Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins

Gerd Bendas, Lubor Borsig, Gerd Bendas, Lubor Borsig

Abstract

Cell adhesion molecules play a significant role in cancer progression and metastasis. Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Clinical evidence indicates that heparin, commonly used for treatment of thromboembolic events in cancer patients, is beneficial for their survival. Preclinical studies confirm that heparin possesses antimetastatic activities that lead to attenuation of metastasis in various animal models. Heparin contains several biological activities that may affect several steps in metastatic cascade. Here we focus on the role of cellular adhesion receptors in the metastatic cascade and discuss evidence for heparin as an inhibitor of cell adhesion. While P- and L-selectin facilitation of cellular contacts during hematogenous metastasis is being accepted as a potential target of heparin, here we propose that heparin may also interfere with integrin activity and thereby affect cancer progression. This review summarizes recent findings about potential mechanisms of tumor cell interactions in the vasculature and antimetastatic activities of heparin.

Figures

Figure 1
Figure 1
Selectins and integrins contribute to metastatic spread. (a) Schematic presentation of selectin- and integrin-mediated cancer cell interactions with several blood constituents (e.g., platelets, leukocytes, and endothelial cells) during hematogenous metastasis. (b) Heparin application in mouse models blocks both P- and L-selectin-mediated; and VLA4-mediated interactions of cancer cells within blood circulation thereby affecting metastasis.

