• Maxillofacial Plastic and Reconstructive Surgery
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• v.36 no.3
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• pp.85-93
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• 2014

Purpose: Nodal metastasis is the main prognostic factor in the patients with oral squamous cell carcinoma (OSCC). We investigated the association between tumor-associated lymphatics and OSCC characteristics. Methods: Thirty-four specimens were used for the immunohistochemical staining with the antibody for vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, phosphorylated VEGFR-3, D2-40, and matrix metallproteinases (MMPs). We observed the distribution of the lymphangiogenic factors and quantified the degree of expression. We determined lymphatic vessel density (LVD) and lymphatic vessel dilatation with D2-40 immunostaining. We assessed the association of LVD or lymphatic vessel dilatation with tumor progression or tumor differentiation. Results: OSCC cells expressed lymphangiogenic ligands. Lymphangiogenic receptor, VEGFR-3, was expressed and activated in some tumor cells as well as in tumor-associated endothelial cells. LVD was not associated with tumor size or nodal status, but lymphatic vessel dilatation was higher in tumors with nodal metastasis, and also higher in poorly differentiated tumors. In stromal area of OSCC, MMP-1 and MMP-10 were up-regulated and the basement membrane of tumor-associated endothelial cells was destroyed by these collagenases. Conclusion: In the primary tumors with nodal metastasis, especially in poorly differentiated OSCC, tumor cells invaded the dilated lymphatic vessels via ruptured sites. MMP-1 and MMP-10 are important in the lysis of the glycocalyx inside the tumor-associated lymphatic endothelial cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.2221-2224
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• 2014

Objective: To explore the relationship between expressions of cell adhesion molecules CD44 v6 and E-cadherin (E-cad) and lymphatic metastasis in non-small cell lung cancer (NSCLC). Materials and Methods: Eightyseven tissue samples obtained from patients with primary NSCLC were collected in our hospital from Dec., 2007 to Dec., 2012, and the expressions of CD44 v6 and E-cad gene proteins in these samples were detected by immunohistochemical method. Results: In the tissue without lymphatic metastasis, the positive expression rate of CD44 v6 was significantly lower, whereas the normal expression rate of E-cad was notably higher than that with lymphatic metastasis (55.6% vs. 78.4%, 47.2% vs. 21.6%), and both differences had statistical significance (P<0.05). Besides, CD44 v6 and E-cad expressions had a significant correlation in the NSCLC tissue with lymphatic metastasis (P<0.05). Conclusions: The positive expression of CD44 v6 and abnormal expression of E-cad may play a very important role in promoting lymphatic metastasis of NSCLC, with synergistic effect. Hence, detection of CD44 v6 and E-cad expressions is conductive to judging the lymphatic metastasis in NSCLC.

• Animal Bioscience
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• v.34 no.4
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• pp.533-538
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• 2021

Objective: Pluripotent stem cell-derived lymphatic endothelial cells (LECs) show great promise in their therapeutic application in the field of regenerative medicine related to lymphatic vessels. We tested the approach of forced differentiation of mouse embryonal stem cells into LECs using biodegradable poly lactic-co-glycolic acid (PLGA) nanospheres in conjugation with growth factors (vascular endothelial growth factors [VEGF-A and VEGF-C]). Methods: We evaluated the practical use of heparin-conjugated PLGA nanoparticles (molecular weight ~15,000) in conjugation with VEGF-A/C, embryoid body (EB) formation, and LEC differentiation using immunofluorescence staining followed by quantification and quantitative real-time polymerase chain reaction analysis. Results: We showed that formation and differentiation of EB with VEGF-A/C-conjugated PLGA nanospheres, compared to direct supplementation of VEGF-A/C to the EB differentiation media, greatly improved yield of LYVE1(+) LECs. Our analyses revealed that the enhanced potential of LEC differentiation using VEGF-A/C-conjugated PLGA nanospheres was mediated by elevation of expression of the genes that are important for lymphatic vessel formation. Conclusion: Together, we not only established an improved protocol for LEC differentiation using PLGA nanospheres but also provided a platform technology for the mechanistic study of LEC development in mammals.

