The Use of Heparin for Treating Human Malignancies

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

Wong

Feramisco

et al. 2001

627

650

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.

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

confidence: 99%

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

confidence: 99%

Section: Enhanced Monocyte (Macrophage Precursor) Association With Tumormentioning

confidence: 99%

See 1 more Smart Citation

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

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

Wong

Feramisco

et al. 2001

627

650

“…[39][40][41][42][43]. The glycosaminoglycan heparin, which is clinically used as an anticoagulant, is known to inhibit tumor growth and metastasis (44)(45)(46)(47)(48). Heparin also is a potent inhibitor of P-and L-selectin (49,50).…”

mentioning

confidence: 99%

Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis

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

Wong

Hynes

et al. 2002

368

398

Here we show similar findings with a murine adenocarcinoma in syngeneic immunocompetent mice but involving a different P-selectin ligand, possibly a sulfated glycolipid. Thus, metastatic spread can be facilitated by tumor cell selectin ligands other than mucins. Surprisingly, L-selectin expressed on endogenous leukocytes also facilitates metastasis in both the syngeneic and xenogeneic (T and B lymphocyte deficient) systems. PL-selectin double deficient mice show that the two selectins work synergistically. Although heparin can block both P-and L-selectin in vitro, the in vivo effect of a single heparin dose given before tumor cells seems to be completely accounted for by blockade of P-selectin function. Thus, L-selectin on neutrophils, monocytes, and͞or NK cells has a role in facilitating metastasis, acting beyond the early time points wherein P-selectin mediates interactions of platelet with tumor cells.cancer ͉ heparin ͉ glycolipids ͉ platelets H ematogeneous metastasis occurs when tumor cells enter the bloodstream, interact with host blood cells, and eventually colonize a distant tissue. Much evidence indicates that hematogenously disseminating tumor cells interact with platelets and leukocytes, forming microemboli that facilitate their arrest in the vasculature (1-4). Although the contribution of platelets to metastasis has been confirmed in several experimental settings (1, 2, 5-10), the mechanisms and significance of leukocyte participation in tumor microemboli remain largely unknown.Altered cell surface glycosylation is a prominent feature of tumor cells (11)(12)(13)(14)(15). In particular, the expression of sialylated fucosylated glycans like sialyl Lewis x/a correlate with a poor prognosis because of tumor progression and a high rate of metastasis (for examples, see refs. 16-18). Selectins are vascular cell adhesion molecules that recognize certain sialyl Lewis x/a carrying mucin-type glycoproteins found on normal leukocytes and endothelium (11,(19)(20)(21)(22)(23). Carcinoma cell surface molecules carrying sialyl Lewis x/a also can be recognized by all three selectins (11-15, 17, 24-27), mediating tumor cell interactions with platelets, leukocytes, and endothelium in vitro (10,25,27,28). Based on such data, an in vivo role for E-and P-selectins in metastatic spread has been suggested. The hypothesis that E-selectin on activated endothelium might facilitate cancer cell seeding (14, 29) is supported by transgenic over-expression of E-selectin in the mouse liver, which redirected metastases to this organ (30), and a system where tumor cell expression of sialylated fucosylated glycans was increased by transfecting a fucosyltransferase (31). Carcinoma lines expressing E-selectin ligands also displayed an increased metastatic capacity in cytokine-pretreated mice (32). However, E-selectin is not constitutively expressed in vivo but must be transcriptionally activated by certain stimuli. We have previously shown that platelets adhere to some human carcinoma cells mostly via P-selectin and that inhibition of th...

“…Thromboprophylaxis with unfractionated heparin and low-molecular weight heparin (LMWH) has been used for management of hypercoagulable state in cancer patients, and LMWH is the recommended anticoagulant regimen by international guidelines [1,2]. Many retrospective analyses of clinical data indicated that heparin treatment affects survival of cancer patients with various tumors, especially in patients with the early stage of a disease [3][4][5]. Based on these observations several prospective clinical trials has been performed to evaluate heparins for its anticancer potential [6][7][8][9][10][11][12][13][14].…”

Section: Heparin Affects On Cancer: Clinical Evidencementioning

confidence: 99%

Heparin as an Inhibitor of Cancer Progression

Progress in Molecular Biology and Translational Science

2010

Heparin is frequently used for treatment of cancer-associated thromboembolism. Accumulating clinical evidence indicates that cancer patients treated with unfractionated and low-molecular weight heparin survives longer that patients treated by other anticoagulants, especially patients in the early stage of a disease. Experimental analysis from a number of animal models constantly provides evidence about the ability of heparin to attenuate metastasis. The non-anticoagulant activity of heparin on metastasis includes the ability to inhibit cell-cell-interaction through blocking of P-and L-selectin, to inhibit extracellular matrix protease-heparanase, and to inhibit angiogenesis. This chapter summarizes the current experimental evidence on the biology of heparin during cancer progression with the focus on potential mechanism of heparin antimetastatic activity.