References

    1. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer. 2002;2(8):563–572.
    1. Fidler IJ. The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nature Reviews Cancer. 2003;3(6):453–458.
    1. Witz IP. The selectin-selectin ligand axis in tumor progression. Cancer and Metastasis Reviews. 2008;27(1):19–30.
    1. Paschos KA, Canovas D, Bird NC. The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis. Cellular Signalling. 2009;21(5):665–674.
    1. Läubli H, Borsig L. Selectins promote tumor metastasis. Seminars in Cancer Biology. 2010;20(3):169–177.
    1. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nature Reviews Cancer. 2010;10(1):9–22.
    1. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(6):3352–3357.
    1. Schlesinger M, Naggi A, Torri G, et al. Blocking of integrin-mediated human MV3 melanoma cell binding by commercial and modified heparins. International Journal of Clinical Pharmacology and Therapeutics. 2010;48(7):448–450.
    1. Borsig L. Selectins facilitate carcinoma metastasis and heparin can prevent them. News in Physiological Sciences. 2004;19(1):16–21.
    1. Kakkar AK, MacBeth F. Antithrombotic therapy and survival in patients with malignant disease. British Journal of Cancer. 2010;102(1):S24–S29.
    1. Zacharski LR, Loynes JT. Low-molecular-weight heparin in oncology. Anticancer Research. 2003;23(3):2789–2793.
    1. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood. 1996;88(9):3259–3287.
    1. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Reviews Immunology. 2007;7(9):678–689.
    1. Sperandio M, Gleissner CA, Ley K. Glycosylation in immune cell trafficking. Immunological Reviews. 2009;230(1):97–113.
    1. Varki A. Selectin ligands: will the real ones please stand up? Journal of Clinical Investigation. 1997;99(2):158–162.
    1. Kannagi R, Izawa M, Koike T, Miyazaki K, Kimura N. Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Science. 2004;95(5):377–384.
    1. Kim YJ, Varki A. Perspectives on the significance of altered glycosylation of glycoproteins in cancer. Glycoconjugate Journal. 1997;14(5):569–576.
    1. Borsig L, Stevenson JL, Varki A. Heparin in cancer: role of selectin interactions. In: Khorana AA, Francis CW, editors. Cancer-Associated Thrombosis. New York, NY, USA: Informa Healthcare; 2007. pp. 97–113.
    1. Kim YJ, Borsig L, Han HL, Varki NM, Varki A. Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium. American Journal of Pathology. 1999;155(2):461–472.
    1. Mannori G, Crottet P, Cecconi O, et al. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Research. 1995;55(19):4425–4431.
    1. Borsig L, Wong R, Hynes RO, Varki NM, Varki A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(4):2193–2198.
    1. Kim YJ, Borsig L, Varki NM, Varki A. P-selectin deficiency attenuates tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(16):9325–9330.
    1. Köhler S, Ullrich S, Richter U, Schumacher U. E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung. British Journal of Cancer. 2010;102(3):602–609.
    1. Läubli H, Borsig L. Selectins as mediators of lung metastasis. Cancer Microenvironment. 2010;3(1):97–105.
    1. Karpatkin S, Pearlstein E, Ambrogio C, Coller BS. Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. Journal of Clinical Investigation. 1988;81(4):1012–1019.
    1. Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Research. 1999;59(6):1295–1300.
    1. Honn KV, Tang DG, Crissman JD. Platelets and cancer metastasis: a causal relationship? Cancer and Metastasis Reviews. 1992;11(3-4):325–351.
    1. Fuster MM, Brown JR, Wang L, Esko JD. A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Research. 2003;63(11):2775–2781.
    1. Ludwig RJ, Boehme B, Podda M, et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Research. 2004;64(8):2743–2750.
    1. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110(6):1723–1729.
    1. Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. Journal of Clinical Investigation. 2003;112(6):853–862.
    1. Shao B, Wahrenbrock MG, Yao L, et al. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood. 2011;118(15):4015–4023.
    1. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–827.
    1. Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Seminars in Cancer Biology. 2011;21(2):139–146.
    1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444.
    1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867.
    1. Läubli H, Stevenson JL, Varki A, Varki NM, Borsig L. L-selectin facilitation of metastasis involves temporal induction of Fut7-dependent ligands at sites of tumor cell arrest. Cancer Research. 2006;66(3):1536–1542.
    1. Läubli H, Spanaus KS, Borsig L. Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes. Blood. 2009;114(20):4583–4591.