• IMMUNE NETWORK
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• v.14 no.4
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• pp.182-186
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• 2014

Lymphatic vessels are routes for leukocyte migration and fluid drainage. In addition to their passive roles in migration of leukocytes, increasing evidence indicates their active roles in immune regulation. Tissue inflammation rapidly induces lymphatic endothelial cell proliferation and chemokine production, thereby resulting in lymphangiogenesis. Furthermore, lymphatic endothelial cells induce T cell tolerance through various mechanisms. In this review, we focus on the current knowledge on how inflammatory cytokines affect lymphangiogenesis and the roles of lymphatic vessels in modulating immune responses.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.28 no.1
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• pp.7-15
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• 2002

The present study was carried out to evaluate the correlation of metastasis and prognostic factors in squamous cell carcinoma of head and neck. Examination was performed on a series of thirty-seven patients who were confirmed to squamous cell carcinoma and its lymphatic metastasis by pathologist. Correlations of metastasis and other factors such as angiogenesis, histologic grading, and p53 expression and ras oncogene were studied. The depth of tumors was around 1 to 27mm. Twenty cases were more than 10mm deep, of which seventeen cases were shown lymphatic metastasis. Total score of histologic grading including keratinization, nuclear atypia, growth pattern and intensity of inflammation was ranged from 5 to 10 points. Of these factors, nuclear atypia with intensity of inflammation, and nuclear atypia with growth pattern was correlated with nuclear atypia each. For angiogenesis, number of new-formed vessels were counted 13 to 58 each. Twenty-eight cases were shown to lymphatic metastasis. No correlation with histologic grading and lymphatic metastasis was found. The results of immunohistochemical staining for p53 and ras oncogene revealed that positive cases were 16 and 22, negative for 21 and 15 each. However, both were not correlated with histologic grading and lymphatic metastasis. These results were revealed that angiogenesis was not correlated with lymphatic metastasis of squamous cell carcinoma arising in head and neck. Nuclear atypia with intensity of inflammation and dysplasia with growth pattern were correlated with histologic grading, which suggested that more careful and adequate advice is needed for effective treatment.

• Molecules and Cells
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• v.37 no.7
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• pp.503-510
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• 2014

Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.32 no.1
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• pp.1-8
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• 2010

Background and Purpose: Vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 are involved in tumor lymphangiogenesis. Oral mucosal squamous cell carcinoma (OMSCC) preferentially metastasizes to cervical lymph nodes, so we investigated the expression and distribution of VEGFR-3 signaling proteins in OMSCC. Materials and Methods: Tissue samples of 18 OMSCC, 10 oral mucosal leukoplakia, and 3 normal oral mucosa were evaluated for expression of VEGF-C, VEGF-D, and VEGFR-3 by immunohistochemical staining. The presence of lymphatic vessels was determined using D2-40 staining, by which we also measured lymphatic vessel density (LVD). Results: 72% (13/18) and 56% (10/18) of tissue samples showed VEGF-C and VEGF-D immunopositivity in tumor cells and tumor-associated endothelial cells. VEGFR-3 was also expressed in most of OMSCC, which was up-regulated when compared with normal mucosa or with leukoplakia. Furthermore, LVD was higher in OMSCC than in leukoplakia. Conclusion: Taken together, our results suggest that autocrine activation of lymphatic endothelial cell via VEGFR-3 by VEGF-C and/or VEGF-D could be involved in progression of OMSCC. Therefore, VEGF-C/VEGFR-3 signaling pathway can be a molecular target for anti-metastatic therapy in OMSCC.

