肝素及其类似物抗乳腺癌作用研究进展
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摘要
肿瘤是深静脉血栓形成的高危因素之一,因而很多肿瘤患者会伴发静脉血栓形成,这使得抗凝治疗必不可少。近期很多临床研究及Meta分析表明,肿瘤患者在接受抗凝治疗后,生存期得到明显改善。肝素是一种广泛应用于静脉血栓的抗凝剂,据此,研究人员提出猜想:肝素是否具有抗肿瘤活性?大量实验性研究就此全面开展,结果证实:普通肝素、低分子肝素、肝素各种化学衍生物与多种肿瘤的发生、发展进程相关。该文主要概述了肝素及其类似物抗乳腺癌的作用及其可能的内在机制。
Tumor is one of the most risk factors for deep venous thrombosis. So many patients with cancer will be associated with venous thrombosis, which makes anticoagulant therapy indispensable. A lot of recent clinical studies and Meta analysis showed that the survival time of tumor patients after anticoagulant therapy had been significantly improved. Heparin is an anticoagulant widely used in venous thromboembolism. Based on this, researchers have speculated that whether heparin has anti-tumor activity. In response to this, a large number of experimental studies were carried out, which confirmed that heparin, low molecular weight heparin, and various chemical derivatives of heparin had been involved in the occurrence and development of multiple tumors. This article mainly outlines the relationship and mechanisms between breast cancer and heparin as well as its analogues.
Tumor is one of the most risk factors for deep venous thrombosis. So many patients with cancer will be associated with venous thrombosis, which makes anticoagulant therapy indispensable. A lot of recent clinical studies and Meta analysis showed that the survival time of tumor patients after anticoagulant therapy had been significantly improved. Heparin is an anticoagulant widely used in venous thromboembolism. Based on this, researchers have speculated that whether heparin has anti-tumor activity. In response to this, a large number of experimental studies were carried out, which confirmed that heparin, low molecular weight heparin, and various chemical derivatives of heparin had been involved in the occurrence and development of multiple tumors. This article mainly outlines the relationship and mechanisms between breast cancer and heparin as well as its analogues.
引文
[1] 陈万青,郑荣寿.中国女性乳腺癌发病死亡和生存状况[J].中国肿瘤临床,2015,53(13):668-674.
[2] Ludwig RJ.Therapeutic use of heparin beyond anticoagulation[J].Curr Drug Discov Technol,2009,6(4):281-289.
[3] Yin W,Zhang J,Jiang Y,et al.Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice[J].Exp Ther Med,2014,8(4):1213-1218.
[4] Phillips PG,Yalcin M,Cui H,et al.Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin[J].Anticancer Res,2011,31(2):411-419.
[5] Conti P,Castellani ML,Kempuraj D,et al.Role of mast cells in tumor growth[J].Ann Clin Lab Sci,2007,37(4):315-322.
[6] Kankkunen JP,Harvima IT,Naukkarinen A.Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions[J].Int J Cancer,1997,72(3):385-388.
[7] Samoszuk M,Corwin MA.Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer[J].Int J Cancer,2003,107(1):159-163.
[8] Wedemeyer J,Galli SJ.Decreased susceptibility of mast cell-deficient Kit(W)/Kit(W-v) mice to the development of 1,2-dimethylhydrazine-induced intestinal tumors[J].Lab Invest,2005,85(3):388-396.
[9] Samoszuk M,Kanakubo E,Chan JK.Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts[J].BMC Cancer,2005,5:121.
[10] Samoszuk M,Corwin MA.Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec)[J].Int J Cancer,2003,106(5):647-652.
[11] Samoszuk M,Corwin M,Yu H,et al.Inhibition of thrombosis in melanoma allografts in mice by endogenous mast cell heparin[J].Thromb Haemost,2003,90(2):351-360.