    1. Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Research. 1999;59(6):1356–1361.
    1. Gout S, Tremblay PL, Huot J. Selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis. Clinical and Experimental Metastasis. 2008;25(4):335–344.
    1. Brodt P, Fallavollita L, Bresalier RS, Meterissian S, Norton CR, Wolitzky BA. Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. International Journal of Cancer. 1997;71(4):612–619.
    1. Hiratsuka S, Goel S, Kamoun WS, et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(9):3725–3730.
    1. Morgan MR, Humphries MJ, Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nature Reviews Molecular Cell Biology. 2007;8(12):957–969.
    1. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–687.
    1. Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO Journal. 2009;28(9):1351–1361.
    1. Huveneers S, Danen EHJ. Adhesion signaling—crosstalk between integrins, Src and Rho. Journal of Cell Science. 2009;122(8):1059–1069.
    1. Dardik R, Savion N, Kaufmann Y, Varon D. Thrombin promotes platelet-mediated melanoma cell adhesion to endothelial cells under flow conditions: role of platelet glycoproteins P-selectin and GPIIb-IIIA. British Journal of Cancer. 1998;77(12):2069–2075.
    1. Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thrombosis and Haemostasis. 1995;74(1):282–290.
    1. Boukerche H, Berthier-Vergnes O, Tabone E, Dore JF, Leung LLK, McGregor JL. Platelet-melanoma cell interaction is mediated by the glycoprotein IIb-IIIa complex. Blood. 1989;74(2):658–663.
    1. Felding-Habermann B, Habermann R, Saldívar E, Ruggeri ZM. Role of β3 integrins in melanoma cell adhesion to activated platelets under flow. Journal of Biological Chemistry. 1996;271(10):5892–5900.
    1. Felding-Habermann B, O’Toole TE, Smith JW, et al. Integrin activation controls metastasis in human breast cancer. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(4):1853–1858.
    1. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nature Reviews Cancer. 2008;8(8):604–617.
    1. Brooks PC, Clark RAF, Cheresh DA. Requirement of vascular integrin α(v)β3 for angiogenesis. Science. 1994;264(5158):569–571.
    1. Jin H, Aiyer A, Su J, et al. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. Journal of Clinical Investigation. 2006;116(3):652–662.
    1. Humphries MJ, Yamada KM, Olden K. Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells. Journal of Clinical Investigation. 1988;81(3):782–790.
    1. Okahara H, Yagita H, Miyake K, Okumura K. Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor α enhancement of experimental metastasis. Cancer Research. 1994;54(12):3233–3236.
    1. Garofalo A, Chirivi RGS, Foglieni C, et al. Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. Cancer Research. 1995;55(2):414–419.
    1. Klemke M, Weschenfelder T, Konstandin MH, Samstag Y. High affinity interaction of integrin α4β1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. Journal of Cellular Physiology. 2007;212(2):368–374.
    1. Liang S, Dong C. Integrin VLA-4 enhances sialyl-Lewisx/a-negative melanoma adhesion to and extravasation through the endothelium under low flow conditions. American Journal of Physiology. 2008;295(3):C701–C707.
    1. Strocken PJM, Van Rijthoven EAM, Van Der Valk MA, Roos E. Targeted disruption of the β1 integrin gene in a lymphoma cell line greatly reduces metastatic capacity. Cancer Research. 1998;58(7):1569–1577.
    1. Brakebusch C, Wennerberg K, Krell HW, et al. β1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts. Oncogene. 1999;18(26):3852–3861.
    1. Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer. 2007;110(5):1149–1161.
    1. Tagalakis V, Blostein M, Robinson-Cohen C, Kahn SR. The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treatment Reviews. 2007;33(4):358–368.
    1. Esko JD, Lindahl U. Molecular diversity of heparan sulfate. Journal of Clinical Investigation. 2001;108(2):169–173.
    1. Borsig L. Antimetastatic activities of heparins and modified heparins. Experimental evidence. Thrombosis research. 2010;125, supplement:S66–S71.
    1. Niers TMH, Klerk CPW, DiNisio M, et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Critical Reviews in Oncology/Hematology. 2007;61(3):195–207.
    1. Sciumbata T, Caretto P, Pirovano P, et al. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival. Invasion and Metastasis. 1996;16(3):132–143.
    1. Kragh M, Binderup L, Vig Hjarnaa PJ, Bramm E, Johansen KB, Frimundt Petersen C. Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth. Oncology Reports. 2005;14(1):99–104.
    1. Casu B, Naggi A, Torri G. Heparin-derived heparan sulfate mimics to modulate heparan sulfate-protein interaction in inflammation and cancer. Matrix Biology. 2010;29(6):442–452.
    1. Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins: implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. Journal of Clinical Investigation. 1998;101(4):877–889.
