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Cited by 714Cell Adhesion Molecules ResearchGlycosylation and Glycoproteins ResearchProteoglycans and glycosaminoglycans research

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

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Borsig, Lubor, Wong, Richard, Feramisco, James, Nadeau, David R., Varki, Nissi M., Varki, Ajit·2001·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.061615598PMC PMC30657
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Abstract

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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Crossref · 10.1073/pnas.061615598

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  • P-selectin facilitates human carcinoma metastasis in immunodeficient mice by mediating early interactions of platelets with blood-borne tumour cells via their cell-surface mucins.

    “P-selectin facilitates human carcinoma metastasis in immunodeficient mice by mediating early interactions of platelets with blood-borne tumour cells via their cell-surface mucins”

    From Inflammation and cancer (2002) · cites this paper as [54]

  • The process by which P-selectin facilitates human carcinoma metastasis can be blocked by heparin.

    “a process that can be blocked by heparin54.”

    From Inflammation and cancer (2002) · cites this paper as [54]

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Authors
Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M., & Varki, A.
Affiliations
San Diego Supercomputer Center (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2001-03-13
Volume
98
Issue
6
Pages
3352-3357
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.061615598
PMC
PMC30657
OpenAlex
W2060529002
Cited by
714
References
60
Citations by year
2026: 13 · 2025: 23 · 2024: 26 · 2023: 23 · 2022: 17 · 2021: 26 · 2020: 28 · 2019: 23 · 2018: 31 · 2017: 33 · 2016: 26 · 2015: 32 · 2014: 23 · 2013: 15 · 2012: 34
FWCI
13.60
Type
journal article
Language
en
Update notices
correction (2001-04-24)
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (P50 HL 23594)
  • National Cancer Institute (R01 CA 38701, R01CA038701)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
heparin, metastasis, P-selectin, platelets, platelet-tumor cell interaction, metastasis prevention, tumor cell colonization
MeSH terms
Adenocarcinoma, Animals, Blood Platelets, Heparin, Humans, Mice, Inbred C57BL, Monocytes, Mucins, Neoplasm Metastasis, Neoplasms, Neoplasms, Experimental, Tumor Cells, Cultured, Mice, Knockout, P-Selectin, Mice

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