α₂-Antiplasmin: New Insights and Opportunities for Ischemic Stroke

 

 Buy Article Permissions and Reprints

Abstract

Thrombotic vascular occlusion is the leading cause of ischemic stroke. High blood levels of α₂-antiplasmin (a2AP), an ultrafast, covalent inhibitor of plasmin, have been linked in humans to increased risk of ischemic stroke and failure of tissue plasminogen activator (tPA) therapy. Consistent with these observations, a2AP neutralizes the therapeutic benefit of tPA therapy in experimental stroke. In addition, a2AP has deleterious, dose-related effects on ischemic brain injury in the absence of therapy. Experimental therapeutic inactivation of a2AP markedly reduces microvascular thrombosis, ischemic brain injury, brain swelling, brain hemorrhage, and death after thromboembolic stroke. These data provide new insights into the critical importance of a2AP in the pathogenesis of ischemic brain injury and suggest that transiently inactivating a2AP may have therapeutic value in ischemic stroke.

• References

• 1 Collen D. Identification and some properties of a new fast-reacting plasmin inhibitor in human plasma. Eur J Biochem 1976; 69 (1) 209-216
  CrossrefPubMedGoogle Scholar
• 2 Moroi M, Aoki N. Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis. J Biol Chem 1976; 251 (19) 5956-5965
  PubMedGoogle Scholar
• 3 Müllertz S, Clemmensen I. The primary inhibitor of plasmin in human plasma. Biochem J 1976; 159 (3) 545-553
  CrossrefPubMedGoogle Scholar
• 4 Edy J, Collen D. The interaction in human plasma of antiplasmin, the fast-reacting plasmin inhibitor, with plasmin, thrombin, trypsin and chymotrypsin. Biochim Biophys Acta 1977; 484 (2) 423-432
  CrossrefPubMedGoogle Scholar
• 5 Aoki N, Moroi M, Matsuda M, Tachiya K. The behavior of alpha2-plasmin inhibitor in fibrinolytic states. J Clin Invest 1977; 60 (2) 361-369
  CrossrefPubMedGoogle Scholar
• 6 Sakata Y, Aoki N. Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69 (3) 536-542
  CrossrefPubMedGoogle Scholar
• 7 Reed GL, Matsueda GR, Haber E. Platelet factor XIII increases the fibrinolytic resistance of platelet-rich clots by accelerating the crosslinking of alpha 2-antiplasmin to fibrin. Thromb Haemost 1992; 68 (3) 315-320
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Abdul S, Leebeek FW, Rijken DC, Uitte de Willige S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood 2016; 127 (5) 538-545
  CrossrefPubMedGoogle Scholar
• 9 Wiman B, Collen D. On the kinetics of the reaction between human antiplasmin and plasmin. Eur J Biochem 1978; 84 (2) 573-578
  CrossrefPubMedGoogle Scholar
• 10 Barker R, Kehoe PG, Love S. Activators and inhibitors of the plasminogen system in Alzheimer's disease. J Cell Mol Med 2012; 16 (4) 865-876
  CrossrefPubMedGoogle Scholar
• 11 Collen D, Wiman B. Turnover of antiplasmin, the fast-acting plasmin inhibitor of plasma. Blood 1979; 53 (2) 313-324
  CrossrefPubMedGoogle Scholar
• 12 Collen D, Bounameaux H, De Cock F, Lijnen HR, Verstraete M. Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction. Circulation 1986; 73 (3) 511-517
  CrossrefPubMedGoogle Scholar
• 13 Kluft C, Los P, Jie AF , et al. The mutual relationship between the two molecular forms of the major fibrinolysis inhibitor alpha-2-antiplasmin in blood. Blood 1986; 67 (3) 616-622
  CrossrefPubMedGoogle Scholar
• 14 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood 2010; 116 (4) 529-536
  CrossrefPubMedGoogle Scholar
• 15 Suri MF, Yamagishi K, Aleksic N, Hannan PJ, Folsom AR. Novel hemostatic factor levels and risk of ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Cerebrovasc Dis 2010; 29 (5) 497-502
