Chemically modified heparin inhibits the in vitro adhesion of nonsmall cell lung cancer cells to P-selectin

Gao, Ya; Wei, Min; Zheng, Shu; Ba, Xueqing; Hao, Shui; Zeng, Xianlu

doi:10.1007/s00432-005-0061-9

Cited by 23 publications

(23 citation statements)

References 33 publications

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“…It has been reported that among various proteoglycans, the heparin sulfate-like proteoglycan molecules play an important role in the adhesion of tumor cells to P-selectin. 17,27,35 We want to know if the heparin sulfate-like proteoglycan on the A375 cell surface can act as a ligand of a IIb b 3 in the interaction of A375 cells with platelets. The enzyme treatment experiments demonstrated that the structure of heparin sulfate-like proteoglycans is responsible for the adhesion of A375 cells to a IIb b 3 .…”

Section: Discussionmentioning

confidence: 99%

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo

Zhang

Liu

Gao

et al. 2009

Intl Journal of Cancer

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The adhesion of tumor cells with platelets is important in the process of tumor metastasis. A huge work has indicated that antiadhesion is an effective strategy for metastasis inhibition. In this article, we assess the role of platelet integrin a IIb b 3 in adhesion of melanoma cells to platelets and the effects of heparin and modified heparins on the adhesion in vitro and in vivo. We show that platelet integrin a IIb b 3 is involved in the interaction of human melanoma A375 cells with platelets, and the high affinity epitope resides on the a IIb subunit rather than b 3 subunit. Heparin sulfatelike proteoglycans on tumor cell surface are implicated in the adhesion of A375 cells to integrin a IIb b 3 . We also show that RO-heparin, CR-heparin, N-2,3-DS-heparin and 2,3-O-DS-heparin can significantly inhibit A375 cells binding to the CHO cells expressing integrin a IIb b 3 under static and flow conditions, and remarkably inhibit the adhesion of A375 cells to the immobilized platelet layers under flow conditions. We find that A375 cells and B16F10 cells are arrested in the pulmonary vessels and adhered to platelets, and the initial interaction of tumor cells with platelets in lung vessel and long-term establishment of metastatic foci can be inhibited by heparin as well as CR-heparin and N-2,3-DS-heparin. These data suggest that modified heparins can inhibit tumor cellplatelet interaction mediated by platelet integrin a IIb b 3 and modified heparins may be a potential substitute for heparin in inhibiting tumor metastasis. ' UICCKey words: metastasis; adhesion; platelet; Integrin a IIb b 3; ; modified heparin Hematogenous metastasis of tumor cells is a cascade of events in which tumor cells separate from a primary tumor, intravasate into the bloodstream, evade innate immune surveillance, adhere to vascular endothelial cells of distant organs, and extravasate into tissue to generate new colonies. 1,2 It is well accepted that within vasculature circulating the interactions of tumor cells with platelets enhance tumor dissemination. Platelets may limit the ability of NK cells to lyse tumor cells and shield tumor cells from high shear forces that could potentially damage the tumor cells. 3,4 Furthermore, platelets facilitate the adhesion of tumor cells to vascular endothelium and release a number of growth factors, such as platelet-derived growth factor (PDGF), angiogenic growth factor, vascular endothelial growth factor (VEGF) and angiopoietin-1, which are required for metastasis and angiogenesis.Several studies support the view that tumor cell-associated platelets facilitate tumor cell metastasis. It has been shown that the elimination of circulating platelets with anti-platelet antibody result in a significant diminution of metastasis in several transplantable murine tumor models. 5,6 In addition, inhibition of platelet activation can decrease the metastatic potential of circulating tumor cells. 7,8 It is well known that platelets specifically express a IIb b 3, which has been reported to be involved in the interactio...