    1. Hostettler N, Naggi A, Torri G, et al. P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FASEB Journal. 2007;21(13):3562–3572.
    1. Naggi A, Casu B, Perez M, et al. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. Journal of Biological Chemistry. 2005;280(13):12103–12113.
    1. Fritzsche J, Simonis D, Bendas G. Melanoma cell adhesion can be blocked by heparin in vitro: suggestion of VLA-4 as a novel target for antimetastatic approaches. Thrombosis and Haemostasis. 2008;100(6):1166–1175.
    1. Coombe DR, Watt SM, Parish CR. Mac-1 (CD11b/CD18) and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cell elements via recognition of stromal heparan sulfate. Blood. 1994;84(3):739–752.
    1. Diamond MS, Alon R, Parkos CA, Quinn MT, Springer TA. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD18) Journal of Cell Biology. 1995;130(6):1473–1482.
    1. Vorup-Jensen T, Chi L, Gjelstrup LC, et al. Binding between the integrin αXβ2 (CD11c/CD18) and heparin. Journal of Biological Chemistry. 2007;282(42):30869–30877.
    1. Zhang C, Liu Y, Gao Y, et al. Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo. International Journal of Cancer. 2009;125(9):2058–2065.
    1. Schlesinger M, Simonis D, Schmitz P, Fritzsche J, Bendas G. Binding between heparin and the integrin VLA-4. Thrombosis and Haemostasis. 2009;102(5):816–822.
    1. Schlesinger M, Schmitz P, Zeisig R, et al. The inhibition of the integrin VLA-4 in MV3 melanoma cell binding by non-anticoagulant heparin derivatives. Thrombosis Research. In press.
    1. Balkwill F. Cancer and the chemokine network. Nature Reviews Cancer. 2004;4(7):540–550.
    1. Harvey JR, Mellor P, Eldaly H, Lennard TWJ, Kirby JA, Ali S. Inhibition of CXCR4-mediated breast cancer metastasis: a potential role for heparinoids? Clinical Cancer Research. 2007;13(5):1562–1570.
    1. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107(5):1761–1767.
    1. Hoogewerf AJ, Kuschert GSV, Proudfoot AEI, et al. Glycosaminoglycans mediate cell surface oligomerization of chemokines. Biochemistry. 1997;36(44):13570–13578.
    1. Charni F, Friand V, Haddad O, et al. Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochimica et Biophysica Acta. 2009;1790(10):1314–1326.
    1. Dagouassat M, Suffee N, Hlawaty H, et al. Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. International Journal of Cancer. 2010;126(5):1095–1108.
    1. Zhou H, Roy S, Cochran E, et al. M402, a novel Heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. PLoS One. 2011;6(6, article e21106)
    1. Sharma A, Askari JA, Humphries MJ, Yvonne Jones E, Stuart DI. Crystal structure of a heparin- and integrin-binding segment of human fibronectin. EMBO Journal. 1999;18(6):1468–1479.
    1. Mostafavi-Pour Z, Askari JA, Parkinson SJ, Parker PJ, Ng TTC, Humphries MJ. Integrin-specific signaling pathways controlling focal adhesion formation and cell migration. Journal of Cell Biology. 2003;161(1):155–167.
    1. Bloom L, Ingham KC, Hynes RO. Fibronectin regulates assembly of actin filaments and focal contacts in cultured cells via the heparin-binding site in repeat III13. Molecular Biology of the Cell. 1999;10(5):1521–1536.
    1. Woods A, Couchman JR. Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. Molecular Biology of the Cell. 1994;5(2):183–192.
    1. Walsh CT, Radeff-Huang J, Matteo R, et al. Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61. FASEB Journal. 2008;22(11):4011–4021.
    1. Lin MT, Chang CC, Lin BR, et al. Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin α2β1. Journal of Biological Chemistry. 2007;282(47):34594–34604.
    1. Tsai MS, Bogart DF, Castañeda JM, Li P, Lupu R. Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene. 2002;21(53):8178–8185.
    1. Holloway SE, Beck AW, Girard L, et al. Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer. Journal of the American College of Surgeons. 2005;200(3):371–377.
    1. Watari H, Xiong Y, Hassan MK, Sakuragi N. Cyr61, a member of ccn (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family, predicts survival of patients with endometrial cancer of endometrioid subtype. Gynecologic Oncology. 2009;112(1):229–234.
    1. Babic AM, Kireeva ML, Kolesnikova TV, Lau LF. CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(11):6355–6360.
    1. Babic AM, Chen CC, Lau LF. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin α(v)β3, promotes endothelial cell survival, and induces angiogenesis in vivo. Molecular and Cellular Biology. 1999;19(4):2958–2966.
    1. Franzen CA, Chen CC, Todorović V, Juric V, Monzon RI, Lau LF. Matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis. Molecular Cancer Research. 2009;7(7):1045–1055.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa