Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis
Open accessAbstract
P-selectin facilitates human carcinoma metastasis in immunodeficient mice by mediating early interactions of platelets with bloodborne tumor cells via their cell surface mucins, and this process can be blocked by heparin [Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M. & Varki, A. (2001) Proc. Natl. Acad. Sci. USA 98, 3352–3357]. 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, and/or NK cells has a role in facilitating metastasis, acting beyond the early time points wherein P-selectin mediates interactions of platelet with tumor cells.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
L-selectin on neutrophils, monocytes and/or NK cells may facilitate metastasis.
“L-selectin on neutrophils, monocytes and/or NK cells also may facilitate metastasis55.”
From Inflammation and cancer (2002) · cites this paper as [55]
Cites
Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity
Butcher, E. C. (1991) · Cell · doi:10.1016/0092-8674(91)90279-8 · Cited by 2,789 · see citing works
Selectins and their ligands: Current concepts and controversies
Kansas, G. (1996) · Blood · doi:10.1182/blood.v88.9.3259.bloodjournal8893259 · Cited by 1,415 · see citing works
Fidler, I. J. (1990) · PubMed · Cited by 1,141 · see citing works
Neutrophil Mac-1 and MEL-14 Adhesion Proteins Inversely Regulated by Chemotactic Factors
Kishimoto, T., Jutila, M. A., Berg, E. L., & Butcher, E. C. (1989) · Science · doi:10.1126/science.2551036 · Cited by 1,089 · see citing works
Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism.
Hakomori, S. (1996) · PubMed · Cited by 987 · see citing works
Lysis of tumor cells by natural killer cells in mice is impeded by platelets.
Nieswandt, B., Hafner, M., Echtenacher, B., & Männel, D. N. (1999) · PubMed · Cited by 832 · see citing works
Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M., & Varki, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061615598 · Cited by 714 · see citing works
Self-citationAl‐Mehdi, A., Tozawa, K., Fisher, A. B., Shientag, L., Lee, A., & Muschel, R. J. (2000) · Nature Medicine · doi:10.1038/71429 · Cited by 703 · see citing works
McEver, R. P., & Cummings, R. D. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119556 · Cited by 647 · see citing works
Sequential contribution of L- and P-selectin to leukocyte rolling in vivo.
Ley, K. F., Bullard, D. C., Arbonés, M. L., Bosse, R. C., Vestweber, D., Tedder, T. F., & Beaudet, A. L. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.2.669 · Cited by 574 · see citing works
High endothelial venules (HEVs): specialized endothelium for lymphocyte migration
Girard, J., & Springer, T. A. (1995) · Immunology Today · doi:10.1016/0167-5699(95)80023-9 · Cited by 557 · see citing works
Takada, A., Ohmori, K., Yoneda, T., Tsuyuoka, K., Hasegawa, A., Kiso, M., & Kannagi, R. (1993) · PubMed · Cited by 544 · see citing works
Perspectives on the significance of altered glycosylation of glycoproteins in cancer
Kim, Y. J., & Varki, A. P. (1997) · Glycoconjugate Journal · doi:10.1023/a:1018580324971 · Cited by 536 · see citing works
Self-citationP-selectin deficiency attenuates tumor growth and metastasis
Kim, Y. J., Borsig, L., Varki, N. M., & Varki, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9325 · Cited by 454 · see citing works
Self-citationNakamori, S., Kameyama, M., Imaoka, S., Furukawa, H., Ishikawa, O., Sasaki, Y., Kabuto, T., Iwanaga, T., Matsushita, Y., & Irimura, T. (1993) · PubMed · Cited by 425 · see citing works
Possible roles of tumor-associated carbohydrate antigens.
Fukuda, M. (1996) · PubMed · Cited by 422 · see citing works
Koenig, A. L., Norgard-Sumnicht, K. E., Linhardt, R. J., & Varki, A. P. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1509 · Cited by 403 · see citing works
Self-citationLuscinskas, F. W., Kansas, G. S., Ding, H. T., Pizcueta, P. M., Schleiffenbaum, B. E., Tedder, T. F., & Gimbrone, M. A. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.125.6.1417 · Cited by 376 · see citing works
Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo.