[12] Frungieri MB,Weidinger S,Meineke V,et al.Proliferative action of mast-cell tryptase is mediated by PAR2,COX2,prostaglandins,and PPARgamma:Possible relevance to human fibrotic disorders[J].Proc Natl Acad Sci USA,2002,99(23):15072-15077.
[13] Orimo A,Gupta PB,Sgroi DC,et al.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J].Cell,2005,121(3):335-348.
[14] Imagawa W,Cunha GR,Young P,et al.Keratinocyte growth factor and acidic fibroblast growth factor are mitogens for primary cultures of mammary epithelium[J].Biochem Biophys Res Commun,1994,204(3):1165-1169.
[15] Afratis N,Gialeli C,Nikitovic D,et al.Glycosaminoglycans:key players in cancer cell biology and treatment[J].FEBS J,2012,279(7):1177-1197.
[16] Vlodavsky I,Friedmann Y.Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J].J Clin Invest,2001,108(3):341-347.
[17] David G.Integral membrane heparan sulfate proteoglycans.FASEB journal:official publication of the Federation of American Societies for Experimental[J].Biology.1993,7(11):1023-1030.
[18] Lander AD,Stipp CS,Ivins JK.The glypican family of heparan sulfate proteoglycans:major cell-surface proteoglycans of the developing nervous system[J].Perspect Dev Neurobiol,1996,3(4):347-358.
[19] Stanley MJ,Stanley MW,Sanderson RD,et al.Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma[J].Am J Clin Pathol,1999,112(3):377-383.
[20] Ethier SP.Growth factor synthesis and human breast cancer progression[J].J Natl Cancer Inst,1995,87(13):964-973.
[21] Sommer A,Rifkin DB.Interaction of heparin with human basic fibroblast growth factor:protection of the angiogenic protein from proteolytic degradation by a glycosaminoglycan[J].J Cell Physiol,1989,138(1):215-220.
[22] Delehedde M,Deudon E,Boilly B,et al.Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells[J].Exp Cell Res,1996,229(2):398-406.
[23] Matsuda K,Maruyama H,Guo F,et al.Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells[J].Cancer Res,2001,61(14):5562-5569.
[24] Iozzo RV.Cell surface heparan sulfate proteoglycan and the neoplastic phenotype[J].J Cell Biochem,1988,37(1):61-78.
[25] Angello JC,Hosick HL,Anderson LW.Glycosaminoglycan synthesis by a cell line (C1-S1) established from a preneoplastic mouse mammary outgrowth[J].Cancer Res,1982,42(12):4975-4978.
[26] Rohde LH,Julian J,Babaknia A,et al.Cell surface expression of HIP,a novel heparin/heparan sulfate binding protein,of human uterine epithelial cells and cell lines[J].T J Biol Chem,1996,271(20):11824-11830.
[27] Liu S,Hoke D,Julian J,et al.Heparin/heparan sulfate (HP/HS) interacting protein (HIP) supports cell attachment and selective,high affinity binding of HP/HS[J].J Biol Chem,1997,272(41):25856-25862.
[28] Marchetti D,Liu S,Spohn WC,et al.Heparanase and a synthetic peptide of heparan sulfate-interacting protein recognize common sites on cell surface and extracellular matrix heparan sulfate[J].J Biol Chem,1997,272(25):15891-15897.
[29] Liu S,Julian J,Carson DD.A peptide sequence of heparin/heparan sulfate (HP/HS)-interacting protein supports selective,high affinity binding of HP/HS and cell attachment[J].J Biol Chem,1998,273(16):9718-9726.
[30] Liekens S,Schols D,Hatse S.CXCL12-CXCR4 axis in angiogenesis,metastasis and stem cell mobilization[J].Curr Pharm Des,2010,16(35):3903-3920.
[31] Balkwill F.The significance of cancer cell expression of the chemokine receptor CXCR4[J].Semin Cancer Biol,2004,14(3):171-179.
[32] Müller A,Homey B,Soto H,et al.Involvement of chemokine receptors in breast cancer metastasis[J].Nature,2001,410(6824):50-56.
