Downregulation of Integrins in Cancer Cells and Anti-Platelet Properties Are Involved in Holothurian Glycosaminoglycan-Mediated Disruption of the Interaction of Cancer Cells and Platelets in Hematogenous Metastasis.
Activated platelets have been recognized as an accessory character in the cascade of tumor hematogenous metastasis, and intervention of tumor cell attachment to the activated platelets or microemboli formation might be a leading strategy to prevent tumor cells surviving in the blood vessels and sequential metastasis. Recently, we have demonstrated that holothurian glycosaminoglycan (hGAG), a sulfated polysaccharide with potent anticoagulant activity extracted from the sea cucumber Holothuria leucospilota Brandt, was highly efficacious against tumor metastasis. In this study, we identified the potential effects of hGAG on the disruption of interactions of cancer cells and platelets and the underlying mechanisms, which were supported by the following evidence: hGAG (1) inhibited thrombin-induced platelet activation and aggregation, (2) reduced adhesion between platelet and breast cancer cells, and abrogated platelets/cancer cells adhering to fibrinogen, (3) attenuated platelet-cancer cell complex formation (the number and size of aggregates) and (4) suppressed both mRNA and protein levels of β1 and β3 integrins, matrix metalloproteinase (MMP)-2 and MMP-9, while increasing the expression of the MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 in MDA-MB-231 cells. These results suggested that both the antiplatelet properties and mitigation of the levels of cellular adhesion molecules contributed to the anticancer effects of hGAG, and might thus be exploited for clinical adjuvant therapy to attenuate tumor hematogenous metastasis.
Department of Pharmaceutics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Wenhui
W
Qian
Li
L
Tao
Yingyu
Y
Wang
Feng
F
Zhang
Mengqiu
M
Li
Shile
S
Huang
Aiyun
A
Wang
Wenxing
W
Chen
Zhiqiang
Z
Yue
Lei
L
Chen
Yuping
Y
Liu
Chenhu
C
Huang
Lei
L
Zhang
Yao
Y
Li
Yin
Y
Lu
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006025:Glycosaminoglycans / Q000302:isolation & purification / Q000494:pharmacology*; D047332:Holothuria / Q000737:chemistry*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D006025:Glycosaminoglycans; C061248:ITGB3 protein, human; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D005340:Fibrinogen; D013917:Thrombin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9