Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis

Ludwig, Ralf J.; Boehme, Beatrice; Podda, Maurizio; Henschler, Reinhard; Jäger, Elke; Tandi, Christa; Boehncke, Wolf‐Henning; Zollner, Thomas M.; Kaufmann, Roland; Gille, Jens

doi:10.1158/0008-5472.can-03-1054

Cited by 185 publications

(210 citation statements)

References 42 publications

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“…Importantly, both platelet-cancer cell aggregation and experimental metastasis of human cancer cells were significantly inhibited in P-selectin-deficient mice [41,42]. Previous reports indicate that CD24 takes part in metastasis as a ligand of P-selectin.…”

Section: Discussionmentioning

confidence: 91%

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Niers

Brüggemann

Klerk

et al. 2008

Clin Exp Metastasis

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Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L-and Pselectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L-and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.Keywords B16 melanoma Á CT26 colon carcinoma Á K1735 melanoma Á Hirudin Á Low molecular weight heparin Á Selectin Á PAR

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Section: Discussionmentioning

confidence: 91%

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Niers

Brüggemann

Klerk

et al. 2008

Clin Exp Metastasis

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“…After 2 weeks, the mice were sacrificed, and the dissected lungs were analyzed for the presence of metastatic foci by counting tumor foci on the lung surface. 19 …”

Section: Experimental Lung Metastasis Assaymentioning

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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“…These findings suggest that activation of the vascular endothelium is likely to occur during metastasis development. Moreover, there is evidence to suggest that tumor cells use inducible CAMs to promote their adhesion to the vascular endothelium, and both VCAM-1 and E/P-selectin have been found to be up-regulated in lung and liver metastases (13)(14)(15)(16). Based on these findings, we hypothesized that local up-regulation of VCAM-1 may occur in the very early stages of metastasis in the brain.…”

mentioning

confidence: 94%

Molecular MRI enables early and sensitive detection of brain metastases

Serres

Soto

Hamilton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

129

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Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10 5 cells) than those volumes detectable clinically (10 7 -10 8 cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.

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Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis

Cited by 185 publications

References 42 publications

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

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

Molecular MRI enables early and sensitive detection of brain metastases

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Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis

Cited by 185 publications

References 42 publications

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

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

Molecular MRI enables early and sensitive detection of brain metastases

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Product

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