Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis.
Ontology highlight
ABSTRACT: Background
Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours.Methods
We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours.Results
While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 μg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis.Conclusions
These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.
SUBMITTER: Schmaus A
PROVIDER: S-EPMC4119989 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo. Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-β-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.
| S-EPMC5139649 | biostudies-literature
Project description:Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses.
| S-EPMC4880189 | biostudies-literature
Project description:The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.
| S-EPMC6219737 | biostudies-literature
Project description:Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8(+) tumor cells. The proinflammatory mediators TNF, IL-1?, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1-CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.
| S-EPMC3727324 | biostudies-other
Project description:Lymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC-lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin+/LYVE-1+, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.
| S-EPMC7977063 | biostudies-literature
Project description:BackgroundLymph node metastasis constitutes a key event in tumor progression. The molecular control of this process is poorly understood. Heparan sulfate is a linear polysaccharide consisting of unique sulfate-modified disaccharide repeats that allow the glycan to bind a variety of proteins, including chemokines. While some chemokines may drive lymphatic trafficking of tumor cells, the functional and genetic importance of heparan sulfate as a possible mediator of chemokine actions in lymphatic metastasis has not been reported.ResultsWe applied a loss-of-function genetic approach employing lymphatic endothelial conditional mutations in heparan sulfate biosynthesis to study the effects on tumor-lymphatic trafficking and lymph node metastasis. Lymphatic endothelial deficiency in N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in sulfating nascent heparan sulfate chains, resulted in altered lymph node metastasis in tumor-bearing gene targeted mice. This occurred in mice harboring either a pan-endothelial Ndst1 mutation or an inducible lymphatic-endothelial specific mutation in Ndst1. In addition to a marked reduction in tumor metastases to the regional lymph nodes in mutant mice, specific immuno-localization of CCL21, a heparin-binding chemokine known to regulate leukocyte and possibly tumor-cell traffic, showed a marked reduction in its ability to associate with tumor cells in mutant lymph nodes. In vitro modified chemotaxis studies targeting heparan sulfate biosynthesis in lymphatic endothelial cells revealed that heparan sulfate secreted by lymphatic endothelium is required for CCL21-dependent directional migration of murine as well as human lung carcinoma cells toward the targeted lymphatic endothelium. Lymphatic heparan sulfate was also required for binding of CCL21 to its receptor CCR7 on tumor cells as well as the activation of migration signaling pathways in tumor cells exposed to lymphatic conditioned medium. Finally, lymphatic cell-surface heparan sulfate facilitated receptor-dependent binding and concentration of CCL21 on the lymphatic endothelium, thereby serving as a mechanism to generate lymphatic chemokine gradients.ConclusionsThis work demonstrates the genetic importance of host lymphatic heparan sulfate in mediating chemokine dependent tumor-cell traffic in the lymphatic microenvironment. The impact on chemokine dependent lymphatic metastasis may guide novel therapeutic strategies.
| S-EPMC3019167 | biostudies-literature
Project description:The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.
