Search Results (207)

The Krüppel-like factor (KLF) family of transcription regulators plays pivotal roles in adipogenesis, myogenesis, and metabolism. While comprehensively studied in humans and mice, its characterization in cattle remains limited, especially within the skeletal muscle niche. This study aimed to systematically characterize the KLF family in Bos taurus and elucidate its role in breed-specific muscular development. We employed an integrated approach of comparative genomics and single-nucleus RNA sequencing (snRNA-seq) on longissimus dorsi muscle from Angus (ANG, beef breed) and Holstein (HST, dairy breed) cattle. Phylogenomic analysis identified 14 KLF genes, revealing evolutionary conservation and potential functional divergence. snRNA-seq delineated 11 distinct cell populations and uncovered cell-type-specific expression patterns of KLFs. Further machine learning based analysis pinpointed KLF6, KLF9, KLF10, and KLF12 as key global drivers of transcriptional differences between breeds, while KLF6 was identified as a major cell-type-specific contributor in lymphatic endothelial cells. Our work provides a foundational resource for understanding the KLF family in cattle and identifies promising candidate genes for improving meat production traits through molecular breeding. Full article

Background: Podocalyxin (PODXL) has been identified as a promising therapeutic target and a potential diagnostic biomarker in various tumors. Despite the therapeutic potential of anti-PODXL monoclonal antibodies (mAbs), their further development has been limited by concerns regarding potential on-target off-tumor toxicities. To minimize adverse effects on normal tissues, developing a cancer-specific mAb (CasMab) against PODXL is essential. Methods: Our group established a cancer-specific anti-PODXL mAb, PcMab-60 (IgM, κ), through the screening of over one hundred hybridoma clones. In this study, PcMab-60 was engineered into a humanized IgG₁-type mAb (humPcMab-60), and its antitumor activity was examined using mouse xenograft models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer. Results: HumPcMab-60 retains cancer-specific reactivity; humPcMab-60 reacted to PDAC cell lines (PK-45H and MIA PaCa-2) and the colorectal cancer cell line (Caco-2), but not to a normal lymphatic endothelial cell line in flow cytometry. Furthermore, humPcMab-60 exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against PODXL-expressing cell lines and showed antitumor effects against the tumor xenografts. Conclusions: A humanized anti-PODXL CasMab, humPcMab-60, could be a promising mAb-based tumor therapy. Full article

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

Valvular hemangiomas are uncommon vascular anomalies that appear on the surface of heart valves. They can cause an array of non-specific symptoms and are consequently rarely diagnosed, with only 31 such cases (including the present one) reported to date in the literature; the present case is the first report of an arteriovenous hemangioma with a tricuspid localization. During the preoperative echocardiographic examination for a ventricular septal defect, a mass was incidentally discovered on the tricuspid valve of a 9-month-old infant. The involved leaflet was surgically removed and sent to the pathology department for analysis and subsequently diagnosed as an arteriovenous hemangioma. The patient recovered well, with no local tumor recurrence or other complications. The microscopic examination showed multiple blood vessels which stained positive for the endothelial markers CD31 and CD34 and which did not express D2-40, normally found in lymphatic endothelia. Surprisingly, endothelial cells lining the vessels also showed positivity for SMA, a mesenchymal cell marker, indicating a possible involvement of endothelial-to-mesenchymal transition and its opposite process, mesenchymal-to-endothelial transition, in the pathogenesis of these vascular anomalies. Full article