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Section: Discussionmentioning

confidence: 99%

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo

Zhang

Liu

Gao

et al. 2009

Intl Journal of Cancer

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“…We previously showed that heparin or chemically modified heparins inhibited P-selectin-mediated adhesion (15,21). In this study, we prepared four chemically modified heparin deriva-tives with low anticoagulant activities (data not shown), including RO-heparin, CR-heparin, 2/3ODS-heparin and N/2/3DS-heparin, using various well-established methods.…”

Section: Resultsmentioning

confidence: 95%

“…The adhesion of tumor cells to transfected CHO cells or anchored-platelets expressing P-selectin under flow conditions (0.3 dyn/cm 2 ) was measured by real-time video microscopy as described previously (21). The number of bound cells was quantified from videotape recordings of 10-20 fields of view obtained at the end of a 3-min perfusion.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory effects of chemically modified heparin on the P-selectin-mediated adhesion of breast cancer cells in vitro

Gao²,

Zheng³

et al. 2009

Mol Med Rep

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Abstract. P-selectin plays a crucial role during hematogenous metastasis, and the blockade of P-selectin binding to its ligand can attenuate metastasis in various tumor models. Heparin or chemically modified heparins with decreased anticoagulant activities exhibit marked inhibitory effects on P-selectinmediated adhesion. Here, we prepared chemically modified heparins with reduced anticoagulant activities and investigated whether they effectively inhibited P-selectin binding to breast cancer cells under static and flow conditions. The results indicated that P-selectin binding to ZR-75-30 cells was attenuated by chemically modified heparins in a sulfationdependent manner under static and flow conditions. Flow cytometric analysis with heparan sulfate-specific monoclonal antibody revealed that heparan sulfate-like proteoglycans on the tumor cell surface were not implicated in this process. Instead, other glycoproteins were found to serve as P-selectin ligands. These findings suggest that further detailed research involving chemically modified heparins with low or no anticoagulant activities is warranted, and that chemically modified heparins should be considered in the treatment of metastatic breast cancer disease, with P-selectin potentially being a good target.

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“…The involvement of selectins in metastasis has been shown in selectin-deficient mouse models (Borsig et al, 2002;Kim et al, 1998;O et al, 2002). Several studies have shown that heparin and heparinoids inhibit selectin-mediated cell adhesion, an important phase of metastasis (Borsig, 2010;Borsig et al, 2001;Borsig et al, 2002;Gao et al, 2006;Ma & Geng, 2000;Maraveyas et al, 2010;Stevenson et al, 2005;Stevenson et al, 2007;Varki, 2007;Wahrenbrock et al, 2003;Wei et al, 2004). To investigate the antimetastatic potency of ODSH, we used U937 cells, a human monocytic leukemia cells.…”

Section: Odsh Has Anti-metastatic and Anti-inflammatory Activities Inmentioning

confidence: 99%

Low-Anticoagulant Heparins in the Treatment of Metastasis

Rao¹,

Prestwich²,

Hoidal³

et al. 2011

Research on Melanoma - A Glimpse Into Current Directions and Future Trends

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Chemically modified heparin inhibits the in vitro adhesion of nonsmall cell lung cancer cells to P-selectin

Abstract: These findings suggest that some chemically modified heparins with low anticoagulant activity may deserve further testing in the experimental NSCLC treatment protocols.

Cited by 23 publications

References 33 publications

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo

Inhibitory effects of chemically modified heparin on the P-selectin-mediated adhesion of breast cancer cells in vitro

Low-Anticoagulant Heparins in the Treatment of Metastasis

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Chemically modified heparin inhibits the in vitro adhesion of nonsmall cell lung cancer cells to P-selectin

Abstract: These findings suggest that some chemically modified heparins with low anticoagulant activity may deserve further testing in the experimental NSCLC treatment protocols.

Cited by 23 publications

References 33 publications

Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo

Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo

Inhibitory effects of chemically modified heparin on the P-selectin-mediated adhesion of breast cancer cells in vitro

Low-Anticoagulant Heparins in the Treatment of Metastasis

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Product

Resources

About

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo

Modified heparins inhibit integrin α_IIbβ₃ mediated adhesion of melanoma cells to platelets in vitro and in vivo