VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma

Du, Licheng; Chen, Xiancheng; Wang, Dong; Wang, Yuming; Wang, Chunting; Wang, Xuemei; Kan, Bing; Wei, Yuquan; Zhao, Xia

doi:10.1186/1477-7827-12-14

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…15 A number of growth factors are known to influence endothelial cell integrity, including vascular endothelial growth factor (VEGF) and angiopoietin/TIE family members. 16,17 For example, downregulation of barrier function of lymphatic endothelial monolayer has been shown to facilitate sarcoma cell entry into the lymphatic circulation by VEGF-D. 18 However, these data are not sufficient to explain the mechanisms by which cancer cells disseminate into vessels surrounding tumors. In addition to growth factors, ECM components and their degradative products are other kinds of active stimulating factors during remodeling of tumor microenvironment.…”

Section: Introductionmentioning

confidence: 98%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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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-b-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.

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Section: Introductionmentioning

confidence: 98%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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“…To our knowledge, there are no previous reports about the determination of metastasis. In our study, we established the lymphogeneous high metastasis animal model with SKOV-3 cells transfected with VEGF-D [6] , and explored the underlying mechanisms of the lymph metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the up-regulation of VEGF-D was signi cantly correlated with CXCR4, CCR7 and VEGF-C in the lymph node metastasis of patients with cervical cancer [19] . Besides, we had veri ed that VEGF-D could promote the lymph metastasis [6] . Our study revealed that the over-expression of VEGF-D was positive to the tumor growth, indicating that VEGF-D could raise the proliferative capability of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Lymphatic metastasis is one of the main ways of tumor metastasis and is related to the prognosis of EOC patients. It has been reported that EOC patients has an incidence of 67.2% in Para-aortic and pelvic lymph node metastasis at advanced stage [6] , while the rate of lymph metastasis reached to 10%-30% even at early stage [7,8] . Therefore, it is necessary to explore the underlying molecular mechanisms of lymph metastasis to improve the prognosis and prolong the overall survival of patients with EOC.…”

Section: Introductionmentioning

confidence: 99%

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Consecutive Observation of Dynamic Metastases of Human Ovarian Carcinoma to Grading Lymph Nodes in Mouse Model

Du¹,

Kong²,

Yang³

et al. 2020

Preprint

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Background：Lymphogenous metastasis, one of the most common dissemination routes for ovarian carcinoma, predicts a poor prognosis and relates to most cancer-related death. Now there were no effective therapy and control methods for ovarian carcinoma. Hence, it is necessary to build an animal model of lymph node metastasis in ovarian cancer to seek for the tools to find effective treatments. Our purpose of this study was to investigate the tumor cell dissemination of ovarian carcinoma to the gradient lymph nodes of nude mice and its possible mechanism. Methods: The mice models of VEGF-D over-expressed were built and the tumor growth and sentinel lymph nodes were evaluated weekly, while the visible lymph nodes and tumor masses were excised for histological examination using HE examination. Then Evan’s Blue was conducted to observe the unveil lymphatic network. Subsequently, immunohistochemistry was performed to check the expression of relative genes. Meanwhile, microvessel counting was performed within the tumor tissues and measured using computer assisted morphometric analysis.Results: The over-expression of VEGF-D promoted the tumor growth of ovarian carcinoma, facilitated the hyperplasia of tumor lymphatic and increased the intratumoral lymphatic vessel density. Besides, the up-regulation of VEGF-D induced the expression of MMP-2, which might be the underlying mechanism for the lymph metastasis in ovarian cancer. Conclusion: it was a step-by-step progression from the inoculation of cancer cells, to the proliferation of the primary tumors, and then to the lymphatic metastases, in which VEGF-D and MMP-2 played vital roles.

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“…SPARC was thought to be a key factor that inhibits the activity of VEGFs, platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). Studies reported that the expression of VEGFs highly increased in colon cancer along with the decreased expression of SPARC (23), and VEGF-D induced tumor lymphangiogenesis and increase the lymphatic metastasis in ovarian cancer (24). Through suppressing the expression and secretion of VEGFs, SPARC inhibited glioma growth by reducing tumor vascularity.…”

Section: Discussionmentioning

confidence: 99%

SPARC suppresses lymph node metastasis by regulating the expression of VEGFs in ovarian carcinoma

Peng

Zhong

Liu

et al. 2017

International Journal of Oncology

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Lymph node metastasis is one of the most valuable determinants for the prognosis of ovarian cancer. However, the molecular mechanisms underlying lymphangiogenesis in ovarian cancer is still poorly understood. Secreted protein acidic and rich in cysteine (SPARC), a Ca2+-binding matricellular glycoprotein that modulates cell adhesion, migration and differentiation, is thought to play a decisive role in tumor metastasis. Vascular endothelial growth factor (VEGF)-C and VEGF-D contributes to tumor-associated lymphatic vessel growth, enhancing the metastatic spread of tumor cells to lymph nodes. The aim of the present study was to investigate the relationship among SPARC, VEGFs and lymph node metastasis in ovarian cancer. We found that SKOV3 cells expressed high-level SPARC, much more than SKOV3-PM4 cells (a subline with high directional lymphatic metastatic potentials established from the metastatic lymph node generated by human ovarian carcinoma cell line SKOV3 in nude mice) did at both mRNA and protein levels. A SPARC-overexpressed SKOV3-PM4 cell line was constructed and it was found that upregulation of SPARC expression suppressed the growth, migration and invasion of SKOV3-PM4 cells as well as markedly reduced the expression of VEGF-D at both mRNA and protein level by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay. In 47 of ovarian malignant tissues, the expression of SPARC, VEGF-C and VEGF-D were determined by immunohistochemistry. Lymphatic microvessel density (LVD) and microvessel density (MVD) were evaluated by immunostaining with CD34 and D2-40 antibodies, respectively. We found that SPARC expression was significantly lower in tissues with lymph node metastasis as compared to tissues without lymph node metastasis. SPARC expression was inversely associated with the degree of malignancy and it had a negative correlation with VEGF-C expression, VEGF-D expression, LVD and MVD which were actually higher for advanced tumors than for non-advanced tumors. These results suggest SPARC might function as a tumor suppressor inhibiting angiogenesis and lymphangiogenesis in ovarian cancer by reducing the expression of VEGF-C and VEGF-D.

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VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma

Cited by 14 publications

References 45 publications

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Consecutive Observation of Dynamic Metastases of Human Ovarian Carcinoma to Grading Lymph Nodes in Mouse Model

SPARC suppresses lymph node metastasis by regulating the expression of VEGFs in ovarian carcinoma

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