor receptor beta (PDGFRβ) was highly expressed on various fibroblast cells, novel affibody (ZPDGFRβ) with specific binding to PDGFRβ had been developed. Herein, verified high expression in tissues, ZPDGFRβ radiolabeled 64Cu obtain [64Cu]Cu-NOTA-ZPDGFRβ conjugate radiochemical purity higher than 95%. Biodistribution studies showed uptake reached peak 7.28 ± 0.92 at 6 h postinjection, tumor-to-pancreas ratio continuously increased reach 25.9 8.18 24 postinjection. Positron emission tomography (PET) ideal capability mice bearing both subcutaneous xenografts situ grafts. Our results demonstrated could be applied as promising PDGFRβ-targeted radiotracer PET

Язык: Английский

---

Activated Cancer-Associated Fibroblasts Correlate with Poor Survival and Decreased Lymphocyte Infiltration in Infiltrative Type Distal Cholangiocarcinoma

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Cancer-associated fibroblasts promote tumor progression through growth facilitation, invasion, and immune evasion. This study investigated the impact of activated cancer-associated (aCAFs) on survival outcomes, response, molecular pathways in distal bile duct (DBD) cancer. We analyzed 469 patients (418 from our cohort 51 The Cancer Genome Atlas) with DBD adenocarcinoma. aCAFs were evaluated using hematoxylin eosin staining. developed a machine learning-based prediction model incorporating clinicopathologic parameters. Additionally, we performed differential gene expression analysis, Disease Ontology set enrichment vitro drug screening aCAFs-related genes. presence significantly correlated poor survival, advanced T N stages, infiltrative pattern, lymphatic/perineural/adjacent organ decreased tumor-infiltrating lymphocytes. genes associated system functions, G protein-coupled receptor signaling, metabolic conditions (diabetes, obesity, abnormal C-peptide levels). In models, emerged as strong discriminator for prediction. revealed that refametinib suppressed carcinoma cells expressing high levels fibroblast activation protein-α. conclusion, integration learning systems biology analyses identifies potential biomarkers risk stratification therapeutic targeting

Язык: Английский

---

Molecular Mechanisms of Lymph Node Metastasis in Gallbladder Cancer: Insights into the Tumor Microenvironment

Biomedicines, Год журнала: 2025, Номер 13(6), С. 1372 - 1372

Опубликована: Июнь 4, 2025

Gallbladder cancer (GBC) is a highly aggressive malignancy with propensity for lymph node metastasis (LNM), which significantly worsens prognosis. This review explores the molecular mechanisms underlying LNM in GBC, focusing on roles of vascular endothelial growth factors (VEGFs), chemokines, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), hypoxia-inducible (HIFs), and non-coding RNAs (ncRNAs) shaping tumor microenvironment (TME). Unique features such as its bile-rich hypoxia-driven lymphangiogenesis, are highlighted. We discuss how these promote immune evasion, extracellular matrix (ECM) remodeling, collectively facilitating LNM. Potential therapeutic targets, including VEGF-C/D pathways, metalloproteinase (MMP) inhibitors, immune-modulating therapies, also reviewed. Future research integrating single-cell omics patient-derived organoid models essential advancing precision medicine GBC.

Язык: Английский

---