Introduction: The vascular architecture of the vocal folds plays a critical role in sustaining the dynamic demands of phonation. Disruptions in this microvascular system are linked to various pathological conditions, including Reinke’s edema, hemorrhage, and laryngeal carcinoma. This review explores the structural and functional components of vocal fold microvascularization, with emphasis on pericytes, endothelial interactions, and neurovascular regulation. Materials and Methods: A systematic review of the literature was conducted using databases such as PubMed, Scopus, Web of Science, and Embase. Keywords included “pericytes”, “Reinke’s edema”, and “vocal fold microvascularization”. Selected studies were peer-reviewed and met criteria for methodological quality and relevance to laryngeal microvascular physiology and pathology. Results: The vocal fold vasculature is organized in a parallel, tree-like pattern with distinct arterioles, capillaries, and venules. Capillaries dominate the superficial lamina propria, while transitional vessels connect to deeper arterioles surrounded by smooth muscle. Pericytes, present from birth, form tight associations with endothelial cells and contribute to capillary stability, vessel remodeling, and mechanical protection during vibration. Their thick cytoplasmic processes suggest a unique adaptation to the biomechanical stress of phonation. Arteriovenous anastomoses regulate perfusion by shunting blood according to functional demand. Furthermore, neurovascular control is mediated by noradrenergic fibers and neuropeptides such as VIP and CGRP, modulating vascular tone and glandular secretion. The limited lymphatic presence in the vocal fold mucosa contributes to edema accumulation while also restricting carcinoma spread, offering both therapeutic challenges and advantages. Conclusions: A deeper understanding of vocal fold microvascularization enhances clinical approaches to voice disorders and laryngeal disease, offering new perspectives for targeted therapies and regenerative strategies. Full article

Cancer metastasis often accounts for the primary cause of cancer-related mortality, with the lymphatic system playing a pivotal role in the dissemination of malignant cells. While hematogenous vessel spread is commonly associated with distant organ metastasis, the lymphatic system serves as an early conduit for tumor cell invasion and dissemination. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, intravasation into lymphatic vessels, survival, transport, and colonization of regional lymph nodes (LNs). Cancerous cells then establish micro-metastases at the colonized sites and expand in the new microenvironment, ultimately resulting in the generation of secondary tumors. Tumor-secreted factors, such as vascular endothelial growth factors (VEGF-C and VEGF-D), contribute to metastasis through lymphangiogenesis, the formation of new lymphatic vessels. In addition, cancer cells utilize pre-existing chemokine signaling pathways by expressing chemokine receptors, such as CCR7, which bind to chemokine ligands, such as CCL19 and CCL21, to facilitate targeted migration into the lymphatic vessels. LNs are often the initial sites for metastasis and therefore are indicators of distant organ involvement. It is well established that the location and extent of LN involvement provides significant prognostic information, although the optimal treatment approach for LN metastases remains a subject of debate. Understanding the mechanisms of lymphatic metastasis offers potential therapeutic targets to mitigate cancer progression. Full article

Introduction: Angiosarcomas arise from vascular or lymphatic endothelial cells and can develop at any site. Visceral angiosarcomas are aggressive high-grade tumors with a high risk of recurrence, metastasis, and poor survival. Nationwide studies with long-term follow-up are limited, but crucial for understanding this malignancy. This study aimed to describe a national cohort of patients with visceral angiosarcomas and estimate long-term survival, local recurrence, and metastases. Methods: We included all adult patients in Denmark diagnosed with histologically confirmed visceral angiosarcoma from 2000 to 2017. Data were obtained from the Danish Pathology Register and the Danish Sarcoma Database, both providing nationwide and comprehensive records. Additional information on demographics, comorbidities, symptoms, diagnosis, tumor location, treatment, recurrence, and survival were collected from registries and health records. Results: Eighteen patients with visceral angiosarcoma were identified, corresponding to an incidence of one per 5.5 million inhabitants per year. The median age was 56.5 years (IQR: 50–70), and 56% were female. Tumors were most commonly located in the kidney, liver, and thoracic wall. Metastases were present at diagnosis in 17% and developed later in 50%. Surgery was performed in 61%, with R0 resection in 55%. Median overall survival was 249 days (IQR: 121–858), and the 5-year survival rate was 11%. Only one patient (6%) remained alive at long-term follow-up. Conclusions: This Danish nationwide study confirms that visceral angiosarcomas are rare, highly aggressive tumors with a poor prognosis, consistent with international findings. Despite the small cohort, the disease demonstrated significant heterogeneity in anatomical location, metastatic pattern, and treatment approaches. 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 lymphatic system, a complex and dynamic network comprising lymphatic vessels, lymph nodes (LNs), and associated lymphoid tissues, plays a pivotal role in regulating interstitial fluid balance and providing immune surveillance across the body. In cancer, however, the lymphatic system often transforms into a pathway for malignant cell dissemination, leading to lymphatic metastasis—a significant step in tumor progression associated with worse patient prognoses. Mechanistically, tumor cells exploit lymphangiogenic pathways to facilitate their entry and spread within the lymphatic network. Key mechanisms in this process include the upregulation of vascular endothelial growth factors C and D (VEGF-C/D), which promote lymphatic endothelial proliferation, vessel dilation, and increased permeability. This review seeks to provide an in-depth examination of the biological mechanisms underpinning lymphatic metastasis, explore its impact on cancer progression, and highlight current and emerging strategies aimed at managing metastatic disease. Full article