Karpatkin, S., Pearlstein, E., Ambrogio, C., & Coller, B. S. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113411 · Cited by 346 · see citing works
Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer
Kannagi, R. (1997) · Glycoconjugate Journal · doi:10.1023/a:1018532409041 · Cited by 323 · see citing works
Selectin ligands: will the real ones please stand up?
Varki, A. P. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119142 · Cited by 315 · see citing works
Self-citationCD62/P-selectin recognition of myeloid and tumor cell sulfatides
Aruffo, A. A., Kolanus, W., Walz, G., Fredman, P., & Seed, B. (1991) · Cell · doi:10.1016/0092-8674(91)90570-o · Cited by 302 · see citing works
Mucin glycoproteins in neoplasia
Kim, Y. S., Gum, J. R., & Brockhausen, I. (1996) · Glycoconjugate Journal · doi:10.1007/bf00702333 · Cited by 294 · see citing works
Platelets and cancer metastasis: A causal relationship?
Honn, K. V., Tang, D. G., & Crissman, J. D. (1992) · Cancer and Metastasis Reviews · doi:10.1007/bf01307186 · Cited by 294 · see citing works
Ley, K. F., & Tedder, T. F. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.2.525 · Cited by 290 · see citing works
Role of Platelets in Tumor Cell Metastases
Karpatkin, S., & PEARLSTEIN, E. (1981) · Annals of Internal Medicine · doi:10.7326/0003-4819-95-5-636 · Cited by 266 · see citing works
Role of plasma, platelets, and endothelial cells in tumor metastasis
Gasic, G. (1984) · Cancer and Metastasis Reviews · doi:10.1007/bf00047657 · Cited by 261 · see citing works
Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins.
Mannori, G., Crottet, P., Cecconi, O., Hanasaki, K., Aruffo, A. A., Nelson, R. M., Varki, A. P., & Bevilacqua, M. P. (1995) · PubMed · Cited by 247 · see citing works
Self-citationInhibition of Metastases by Anticoagulants
Hejna, M., Raderer, M., & Zielinski, C. C. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.1.22 · Cited by 239 · see citing works
Heparanase expression in primary and metastatic pancreatic cancer.
Koliopanos, A., Friess, H., Kleeff, J. H., et al. (2001) · PubMed · Cited by 237 · see citing works
L-Selectin Shedding Regulates Leukocyte Recruitment
Hafezi‐Moghadam, A., Thomas, K. L., Prorock, A. J., Huo, Y., & Ley, K. F. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.7.863 · Cited by 224 · see citing works
Eriksson, E. E., Xie, X., Werr, J., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.2.205 · Cited by 219 · see citing works
Sawada, R., Tsuboi, S., & Fukuda, M. N. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42275-7 · Cited by 218 · see citing works
Robinson, S. D., Frenette, P. S., Rayburn, H., Cummiskey, M., Ullman-Culleré, M., Wagner, D. D., & Hynes, R. O. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11452 · Cited by 200 · see citing works
Self-citationKansas, G. S., Ley, K. F., Munro, J. M., & Tedder, T. F. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.177.3.833 · Cited by 199 · see citing works
Herndon, J. E., Fleishman, S. B., Kornblith, A. B., Kosty, M. P., Green, M. R., & Holland, J. C. (1999) · Cancer · doi:10.1002/(sici)1097-0142(19990115)85:2 · Cited by 191 · see citing works
Kim, Y. J., Borsig, L., Han, H., Varki, N. M., & Varki, A. P. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65142-5 · Cited by 189 · see citing works
Self-citationΟhyama, C., Tsuboi, S., & Fukuda, M. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1516 · Cited by 186 · see citing works
Signaling Functions of L-selectin
Waddell, T. K., Fialkow, L., Chan, C. K., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.25.15403 · Cited by 185 · see citing works
Laudanna, C., Constantin, G., Baron, P., Scarpini, E. A., Scarlato, G., Cabrini, G., Dechecchi, M. C., Rossi, F., Cassatella, M. A., & Berton, G. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)41736-4 · Cited by 182 · see citing works
P-selectin mediates adhesion of platelets to neuroblastoma and small cell lung cancer.
Stone, J. P., & Wagner, D. D. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116654 · Cited by 182 · see citing works
Redirection of tumor metastasis by expression of E-selectin in vivo.