| S-EPMC4493418 | biostudies-literature
Project description:BackgroundThe-Optimal-Lymph-Flow (TOLF) intervention aims to promote lymph flow through therapeutic lymphatic exercises to relieve lymphatic pain, swelling, lymphedema symptoms, and to decrease lymph fluid levels among breast cancer survivors. To enhance the efficacy of the TOLF intervention, an innovative, intelligent, Kinect-enhanced lymphatic exercise intervention (Kinect-TOLF) was developed to teach patients to perform the lymphatic exercises correctly.ObjectivesThis feasibility trial aimed to determine the feasibility, usability, and effects of the Kinect-TOLF on lymphatic pain, swelling, lymphedema symptoms, and lymph fluid levels.MethodsA single-arm feasibility trial with a pre- and post-test design was employed to recruit 30 breast cancer survivors with persistent lymphatic pain or swelling. Patients received a single training session to learn how to perform the lymphatic exercises using the Kinect-TOLF program. Descriptive statistics, Wilcoxon signed-rank tests, t-test, Spearman's rank correlation coefficients, linear regressions, and Cohen's d were performed for data analysis. Qualitative data were assessed for common themes.ResultsThe Kinect-TOLF was effective in training patients to perform the lymphatic exercises correctly with high user satisfaction. Significant reductions were found in scores of lymphatic pain (MedΔ = -1.00, CI = [-1.5, -0.1], P = .004), arm/hand swelling (MedΔ = -1.00, CI = [-1.5, -0.5], P = .004), total swelling (MedΔ = -1.5, CI = [-2.0, -1.0], P = .003), number of lymphedema symptoms (MΔ = -3.8, CI = [-5.5, -2.1], P < .001), and lymphedema symptom severity (MΔ = -5.3, CI = [-9.5, -1.1], P = .016). A significant reduction in lymph fluid levels was found in mean L-Dex scores (MΔ = -2.68, CI = [-4.67, -0.69], P = .010). Greater decrease in mean L-Dex scores were found in patients with abnormal lymph fluid levels (L-Dex ≥ 7.1) (MΔ = -5.19, CI = [-1.75, -8.63], P = .008). Patients' qualitative feedback supported the results of the study.ConclusionsThe Kinect-TOLF is safe, feasible, and effective in reducing lymphatic pain, swelling, lymphedema symptoms, and in decreasing lymph fluid levels. Future research should focus on a randomized clinical trial to confirm the unique or synergistic efficacy of the Kinect-TOLF in comparison with current lymphedema treatment and other forms of exercises or movement therapy. This study was registered in ClinicalTrials.gov with US ClinicalTrials.gov Identifier: NCT03999177.
| S-EPMC8226364 | biostudies-literature
Project description:Adrenomedullin (AM) is a potent lymphangiogenic factor that promotes lymphatic endothelial cell (LEC) proliferation through a pharmacologically tractable G-protein-coupled receptor. Numerous types of human cancers have increased levels of AM; however, the functional consequences of this fact have not been characterized. Therefore, we evaluated whether modulating adrenomedullin (Adm) gene dosage within tumor cells affects lymphangiogenesis. Murine Lewis lung carcinoma (LLC) cells that overexpress or underexpress Adm were injected subcutaneously into C57BL/6 mice, and tumors were evaluated for growth and vascularization. A dosage range from ?10 to 200% of wild-type Adm expression did not affect LLC proliferation in vitro or in vivo, nor did it affect angiogenesis. Notably, the dosage of Adm markedly and significantly influenced tumor lymphangiogenesis. Reduced Adm expression in tumors decreased the proliferation of LECs and the number of lymphatic vessels, while elevated tumor Adm expression led to enlarged lymphatic vessels. Moreover, overexpression of Adm in tumors induced sentinel lymph node lymphangiogenesis and led to an increased incidence of Ki67-positive foci within the lung. These data show that tumor-secreted AM is a critical factor for driving both tumor and lymph node lymphangiogenesis. Thus, pharmacological targeting of AM signaling may provide a new avenue for inhibition of tumor lymphangiogenesis.
| S-EPMC3545524 | biostudies-literature
Project description:BackgroundThe mechanism underlying improved survival in non-metastatic colon cancer with higher lymph node (LN) yield is unknown. This study aimed to identify whether molecular features in the primary tumour were predictive of LN yield.MethodsClinical, genomic, transcriptomic, proteomic and methylation data of non-metastatic, colon cancers studied in The Cancer Genome Atlas were interrogated for associations with LN yield. Based on maximal survival effects, patients were segregated into high (>15) and low (≤15) LN yield. Gene set enrichment analysis was performed on transcriptomic changes to identify biological processes associated with LN yield. Correlations were validated in an independent set of Stage II colon cancers.ResultsHigh LN yield was found predictive of overall and disease-free survival. There was no association of higher LN yield and increasing nodal positivity. High LN yield was strongly linked with gene expression changes associated with the adaptive and dendritic cell immune response. This association was most prominent in node-negative cancers. Analogous findings were reproduced in the validation dataset.ConclusionThe study shows a strong association of an activated immune response in tumours with a high LN yield. Immunogenic tumours have a better prognosis, likely explaining the survival benefit with higher LN yields.
| S-EPMC9023574 | biostudies-literature