Cannabidiol (CBD) and tetrahydrocurcumin (THC) have demonstrated anti-inflammatory activity as well as generating new lymph vessels. We present the formulations and evaluations of CBD and THC loaded in hydrogels for the treatment of lymphedema to promote angiogenesis of lymph vessels and an anti-inflammatory response. Six CBD-THC hydrogel formulations were prepared and evaluated. The hydrodynamic particle sizes were 302.0–545.1 nm and the zeta potentials were from −58.80 to −33.63 mV. The hydrogel pHs were 6.43–6.54. The hydrogel formulations were non-toxic for both CBD (<25 µg/mL) and THC (<12.5 µg/mL). It was observed that high-molecular-weight hyaluronic acid in hydrogel affected collagen production. Hydrogel formulations at 2 µg/mL of CBD and 1 µg/mL of THC induced human dermal lymphatic endothelial cell tube formation. CBD-THC hydrogel formulations showed a notable ability to induce angiogenesis, which suggested its potential effectiveness in promoting new lymphatic vessel formation. Moreover, CBD-THC hydrogels showed anti-inflammatory properties. Further research is needed to ensure these treatments effectively enhance lymphatic repair. Full article

Tumor-associated macrophages (TAMs) are known to induce epithelial–mesenchymal transition (EMT) and angiogenesis in areas with a high density of accumulation in the submucosal (SM) layer. However, lymphatic vessels, which are important routes for lymph node metastasis, have rarely been analyzed, and their relationship to TAM accumulation is unknown. In this study, paraffin-embedded sections from 11 cases of human early-stage colorectal cancer (SM invasive carcinoma) were stained with CD34 antibody for vascular endothelium and podoplanin antibody for lymphatic endothelium at the deepest, central, and marginal sites of tumor invasion. Tumor blood vessels increased in the deepest invasive areas, and a positive correlation was observed between the number of TAMs and tumor blood vessels. Interestingly, lymphatic vessels with CD34-positive endothelial cells (CD34-positive lymphatic vessels) were observed within the tumor. The number of CD34-positive lymphatic vessels was significantly higher in the metastasis-positive group. These results suggest that abnormalities in the vascular and lymphatic systems are observed from the early stage of colorectal cancer development and that VEGF-A derived from TAMs is important for tumor angiogenesis. In addition, CD34-positive lymphatic vessels observed in the deepest areas of tumor invasion have not been reported in Japan, with initial reports indicating that they are neoplastic lymphatic vessels. Full article

Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin–angiotensin–aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. Inflammation, mediated by cytokines (interleukin-1, interleukin-4, interleukin-6, tumor necrosis factor-α), chemokines (chemokine ligand 21, C-X-C motif chemokine ligand 12), and reactive oxygen species (ROS), plays a pivotal role. Besides pro-inflammatory cytokines, hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and smooth muscle cells (SMCs) contribute to the process through their activation and altered functions. Once activated, these cell types can worsen ascites accumulationthrough extracellular matrix (ECM) deposition and paracrine signals. Besides this, macrophages, both resident and infiltrating, through their plasticity, participate in this complex crosstalk by promoting inflammation and dysregulating lymphatic system reabsorption. Indeed, the lymphatic system and lymphangiogenesis, essential for fluid reabsorption, is dysregulated in cirrhosis, exacerbating ascites. The gut microbiota and intestinal barrier alterations which occur in cirrhosis and portal hypertension also play a role by inducing inflammation, creating a vicious circle which worsens portal hypertension and fluid accumulation. This review aims to gather these aspects of ascites pathophysiology which are usually less considered and to date have not been addressed using specific therapy. Nonetheless, it emphasizes the need for further research to understand the complex interactions among these mechanisms, ultimately leading to targeted interventions in specific molecular pathways, aiming towards the development of new therapeutic strategies. Full article