[33] Cabioglu N,Yazici MS,Arun B,et al.CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer[J].Clin Cancer Res,2005,11(16):5686-5693.
[34] Salvucci O,Bouchard A,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat,2006,97(3):275-283.
[35] Fernandis AZ,Prasad A,Band H,et al.Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells[J].Oncogene,2004,23(1):157-167.
[36] Ali S,Robertson H,Wain JH,et al.A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation[J].J Immunol,2005,175(2):1257-1266.
[37] Hecht I,Hershkoviz R,Shivtiel S,et al.Heparin-disaccharide affects T cells:inhibition of NF-kappaB activation,cell migration,and modulation of intracellular signaling[J].J Leukoc Biol,2004,75(6):1139-1146.
[38] Harvey JR,Mellor P,Eldaly H,et al.Inhibition of CXCR4-mediated breast cancer metastasis:a potential role for heparinoids?[J].Clin Cancer Res,2007,13(5):1562-1570.
[39] Suarez ER,Paredes-Gamero EJ,Del GA,et al.Heparan sulfate mediates trastuzumab effect in breast cancer cells[J].BMC Cancer,2013,13:444.
[2] Ludwig RJ.Therapeutic use of heparin beyond anticoagulation[J].Curr Drug Discov Technol,2009,6(4):281-289.
[3] Yin W,Zhang J,Jiang Y,et al.Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice[J].Exp Ther Med,2014,8(4):1213-1218.
[4] Phillips PG,Yalcin M,Cui H,et al.Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin[J].Anticancer Res,2011,31(2):411-419.
[5] Conti P,Castellani ML,Kempuraj D,et al.Role of mast cells in tumor growth[J].Ann Clin Lab Sci,2007,37(4):315-322.
[6] Kankkunen JP,Harvima IT,Naukkarinen A.Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions[J].Int J Cancer,1997,72(3):385-388.
[7] Samoszuk M,Corwin MA.Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer[J].Int J Cancer,2003,107(1):159-163.
[8] Wedemeyer J,Galli SJ.Decreased susceptibility of mast cell-deficient Kit(W)/Kit(W-v) mice to the development of 1,2-dimethylhydrazine-induced intestinal tumors[J].Lab Invest,2005,85(3):388-396.
[9] Samoszuk M,Kanakubo E,Chan JK.Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts[J].BMC Cancer,2005,5:121.
[10] Samoszuk M,Corwin MA.Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec)[J].Int J Cancer,2003,106(5):647-652.
[11] Samoszuk M,Corwin M,Yu H,et al.Inhibition of thrombosis in melanoma allografts in mice by endogenous mast cell heparin[J].Thromb Haemost,2003,90(2):351-360.
[12] Frungieri MB,Weidinger S,Meineke V,et al.Proliferative action of mast-cell tryptase is mediated by PAR2,COX2,prostaglandins,and PPARgamma:Possible relevance to human fibrotic disorders[J].Proc Natl Acad Sci USA,2002,99(23):15072-15077.
[13] Orimo A,Gupta PB,Sgroi DC,et al.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J].Cell,2005,121(3):335-348.
[14] Imagawa W,Cunha GR,Young P,et al.Keratinocyte growth factor and acidic fibroblast growth factor are mitogens for primary cultures of mammary epithelium[J].Biochem Biophys Res Commun,1994,204(3):1165-1169.
[15] Afratis N,Gialeli C,Nikitovic D,et al.Glycosaminoglycans:key players in cancer cell biology and treatment[J].FEBS J,2012,279(7):1177-1197.
[16] Vlodavsky I,Friedmann Y.Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J].J Clin Invest,2001,108(3):341-347.
[17] David G.Integral membrane heparan sulfate proteoglycans.FASEB journal:official publication of the Federation of American Societies for Experimental[J].Biology.1993,7(11):1023-1030.
[18] Lander AD,Stipp CS,Ivins JK.The glypican family of heparan sulfate proteoglycans:major cell-surface proteoglycans of the developing nervous system[J].Perspect Dev Neurobiol,1996,3(4):347-358.
