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8 recordsLinked to original sources
PubMed2026

Lymphangiogenesis-related gene signature-based risk model for prognostic assessment of cervical cancer: immune-metabolic characterization and molecular subtype analysis.

BACKGROUND: Lymphangiogenesis promotes tumor dissemination and may shape the immune contexture of cervical cancer, yet lymphangiogenesis-related prognostic stratification and its immunometabolic implications remain insufficiently defined in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). METHODS: TCGA-CESC transcriptomes and clinical data were obtained from UCSC Xena and integrated with normal cervix tissues from the Genotype-Tissue Expression Project after batch correction. Prognostic LYMRGs were first identified from the differentially expressed set using univariable Cox proportional hazards analysis. Candidate genes were then reduced using an L1-regularized Cox model (Least Absolute Shrinkage and Selection Operator), and the remaining markers were entered into a multivariable Cox regression to obtain the final coefficients and compute an individualized risk score. The model's prognostic value was further assessed in an independent Gene Expression Omnibus dataset. In addition, expression patterns of the signature genes were leveraged for molecular subtyping of TCGA samples via non-negative matrix factorization (NMF). Immune infiltration and immunotherapy-associated characteristics were interrogated through a multi-algorithm strategy (single-sample gene set enrichment analysis, CIBERSORT, ESTIMATE, Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore . Additional analyses included pathway enrichment (GSEA/GO/KEGG), drug sensitivity prediction (pRRophetic/CellMiner), and ceRNA network analysis. RESULTS: A six-gene LYMRG signature robustly stratified survival. High-risk patients had significantly worse overall survival in The Cancer Genome Atlas with AUCs of 0.819/0.801/0.801 at 1/3/5 years, and in GSE52903 (P = 0.001) with AUCs of 0.733/0.719/0.725. NMF identified two subtypes with distinct prognosis (P = 0.01) and divergent immune landscapes. Risk groups and subtypes exhibited consistent differences in immune infiltration, checkpoint expression, TIDE/IPS patterns, and pathway enrichment. Predicted chemosensitivity differed by risk group, and the ceRNA network suggested candidate upstream lncRNA regulators of the signature. CONCLUSION: A lymphangiogenesis-related six-gene model enables clinically meaningful prognostic stratification of CESC and links lymphangiogenesis programs to distinct tumor immune phenotypes and therapeutic vulnerabilities.

cancer↗
PubMed2025

Cancer-associated fibroblast-derived SOD3 enhances lymphangiogenesis to drive metastasis in lung adenocarcinoma.

Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAFSOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAFSOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

Lymphangiogenesis↗
PubMed2024

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

Decorin↗
PubMed2025

Decorin Evokes a Pro-lysosomal Pathway in Lymphatic Endothelial Cells.

The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal degradation and lysosomal pathways. Several proteins within these pathways such as lysosome associated membrane protein 1 (Lamp1) and Neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) were differentially regulated following decorin treatment. These proteins and their functional pathways should be considered therapeutic targets and emerge as candidates for further exploration within the context of decorin and cancer suppression.

Journal Article↗
PubMed2024

Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension.

INTRODUCTION: Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD). MATERIALS AND METHODS: Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups. RESULTS: We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH. DISCUSSION AND CONCLUSION: We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.

Humans↗
PubMed2025

Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective.

Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown. Using patient-derived lymphoblastoid cells, we demonstrated that patients with MLC carrying pathogenic stop-gain variants in KIF11 have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused by KIF11 haploinsufficiency. We revealed that KIF11 is expressed in early human and mouse development with the lymphatic markers VEGFR3, podoplanin, and PROX1. In zebrafish, single-cell RNA-Seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells, EG5 inhibition with ispinesib reduced VEGFC-driven AKT phosphorylation, migration, and spheroid sprouting. KIF11 knockdown reduced PROX1 and VEGFR3 expression, providing for the first time to our knowledge a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.

Humans↗
PubMed2025

Pituitary tumor-transforming gene 1 and endocrine cancers: an up-to-date review through history, current insights and future perspectives.

Pituitary tumor-transforming gene 1 (PTTG1), discovered in 1997 by Pei and Melmed, takes part in cellular replication, cell cycle control, DNA repair mechanisms, organogenesis, metabolism regulation, cellular transformation, and senescence. Its biological actions include protein-protein interactions, modulation of gene transcription, and other than intracellular and autocrine mechanisms, even paracrine activities. For the reasons mentioned above, PTTG1 stands out as a multifaceted regulator of cancer biology; it is involved in genomic and chromosomal instability, local invasiveness, neo-lymphangiogenesis, and metastatic spreading. In solid neoplasms, endocrine neoplasms, although deemed rare, have experienced a significant increase in diagnostic incidence in recent years. Endocrine cancers are still a major challenge in healthcare and research since several questions remain unanswered, even though researchers have made considerable efforts to uncover their causes. Twenty-seven years have passed since PTTG1's discovery, and several works have been published. However, only the tip of the iceberg has been unveiled. Herein, we review current knowledge of PTTG1's action in endocrine cancers, such as pituitary, thyroid, testicular, adrenal, pancreatic, and ovarian.

Humans↗
PubMed2026

Lymphatic vascular aging and age-related bone loss: current status and future perspectives.

Age-related bone loss is a major contributor to osteoporosis and fragility fractures in older adults. Skeletal aging is accompanied by reduced bone mineral density, impaired bone microarchitecture, chronic low-grade inflammation, and immune dysregulation. Lymphatic vascular aging refers to age-related structural and functional decline of lymphatic vessels. This decline impairs immune surveillance and inflammatory mediator clearance, thereby disrupting tissue homeostasis. Age-related lymphatic dysfunction impairs drainage and inflammatory clearance. This allows inflammatory mediators, including IL-6 and TNF-α, to persist in bone-associated tissues, thereby promoting osteoclastogenesis and resorption-dominant remodeling. Age-related lymphatic dysfunction also affects VEGF-C/VEGFR-3 signaling, chemokine-mediated immune trafficking, and marrow niche support. These changes link drainage failure to osteoimmune imbalance and delayed bone repair. Current evidence supports a link between lymphatic vascular dysfunction and skeletal degeneration. Most evidence comes from animal models, bone injury studies, or diseases with secondary lymphatic defects, whereas direct clinical evidence in human age-related osteoporosis remains limited. This review summarizes current evidence linking lymphatic dysfunction to skeletal degeneration, examines the context-dependent roles of lymphatic remodeling in skeletal homeostasis, and discusses emerging therapeutic strategies targeting the lymphatic-bone axis. Future studies should define clinically relevant lymphatic alterations and determine whether restoring lymphatic homeostasis can mitigate age-related bone loss.

Humans↗