Biancone, L., Araki, M., Araki, K., VASSALLI, P., & Stamenkovic, I. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.2.581 · Cited by 167 · see citing works
Varki, N. M., & Varki, A. P. (2002) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-2002-20564 · Cited by 164 · see citing works
Self-citationSelectin ligands, leukocyte trafficking, and fucosyltransferase genes
Lowe, J. B. (1997) · Kidney International · doi:10.1038/ki.1997.194 · Cited by 156 · see citing works
Smolen, J. E., Petersen, T. K., Koch, C. A., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m906232199 · Cited by 152 · see citing works
l -Selectin activates the Ras pathway via the tyrosine kinase p56 lck
Brenner, B., Gulbins, E., Schlottmann, K., Koppenhoefer, U., Busch, G. L., Walzog, B., Steinhausen, M., Coggeshall, K. M., Linderkamp, O., & Lang, F. J. W. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.26.15376 · Cited by 147 · see citing works
Suzuki, Y., Toda, Y., Tamatani, T., Watanabe, T., Suzuki, T., Nakao, T., Murase, K., Kiso, M., Hasegawa, A., Tadano‐Aritomi, K., et al. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.1065 · Cited by 142 · see citing works
Selectins and mechanisms of signal transduction
Crockett-Torabi, E. (1998) · Journal of Leukocyte Biology · doi:10.1002/jlb.63.1.1 · Cited by 140 · see citing works
Izumi, Y., Taniuchi, Y., Tsuji, T., et al. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1027 · Cited by 133 · see citing works
Tang, M. L. K., Steeber, D. A., Zhang, X., & Tedder, T. F. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.10.5113 · Cited by 128 · see citing works
Alon, R., Feizi, T., Yuen, C.-T., Fuhlbrigge, R. C., & Springer, T. A. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.10.5356 · Cited by 127 · see citing works
Hickey, M. J., Forster, M., Mitchell, D. J., Kaur, J., Caigny, C. D., & Kubes, P. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.12.7164 · Cited by 111 · see citing works
Dimeric sialyl-Lex expression in gastric carcinoma correlates with venous invasion and poor outcome
Amado, M., Carneiro, F., Seixas, M., Clausen, H., & Sobrinho-Simões, M. A. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70529-3 · Cited by 108 · see citing works
Manzi, A. E., Sjoberg, E. R., Diaz, S. L., & Varki, A. P. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38271-7 · Cited by 92 · see citing works
Self-citationInhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin.
Mannori, G., Santoro, D., Carter, L., Corless, C. L., Nelson, R. M., & Bevilacqua, M. P. (1997) · Europe PMC (PubMed Central) · Cited by 88 · see citing works
L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis
Qian, F., Hanahan, D., & Weissman, I. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061633698 · Cited by 80 · see citing works
Xie, X., Rivier, A.-S., Zakrzewicz, A., Bernimoulin, M. P., Zeng, X., Wessel, H. P., Schapira, M., & Spertini, O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001257200 · Cited by 76 · see citing works
The Effects of Unfractionated Heparin on Survival in Patients with Malignancy – A Systematic Review
Hettiarachchi, R., Vink, R., Büller, H., et al. (1999) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614885 · Cited by 76 · see citing works
CD62/P-Selectin Binding Sites for Myeloid Cells and Sulfatides Are Overlapping
Bajorath, J., Hollenbaugh, D. L., King, G., Harte, W. E., Eustice, D. C., Darveau, R. P., & Aruffo, A. A. (1994) · Biochemistry · doi:10.1021/bi00172a007 · Cited by 73 · see citing works
Selectin ligands: will the real ones please stand up?