  CrossrefPubMedGoogle Scholar
• 16 Feinberg WM, Macy E, Cornell ES , et al; Stroke Prevention in Atrial Fibrillation Investigators. Plasmin-alpha2-antiplasmin complex in patients with atrial fibrillation. Thromb Haemost 1999; 82 (1) 100-103
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Cucuianu M, Knauer O, Roman S. Alpha 2-antiplasmin, plasminogen activator inhibitor (PAI) and dilute blood clot lysis time in selected disease states. Thromb Haemost 1991; 66 (5) 586-591
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012; 10 (7) 1312-1319
  CrossrefPubMedGoogle Scholar
• 19 Teger-Nilsson AC, Gyzander E, Myrwold H, Noppa H, Olsson R, Wallmo L. Determination of fast-acting plasmin inhibitor (alpha2-antiplasmin) in plasma from patients with tendency to thrombosis and increased fibrinolysis. Haemostasis 1978; 7 (2–3) 155-157
  PubMedGoogle Scholar
• 20 Law RH, Sofian T, Kan WT , et al. X-ray crystal structure of the fibrinolysis inhibitor alpha2-antiplasmin. Blood 2008; 111 (4) 2049-2052
  CrossrefPubMedGoogle Scholar
• 21 Lee KN, Jackson KW, Christiansen VJ, Dolence EK, McKee PA. Enhancement of fibrinolysis by inhibiting enzymatic cleavage of precursor α2-antiplasmin. J Thromb Haemost 2011; 9 (5) 987-996
  CrossrefPubMedGoogle Scholar
• 22 Christiansen VJ, Jackson KW, Lee KN, McKee PA. The effect of a single nucleotide polymorphism on human alpha 2-antiplasmin activity. Blood 2007; 109 (12) 5286-5292
  CrossrefPubMedGoogle Scholar
• 23 Leebeek FW, Kluft C, Knot EA, Los P, Cohen AF, Six AJ. Plasmin inhibitors in the prevention of systemic effects during thrombolytic therapy: specific role of the plasminogen-binding form of alpha 2-antiplasmin. J Am Coll Cardiol 1990; 15 (6) 1212-1220
  CrossrefPubMedGoogle Scholar
• 24 Uitte de Willige S, Miedzak M, Carter AM , et al. Proteolytic and genetic variation of the alpha-2-antiplasmin C-terminus in myocardial infarction. Blood 2011; 117 (24) 6694-6701
  CrossrefPubMedGoogle Scholar
• 25 Reed III GL, Matsueda GR, Haber E. Synergistic fibrinolysis: combined effects of plasminogen activators and an antibody that inhibits alpha 2-antiplasmin. Proc Natl Acad Sci U S A 1990; 87 (3) 1114-1118
  CrossrefPubMedGoogle Scholar
• 26 Reed III GL, Singer DE, Picard EH, DeSanctis RW. Stroke following coronary-artery bypass surgery. A case-control estimate of the risk from carotid bruits. N Engl J Med 1988; 319 (19) 1246-1250
  CrossrefPubMedGoogle Scholar
• 27 Reed III GL, Matsueda GR, Haber E. Inhibition of clot-bound alpha 2-antiplasmin enhances in vivo thrombolysis. Circulation 1990; 82 (1) 164-168
  CrossrefPubMedGoogle Scholar
• 28 Butte AN, Houng AK, Jang IK, Reed GL. Alpha 2-antiplasmin causes thrombi to resist fibrinolysis induced by tissue plasminogen activator in experimental pulmonary embolism. Circulation 1997; 95 (7) 1886-1891
  CrossrefPubMedGoogle Scholar
• 29 Matsuno H, Okada K, Ueshima S, Matsuo O, Kozawa O. Alpha2-antiplasmin plays a significant role in acute pulmonary embolism. J Thromb Haemost 2003; 1 (8) 1734-1739
  CrossrefPubMedGoogle Scholar
• 30 Weitz JI, Leslie B, Hirsh J, Klement P. Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis. J Clin Invest 1993; 91 (4) 1343-1350
  CrossrefPubMedGoogle Scholar
• 31 Ho CH, Wang SP. Serial thrombolysis-related changes after thrombolytic therapy with TPA in patients with acute myocardial infarction. Thromb Res 1990; 58 (3) 331-341
  CrossrefPubMedGoogle Scholar
• 32 Rao AK, Pratt C, Berke A , et al. Thrombolysis in Myocardial Infarction (TIMI) Trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11 (1) 1-11
  CrossrefPubMedGoogle Scholar