• BMB Reports
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• v.49 no.8
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• pp.403-404
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• 2016

The Wnt/β-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in embryonic development and adult homeostasis. However, we have limited information about the involvement of Wnt/β-catenin signaling in the lymphatic vascular system that regulates fluid homeostasis by absorbing interstitial fluid and returning it to blood circulation. In this recent publication we report that canonical Wnt/β-catenin signaling is highly active and critical for the formation of lymphovenus valves (LVVs) and lymphatic valves (LVs). β-catenin directly associates with the regulatory elements of the lymphedema-associated transcription factor, FOXC2 and activates its expression in an oscillatory shear stress (OSS)-dependent manner. The phenotype of β-catenin null embryos was rescued by FOXC2 overexpression. These results suggest that Wnt/β-catenin signaling is a mechanotransducer that links fluid force with lymphatic vascular development.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1363-1367
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• 2014

This research was conducted to compare differences in colon cancer lymphatic vessel invasion (LVI) with D2-40 antibody labeling and regular HE staining, blood vessel invasion (BVI) with CD34 antibody labeling and HE staining and to assess the possibility of using D2-40-LVI/CD34-BVI in combination for predicting stage II colon cancer prognosis and guiding adjuvant chemotherapy.Anti-D2-40 and anti-CD34 antibodies were applied to tissue samples of 220 cases of stage II colon cancer to label lymphatic vessels and small blood vessels, respectively. LVI and BVI were assessed and multivariate COX regression analysis was performed for associations with colon cancer prognosis. Regular HE staining proved unable to differentiate lymphatic vessels from blood vessels, while D2-40 selectively labeled lymphatic endothelial cell cytosol and CD34 was widely expressed in large and small blood vessels of tumors as well as normal tissues. Compared to regular HE staining, D2-40-labeling for LVI and CD34-labeling for BVI significantly increased positive rate (22.3% vs 10.0% for LVI, and 19.1% vs 9.1% for BVI). Multivariate analysis indicated that TNM stage, pathology tissue type, post-surgery adjuvant chemotherapy, D2-40-LVI, and CD34-BVI were independent factors affecting whole group colon cancer prognosis, while HE staining-BVI, HE staining-LVI were not significantly related. When CD34-BVI/D2-40-LVI were used in combination for detection, the risk of death for patients with two or one positive results was 5.003 times that in the LVI(-)&BVI(-) group (95% CI 2.365 - 9.679). D2-40 antibody LVI labeling and CD34 antibody BVI labeling have higher specificity and accuracy than regular HE staining and can be used as molecular biological indicators for prognosis prediction and guidance of adjuvant chemotherapy for stage II colon cancer.

• Archives of Plastic Surgery
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• v.48 no.5
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• pp.559-567
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• 2021

The potential to differentiate into different cell lines, added to the easy and cost-effective method of extraction, makes adipose-derived stem cells (ADSCs) an object of interest in lymphedema treatment. Our study's goal was to conduct a comprehensive systematic review of the use of ADSCs in lymphatic tissue engineering and regeneration. On July 23, 2019, using PubMed/MEDLINE, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, and Embase databases, we conducted a systematic review of published literature on the use of ADSCs in lymphatic tissue engineering and regeneration. There were no language or time frame limitations, and the following search strategy was applied: ((Adipose stem cell) OR Adipose-derived stem cell)) AND ((Lymphedema) OR Breast Cancer Lymphedema). Only original research manuscripts were included. Fourteen studies fulfilled the inclusion criteria. Eleven studies were experimental (in vitro or in vivo in animals), and only three were clinical. Publications on the topic demonstrated that ADSCs promote lymphangiogenesis, and its effect could be enhanced by modulation of vascular endothelial growth factor-C, interleukin-7, prospero homeobox protein 1, and transforming growth factor-β1. Pilot clinical studies included 11 patients with breast cancer-related lymphedema, and no significant side effects were present at 12-month follow-up. Literature on the use of ADSCs in lymphatic tissue engineering and regeneration demonstrated promising data. Clinical evidence is still in its infancy, but the scientific community agrees that ADSCs can be useful in regenerative lymphangiogenesis. Data collected in this review indicate that unprecedented advances in lymphedema treatment can be anticipated in the upcoming years.