Varki, A. P. (1997) · PubMed · Cited by 71 · see citing works
Self-citationBerg, E. L., Mullowney, A., Andrew, D. P., et al. (1998) · PubMed · Cited by 44 · see citing works
The Use of Heparin for Treating Human Malignancies
Ornstein, D. L., & Zacharski, L. R. (1999) · Pathophysiology of Haemostasis and Thrombosis · doi:10.1159/000054112 · Cited by 43 · see citing works
In vitro and in vivo selectin-blocking activities of sulfated lipids and sulfated sialyl compounds
Mulligan, M. S. (1998) · International Immunology · doi:10.1093/intimm/10.5.569 · Cited by 38 · see citing works
Murine Colon Adenocarcinomas: Methods for Selective Culture In Vitro 2
Tan, M., Holyoke, E. D., & Goldrosen, M. H. (1976) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/56.4.871 · Cited by 35 · see citing works
Tanaka, N., Tohgo, A., & Ogawa, H. (1986) · PubMed · Cited by 32 · see citing works
P-selectin-mediated attachment of small cell lung carcinoma to endothelial cells
Pottratz, S. T., Hall, T. D., Scribner, W. M., et al. (1996) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1996.271.6.l918 · Cited by 23 · see citing works
Gerli, R., Gresele, P., Bistoni, O., Paolucci, C., Lanfrancone, L., Fiorucci, S., Muscat, C., & Costantini, V. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.832 · Cited by 21 · see citing works
Aviram, R., Raz, N., Kukulansky, T., et al. (2001) · Cancer Immunology Immunotherapy · doi:10.1007/pl00006682 · Cited by 8 · see citing works
A novel detection system for submicroscopic human metastases in athymic mice.
Ba, M., Barrieux, A., & Nm, V. (1991) · PubMed · Cited by 8 · see citing works
A Role for L‐Selectin in Monocyte Activation by Jurkat Tumour Cells
Putz, E., & Männel, D. N. (1996) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.1996.d01-346.x · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Coussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111 · see citing works
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., et al. (2005) · Nature · doi:10.1038/nature04186 · Cited by 3,288 · see citing works
Platelets guide the formation of early metastatic niches
Labelle, M., Begum, S., & Hynes, R. O. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411082111 · Cited by 555 · see citing works
Self-citationSialic acids in cancer biology and immunity
Pearce, O. M. T., & Läubli, H. (2016) · Glycobiology · doi:10.1093/glycob/cwv097 · Cited by 470 · see citing works
Wahrenbrock, M., Borsig, L., Le, D., Varki, N., & Varki, A. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318882 · Cited by 317 · see citing works
Self-citationPlatelets increase the proliferation of ovarian cancer cells
Cho, M. S., Bottsford-Miller, J., Vasquez, H. G., Stone, R., Zand, B., Kroll, M. H., Sood, A. K., & Afshar-Kharghan, V. (2012) · Blood · doi:10.1182/blood-2012-06-438598 · Cited by 245 · see citing works
Selectin Blocking Activity of a Fucosylated Chondroitin Sulfate Glycosaminoglycan from Sea Cucumber
Borsig, L., Wang, L., Cavalcante, M. C. M., Cardilo-Reis, L., Ferreira, P. L., Mourąo, P. A. S., Esko, J. D., & Pavąo, M. S. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610560200 · Cited by 187 · see citing works
Self-citationHeparin inhibits the flow adhesion of sickle red blood cells to P-selectin
Matsui, N. M., Varki, A., & Embury, S. H. (2002) · Blood · doi:10.1182/blood-2002-02-0626 · Cited by 123 · see citing works
Self-citationWahrenbrock, M. G., & Varki, A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3851 · Cited by 58 · see citing works
Self-citationOh, J., Edwards, E. E., McClatchey, P. M., & Thomas, S. N. (2015) · Journal of Cell Science · doi:10.1242/jcs.166439 · Cited by 17 · see citing works
- Authors
- Borsig, L., Wong, R., Hynes, R. O., Varki, N. M., & Varki, A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-02-19
- Volume
- 99
- Issue
- 4
- Pages
- 2193-2198
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC122341
- OpenAlex
- W2170200613
- Cited by
- 400
- References
- 70
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 19 · 2020: 11 · 2019: 10 · 2018: 19 · 2017: 23 · 2016: 18 · 2015: 21 · 2014: 22 · 2013: 13 · 2012: 30
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- L-selectin, P-selectin, metastasis, leukocytes, heparin, neutrophils, monocytes, natural killer cells, platelet-tumor cell interaction
- MeSH terms
- Animals, Blood Platelets, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Heparin, Leukocytes, Ligands, Luminescent Proteins, Mucins, Neoplasm Metastasis, Neoplasm Transplantation, Neoplasms, Experimental, Protein Binding, Tumor Cells, Cultured, P-Selectin, L-Selectin, Green Fluorescent Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