• 33 Williams EC. Plasma alpha 2-antiplasmin activity. Role in the evaluation and management of fibrinolytic states and other bleeding disorders. Arch Intern Med 1989; 149 (8) 1769-1772
  CrossrefPubMedGoogle Scholar
• 34 Favier R, Aoki N, de Moerloose P. Congenital alpha(2)-plasmin inhibitor deficiencies: a review. Br J Haematol 2001; 114 (1) 4-10
  CrossrefPubMedGoogle Scholar
• 35 Yoshioka A, Kamitsuji H, Takase T , et al. Congenital deficiency of alpha 2-plasmin inhibitor in three sisters. Haemostasis 1982; 11 (3) 176-184
  PubMedGoogle Scholar
• 36 Harish VC, Zhang L, Huff JD, Lawson H, Owen J. Isolated antiplasmin deficiency presenting as a spontaneous bleeding disorder in a 63-year-old man. Blood Coagul Fibrinolysis 2006; 17 (8) 673-675
  CrossrefPubMedGoogle Scholar
• 37 Aoki N. The past, present and future of plasmin inhibitor. Thromb Res 2005; 116 (6) 455-464
  CrossrefPubMedGoogle Scholar
• 38 Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M. Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood 1999; 93 (7) 2274-2281
  CrossrefPubMedGoogle Scholar
• 39 Matsuno H, Kozawa O, Okada K, Ueshima S, Matsuo O, Uematsu T. Inhibitors of fibrinolytic components play different roles in the formation and removal of arterial thrombus in mice. J Cardiovasc Pharmacol 2002; 39 (2) 278-286
  CrossrefPubMedGoogle Scholar
• 40 Houng AK, Wang D, Reed GL. Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke. Exp Neurol 2014; 255: 56-62
  CrossrefPubMedGoogle Scholar
• 41 Reed GL, Houng AK, Wang D. Microvascular thrombosis, fibrinolysis, ischemic injury, and death after cerebral thromboembolism are affected by levels of circulating α2-antiplasmin. Arterioscler Thromb Vasc Biol 2014; 34 (12) 2586-2593
  CrossrefPubMedGoogle Scholar
• 42 Martí-Fàbregas J, Borrell M, Cocho D , et al. Hemostatic markers of recanalization in patients with ischemic stroke treated with rt-PA. Neurology 2005; 65 (3) 366-370
  CrossrefPubMedGoogle Scholar
• 43 Isenegger J, Meier N, Lämmle B , et al. D-dimers predict stroke subtype when assessed early. Cerebrovasc Dis 2010; 29 (1) 82-86
  CrossrefPubMedGoogle Scholar
• 44 Lane DA, Wolff S, Ireland H, Gawel M, Foadi M. Activation of coagulation and fibrinolytic systems following stroke. Br J Haematol 1983; 53 (4) 655-658
  CrossrefPubMedGoogle Scholar
• 45 Uchiyama S, Yamazaki M, Hara Y, Iwata M. Alterations of platelet, coagulation, and fibrinolysis markers in patients with acute ischemic stroke. Semin Thromb Hemost 1997; 23 (6) 535-541
  Article in Thieme ConnectPubMedGoogle Scholar
• 46 Kataoka S, Hirose G, Hori A, Shirakawa T, Saigan T. Activation of thrombosis and fibrinolysis following brain infarction. J Neurol Sci 2000; 181 (1–2) 82-88
  CrossrefPubMedGoogle Scholar
• 47 Oláh L, Misz M, Kappelmayer J , et al. Natural coagulation inhibitor proteins in young patients with cerebral ischemia. Cerebrovasc Dis 2001; 12 (4) 291-297
  CrossrefPubMedGoogle Scholar
• 48 Ono N, Koyama T, Suehiro A, Oku K, Fujikake K, Kakishita E. Clinical significance of new coagulation and fibrinolytic markers in ischemic stroke patients. Stroke 1991; 22 (11) 1369-1373
  CrossrefPubMedGoogle Scholar
• 49 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333 (24) 1581-1587
  CrossrefPubMedGoogle Scholar
• 50 Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4 (2) 228-231
  CrossrefPubMedGoogle Scholar
• 51 Nagai N, De Mol M, Lijnen HR, Carmeliet P, Collen D. Role of plasminogen system components in focal cerebral ischemic infarction: a gene targeting and gene transfer study in mice. Circulation 1999; 99 (18) 2440-2444
  CrossrefPubMedGoogle Scholar
• 52 Nagai N, De Mol M, Van Hoef B, Verstreken M, Collen D. Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization. Blood 2001; 97 (10) 3086-3092
