Actions of heparin that may affect the malignant process

Independent studies indicate that expression of sialylated fucosylated mucins by human carcinomas portends a poor prognosis because of enhanced metastatic spread of tumor cells, that carcinoma metastasis in mice is facilitated by formation of tumor cell complexes with blood platelets, and that metastasis can be attenuated by a background of P-selectin deficiency or by treatment with heparin. The effects of heparin are not primarily due to its anticoagulant action. Other explanations have been suggested but not proven. Here, we bring together all these unexplained and seemingly disparate observations, showing that heparin treatment attenuates tumor metastasis in mice by inhibiting P-selectin-mediated interactions of platelets with carcinoma cell-surface mucin ligands. Selective removal of tumor mucin P-selectin ligands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo . Although each of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dimensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet “cloak” around tumor cells while permitting an increased interaction of monocytes (macrophage precursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant inhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisited, with these mechanistic paradigms in mind.

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“…[9][10][11][12]. A few clinical trials also suggested a beneficial effect of heparin in humans with cancer (13)(14)(15)(16)(17).…”

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Borsig

Wong

Feramisco

et al. 2001

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

623

656

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“…As a result, modified heparin derivatives which have low anticoagulant activities and still preserve anti-adhesion biological activities were developed. 37,38 Here we tested the effects of heparin and modified heparins with lower anticoagulant activities in inhibiting the interaction of melanoma cells with platelets mediated by a IIb b 3 . In the eight modified heparins, RO-heparin, CR-heparin, 2,3-O-desulfate heparin and N-2,3-desulfate heparin exhibited excellent ability in inhibiting the stable attachment of A375 cells to GP-CHO cells or platelets.…”

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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“…21 Kakkar and Williamson 22,23 and Engelberg 24 noted the antimetastatic effect of heparin and fractionated heparin, and randomized prospective studies currently are in progress. More specifically, in vitro and in vivo murine models have shown that platelet aggregation is one of the mechanisms that promotes metastatic growth by protecting the metastatic tumor cells from natural killer cell cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Impaired platelet aggregation in melanoma patients treated with interferon‐α‐2b adjuvant therapy

Gutman

Schachter

Stopel

et al. 2002

Cancer

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BACKGROUNDHigh‐dose interferon (INF)‐ α‐2b is the only Food and Drug Administration‐approved adjuvant treatment for patients with melanoma who are at high risk of recurrence. Although circumstantial evidence points to a potentially harmful effect of INF‐α‐2b on platelet function, to the authors' knowledge this has never been studied in humans.METHODSThe study group was comprised of patients who had undergone surgery for melanoma and were free of disease but at a high risk of recurrence. All patients were candidates for adjuvant INF treatment (high‐dose) and were undergoing routine evaluation to which platelet aggregation was added. Aggregation was triggered in standard fashion with adenosine diphosphate, epinephrine, collagen, thrombin, arachidonic acid, and ristocetin. Blood samples were drawn immediately before treatment, during the intravenous loading phase, during the subcutaneous maintenance phase, and 3–6 weeks after cessation of treatment. Patients receiving low‐dose, long‐standing INF‐α‐2b treatment also were tested. All results at each phase were compared with those of normal controls.RESULTSIn those patients receiving high‐dose INF‐α‐2b, ristocetin‐induced aggregation did not appear to be affected. However, the response to ≥ 1 of the other agonists was impaired in 5 of 6 samples during loading, 14 of 15 samples during the maintenance phase, and 8 of 13 samples after treatment, compared with only 1 of 8 samples before treatment (P = 0.025, P = 0.002, and P = 0.067, respectively). During treatment with low‐dose INF, platelet function was affected to a lesser extent.CONCLUSIONSINF treatment in melanoma patients appears to be associated with severe impairment of platelet aggregation, which appears to be dose‐dependent and cumulative–dose‐dependent. This is not detectable by the standard coagulation profile. This effect has significant implications in the event of accidental injury or elective surgery. The antiaggregation activity may be the mechanism by which INF delays, reduces, or prevents the formation of melanoma metastases. Cancer 2002;94:780–5. © 2002 American Cancer Society.DOI 10.1002/cncr.10261

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Actions of heparin that may affect the malignant process

Cited by 118 publications

References 188 publications

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

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

Impaired platelet aggregation in melanoma patients treated with interferon‐α‐2b adjuvant therapy

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Actions of heparin that may affect the malignant process

Cited by 118 publications

References 188 publications

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

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

Impaired platelet aggregation in melanoma patients treated with interferon‐α‐2b adjuvant therapy

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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