[19] Stanley MJ,Stanley MW,Sanderson RD,et al.Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma[J].Am J Clin Pathol,1999,112(3):377-383.
[20] Ethier SP.Growth factor synthesis and human breast cancer progression[J].J Natl Cancer Inst,1995,87(13):964-973.
[21] Sommer A,Rifkin DB.Interaction of heparin with human basic fibroblast growth factor:protection of the angiogenic protein from proteolytic degradation by a glycosaminoglycan[J].J Cell Physiol,1989,138(1):215-220.
[22] Delehedde M,Deudon E,Boilly B,et al.Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells[J].Exp Cell Res,1996,229(2):398-406.
[23] Matsuda K,Maruyama H,Guo F,et al.Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells[J].Cancer Res,2001,61(14):5562-5569.
[24] Iozzo RV.Cell surface heparan sulfate proteoglycan and the neoplastic phenotype[J].J Cell Biochem,1988,37(1):61-78.
[25] Angello JC,Hosick HL,Anderson LW.Glycosaminoglycan synthesis by a cell line (C1-S1) established from a preneoplastic mouse mammary outgrowth[J].Cancer Res,1982,42(12):4975-4978.
[26] Rohde LH,Julian J,Babaknia A,et al.Cell surface expression of HIP,a novel heparin/heparan sulfate binding protein,of human uterine epithelial cells and cell lines[J].T J Biol Chem,1996,271(20):11824-11830.
[27] Liu S,Hoke D,Julian J,et al.Heparin/heparan sulfate (HP/HS) interacting protein (HIP) supports cell attachment and selective,high affinity binding of HP/HS[J].J Biol Chem,1997,272(41):25856-25862.
[28] Marchetti D,Liu S,Spohn WC,et al.Heparanase and a synthetic peptide of heparan sulfate-interacting protein recognize common sites on cell surface and extracellular matrix heparan sulfate[J].J Biol Chem,1997,272(25):15891-15897.
[29] Liu S,Julian J,Carson DD.A peptide sequence of heparin/heparan sulfate (HP/HS)-interacting protein supports selective,high affinity binding of HP/HS and cell attachment[J].J Biol Chem,1998,273(16):9718-9726.
[30] Liekens S,Schols D,Hatse S.CXCL12-CXCR4 axis in angiogenesis,metastasis and stem cell mobilization[J].Curr Pharm Des,2010,16(35):3903-3920.
[31] Balkwill F.The significance of cancer cell expression of the chemokine receptor CXCR4[J].Semin Cancer Biol,2004,14(3):171-179.
[32] Müller A,Homey B,Soto H,et al.Involvement of chemokine receptors in breast cancer metastasis[J].Nature,2001,410(6824):50-56.
[33] Cabioglu N,Yazici MS,Arun B,et al.CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer[J].Clin Cancer Res,2005,11(16):5686-5693.
[34] Salvucci O,Bouchard A,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat,2006,97(3):275-283.
[35] Fernandis AZ,Prasad A,Band H,et al.Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells[J].Oncogene,2004,23(1):157-167.
[36] Ali S,Robertson H,Wain JH,et al.A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation[J].J Immunol,2005,175(2):1257-1266.
[37] Hecht I,Hershkoviz R,Shivtiel S,et al.Heparin-disaccharide affects T cells:inhibition of NF-kappaB activation,cell migration,and modulation of intracellular signaling[J].J Leukoc Biol,2004,75(6):1139-1146.
[38] Harvey JR,Mellor P,Eldaly H,et al.Inhibition of CXCR4-mediated breast cancer metastasis:a potential role for heparinoids?[J].Clin Cancer Res,2007,13(5):1562-1570.
[39] Suarez ER,Paredes-Gamero EJ,Del GA,et al.Heparan sulfate mediates trastuzumab effect in breast cancer cells[J].BMC Cancer,2013,13:444.