  CrossrefPubMedGoogle Scholar
• 53 Nagai N, Vanlinthout I, Collen D. Comparative effects of tissue plasminogen activator, streptokinase, and staphylokinase on cerebral ischemic infarction and pulmonary clot lysis in hamster models. Circulation 1999; 100 (25) 2541-2546
  CrossrefPubMedGoogle Scholar
• 54 Tabrizi P, Wang L, Seeds N , et al. Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a matched genetic background. Arterioscler Thromb Vasc Biol 1999; 19 (11) 2801-2806
  CrossrefPubMedGoogle Scholar
• 55 Albers GW. Antithrombotic agents in cerebral ischemia. Am J Cardiol 1995; 75 (6) 34B-38B
  CrossrefPubMedGoogle Scholar
• 56 Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci 1989; 91 (3) 311-321
  CrossrefPubMedGoogle Scholar
• 57 Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30 (12) 2752-2758
  CrossrefPubMedGoogle Scholar
• 58 Lijnen HR, van Hoef B, Beelen V, Collen D. Characterization of the murine plasma fibrinolytic system. Eur J Biochem 1994; 224 (3) 863-871
  CrossrefPubMedGoogle Scholar
• 59 Sazonova IY, Thomas BM, Gladysheva IP, Houng AK, Reed GL. Fibrinolysis is amplified by converting alpha-antiplasmin from a plasmin inhibitor to a substrate. J Thromb Haemost 2007; 5 (10) 2087-2094
  CrossrefPubMedGoogle Scholar
• 60 Kilic E, Hermann DM, Hossmann KA. Recombinant tissue-plasminogen activator-induced thrombolysis after cerebral thromboembolism in mice. Acta Neuropathol 2000; 99 (3) 219-222
  CrossrefPubMedGoogle Scholar
• 61 Orset C, Macrez R, Young AR , et al. Mouse model of in situ thromboembolic stroke and reperfusion. Stroke 2007; 38 (10) 2771-2778
  CrossrefPubMedGoogle Scholar
• 62 Hara T, Mies G, Hossmann KA. Effect of thrombolysis on the dynamics of infarct evolution after clot embolism of middle cerebral artery in mice. J Cereb Blood Flow Metab 2000; 20 (10) 1483-1491
  CrossrefPubMedGoogle Scholar
• 63 Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008; 112 (9) 3555-3562
  CrossrefPubMedGoogle Scholar
• 64 Momi S, Tantucci M, Van Roy M, Ulrichts H, Ricci G, Gresele P. Reperfusion of cerebral artery thrombosis by the GPIb-VWF blockade with the Nanobody ALX-0081 reduces brain infarct size in guinea pigs. Blood 2013; 121 (25) 5088-5097
  CrossrefPubMedGoogle Scholar
• 65 Heye N, Paetzold C, Cervós-Navarro J. The role of microthrombi and microcirculatory factors in localization and evolution of focal cerebral ischemia. Neurosurg Rev 1991; 14 (1) 7-16
  PubMedGoogle Scholar
• 66 Okada Y, Copeland BR, Fitridge R, Koziol JA, del Zoppo GJ. Fibrin contributes to microvascular obstructions and parenchymal changes during early focal cerebral ischemia and reperfusion. Stroke 1994; 25 (9) 1847-1853 , discussion 1853–1854
  CrossrefPubMedGoogle Scholar
• 67 del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003; 23 (8) 879-894
  CrossrefPubMedGoogle Scholar
• 68 Hoffmeister HM, Szabo S, Kastner C , et al. Thrombolytic therapy in acute myocardial infarction: comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the kallikrein system and plasmin. Circulation 1998; 98 (23) 2527-2533
  CrossrefPubMedGoogle Scholar
• 69 Gross S, Janssen SW, de Vries B, Terao E, Daas A, Buchheit KH. Collaborative study for the validation of alternative in vitro potency assays for human tetanus immunoglobulin. Pharmeur Bio Sci Notes 2009; 2009 (1) 11-25
  PubMedGoogle Scholar
• 70 Singh S, Houng AK, Wang D, Reed GL. Physiologic variations in blood plasminogen levels affect outcomes after acute cerebral thromboembolism in mice: a pathophysiologic role for microvascular thrombosis. J Thromb Haemost 2016; DOI: 10.1111/jth.13390..
