The Novel Platelet Activation Receptor CLEC-2 Regulates Blood/Lymphatic Vessel Separation by Inhibiting Proliferation and Migration of Lymphatic Endothelial Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 160-160 ◽  
Author(s):  
Makoto Osada ◽  
Osamu Inoue ◽  
Guo Ding ◽  
Masanori Hirashima ◽  
Katsue Suzuki-Inoue ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Tumor Metastasis ◽  
Lymphatic Vessel ◽  
Conflicts Of Interest ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Proliferation And Migration

Abstract Abstract 160 CLEC-2 has been described recently as playing crucial roles in thrombosis/hemostasis, tumor metastasis, and lymphangiogenesis. The snake venom rhodocytin is known as a strong platelet activator, and we have shown that this effect is mediated by CLEC-2. Podoplanin, which is expressed on the surface of tumor cells, is an endogenous ligand for CLEC-2 and facilitates tumor metastasis by inducing platelet aggregation. Mice deficient in podoplanin, which is also expressed on the surface of lymphatic endothelial cells, show abnormal patterns of lymphatic vessel formation. We have recently reported on the generation and phenotype of CLEC-2-deficient mice. These mice are lethal at the embryonic/neonatal stages associated with disorganized and blood-filled lymphatic vessels and severe edema, indicating that CLEC-2 is essential for blood/lymphatic vessel separation. However, CLEC-2 is expressed in both platelets and neutrophils in mice and whether CLEC-2 in platelets, but not that in other cells, plays a role in the separation has not been directly proved yet. Moreover, the mechanism how CLEC-2 regulates of blood/lymphatic vessel separation has not been elucidated to date. In the present study, we found that specific deletion of CLEC-2 from platelets mediated by PF4-Cre conferred the defect of blood/lymphatic vessel separation, identifying that CLEC-2 expressed in platelets is required to regulate lymphatic vascular development. Tube formation of lymphatic endothelial cells, but not that of vascular endothelial cells, was inhibited in the presence of platelets. Further, proliferation and migration of lymphatic endothelial cells, but not those of vascular endothelial cells, were inhibited by CLEC-2+/+ platelets, but not by CLEC-2−/− platelets. We propose that CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation and migration of lymphatic endothelial cells through the interaction between CLEC-2 in platelets and podoplanin in lymphatic endothelial cells. CLEC-2 may be a novel therapeutic target protein for lymphatic metastasis of tumor if the interaction of CLEC-2 and podoplanin also regulates lymphangiogenesis by tumor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

2021 ◽  
Author(s):  
Koichi Nishino ◽  
Yasuhiro Yoshimatsu ◽  
Tomoki Muramatsu ◽  
Yasuhito Sekimoto ◽  
Keiko Mitani ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Normal Lung ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

Abstract Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

scholarly journals Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

2021 ◽  
Author(s):  
CeShi Chen ◽  
Fubing Li ◽  
Huichun Liang ◽  
Hua You ◽  
Ji Xiao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Tumor Metastasis ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Tumor Resection ◽  
Inflammatory Factors ◽  
Hematogenous Metastasis ◽  
Surgical Trauma ◽  
Vascular Endothelial

Abstract Metastasis is the leading cause of cancer-related death. Surgery is a common intervention for most primary solid tumors; however, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells. Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in vascular endothelial cells (ECs) significantly reduces tumor metastasis in tumor resection metastasis, LPS-induced metastasis and MMTV-Neu metastasis models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and in human primary umbilical vein ECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 at Ser10 to promote NF-κB target gene transcription. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.

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