Background: The intermediate filament nestin was first described in stem and progenitor cells of neural and mesenchymal origin. Additionally, it is expressed in endothelial cells during wound healing and tumorigenesis. Thus, nestin is widely regarded as a marker for proliferative endothelium. However, little is known about its role in lymphatic endothelium. Methods: Here, we analyzed the expression of nestin in the endothelium of ten human haemangiomas and ten lymphangiomas in situ by immunohistochemistry. This study aimed to investigate the expression of nestin in haemangiomas and lymphangiomas to determine its potential role as a vascular marker. Specifically, we aimed to assess whether nestin expression is restricted to proliferating endothelial cells or also present in non-proliferative blood vessels. Results: Immunohistochemically, haemangiomas were positive for CD31 but negative for D2-40. The endothelial cells within these lesions showed a homogeneous expression of nestin. In contrast, the endothelium of lymphangiomas reacted positively for D2-40 and CD31 but did not show any nestin expression. Additionally, only a few endothelial cells of capillary haemangiomas showed a Ki-67 positivity. Conclusions: The differential expression of nestin in haemangiomas and lymphangiomas indicates a specificity of nestin for the endothelium of blood vessels. The Ki-67 negativity in the majority of the endothelial cells reveals the proliferative quiescence of these cells. These findings indicate that nestin could be used as a marker to differentiate between blood and lymphatic vessels. Full article

Background/Objectives: Lipedema is a progressive disease that results in the bilateral and symmetrical accumulation of subcutaneous fat in the legs and/or arms, affecting almost exclusively women. Methods: A comprehensive review of the peer-reviewed literature was conducted between November 2024 and February 2025. Results: The pathophysiology of lipedema is complex and, especially in the early stages, shows similarities to obesity, involving adipocytes, adipose tissue-resident macrophages, and endothelial cells. In lipedema, systemic levels and the adipocyte expression of the classical adipokines adiponectin and leptin appear normal, while it remains unclear if markers of inflammation and oxidative stress are increased. Macrophages in the adipose tissue of patients have an anti-inflammatory M2 phenotype and express high levels of the scavenger receptor CD163. These cells affect adipogenesis and seem to have a central role in adipose tissue accumulation. Increased lymphatic and blood vessel permeability are comorbidities of lipedema that occur in early disease states and may contribute to disease progression. Conclusions: This review summarizes our current understanding of the pathophysiology of lipedema with a focus on the role of stromal vascular localized M2 macrophages. Full article

Cutaneous angiosarcoma is a rare and aggressive malignant tumor that originates from the endothelial cells of blood vessels or lymphatic vessels. More than half of cutaneous angiosarcoma cases occur in the head and neck regions, particularly on the scalp. However, due to its rarity, scalp angiosarcoma is often overlooked in clinical practice. The lack of distinctive symptoms usually delays the diagnosis and, implicitly, the initiation of appropriate treatment. The treatment of cutaneous angiosarcoma poses great challenges due to its multifocal occurrence and the frequent extensive microscopic spread. A personalized, multimodal therapeutic approach is essential for ensuring a favorable outcome, consisting of a wide surgical excision associated with adjuvant radiotherapy in localized tumors, concurrent adjuvant radiotherapy and chemotherapy, targeted treatments, or immunotherapy in advanced or metastatic diseases. The aim of this manuscript is to review the literature data regarding the individualized management of cutaneous angiosarcoma and to share our own experiences in the field. We wish to underscore the importance of considering cutaneous angiosarcoma in the differential diagnosis of scalp tumors, especially in patients with a history of scalp irradiation as early detection, accurate diagnosis, and a multidisciplinary, personalized management, including surgery with clear margins and adjuvant radiation therapy, are crucial for ensuring a favorable outcome. Full article