  PubMedGoogle Scholar
• 71 Cooper JA, Lo SK, Malik AB. Fibrin is a determinant of neutrophil sequestration in the lung. Circ Res 1988; 63 (4) 735-741
  CrossrefPubMedGoogle Scholar
• 72 Goel MS, Diamond SL. Neutrophil enhancement of fibrin deposition under flow through platelet-dependent and -independent mechanisms. Arterioscler Thromb Vasc Biol 2001; 21 (12) 2093-2098
  CrossrefPubMedGoogle Scholar
• 73 Rosell A, Cuadrado E, Ortega-Aznar A, Hernández-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008; 39 (4) 1121-1126
  CrossrefPubMedGoogle Scholar
• 74 Zhao BQ, Wang S, Kim HY , et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006; 12 (4) 441-445
  CrossrefPubMedGoogle Scholar
• 75 Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8 (1) 82-89
  CrossrefPubMedGoogle Scholar
• 76 Aoki T, Sumii T, Mori T, Wang X, Lo EH. Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke 2002; 33 (11) 2711-2717
  CrossrefPubMedGoogle Scholar
• 77 Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 2000; 20 (12) 1681-1689
  CrossrefPubMedGoogle Scholar
• 78 Reed III GL, Matsueda GR, Haber E. Acceleration of plasma clot lysis by an antibody to alpha 2-antiplasmin. Trans Assoc Am Physicians 1988; 101: 250-256
  PubMedGoogle Scholar
• 79 Mimuro J, Koike Y, Sumi Y, Aoki N. Monoclonal antibodies to discrete regions in alpha 2-plasmin inhibitor. Blood 1987; 69 (2) 446-453
  CrossrefPubMedGoogle Scholar
• 80 Reed GL. Functional characterization of monoclonal antibody inhibitors of alpha 2-antiplasmin that accelerate fibrinolysis in different animal plasmas. Hybridoma 1997; 16 (3) 281-286
  CrossrefPubMedGoogle Scholar
• 81 Reed GL, Houng AK. The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism. Circulation 1999; 99 (2) 299-304
  CrossrefPubMedGoogle Scholar
• 82 Suzuki Y, Chen F, Ni Y, Marchal G, Collen D, Nagai N. Microplasmin reduces ischemic brain damage and improves neurological function in a rat stroke model monitored with MRI. Stroke 2004; 35 (10) 2402-2406
  CrossrefPubMedGoogle Scholar
• 83 Pakola S, Cahillane G, Stassen JM, Lijnen HR, Verhamme P. Neutralization of alpha(2)-antiplasmin by microplasmin: a randomized, double-blind, placebo-controlled, ascending-dose study in healthy male volunteers. Clin Ther 2009; 31 (8) 1688-1706
  CrossrefPubMedGoogle Scholar
• 84 Thijs VN, Peeters A, Vosko M , et al. Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke. Stroke 2009; 40 (12) 3789-3795
  CrossrefPubMedGoogle Scholar
• 85 Marder VJ. Historical perspective and future direction of thrombolysis research: the re-discovery of plasmin. J Thromb Haemost 2011; 9 (Suppl. 01) 364-373
  CrossrefPubMedGoogle Scholar
• 86 Marder VJ, Jahan R, Gruber T, Goyal A, Arora V. Thrombolysis with plasmin: implications for stroke treatment. Stroke 2010; 41 (10, Suppl): S45-S49
  CrossrefPubMedGoogle Scholar
• 87 Marder VJ, Comerota AJ, Shlansky-Goldberg RD , et al. Safety of catheter-delivered plasmin in patients with acute lower extremity arterial or bypass graft occlusion: phase I results. J Thromb Haemost 2012; 10 (6) 985-991
  CrossrefPubMedGoogle Scholar
• 88 Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 2012; 11 (2) 257-266
  CrossrefPubMedGoogle Scholar