The Role of Annexin A2 in Tumorigenesis and Cancer Progression

Annexin A2 is a calcium-dependent, phospholipid-binding protein found on various cell types. It is up-regulated in various tumor types and plays multiple roles in regulating cellular functions, including angiogenesis, proliferation, apoptosis, cell migration, invasion and adhesion. Annexin A2 binds with plasminogen and tissue plasminogen activator on the cell surface, which leads to the conversion of plasminogen to plasmin. Plasmin is a serine protease which plays a key role in the activation of metalloproteinases and degradation of extracellular matrix components essential for metastatic progression. We have recently found that both annexin A2 and plasmin are increased in conditioned media of co cultured ovarian cancer and peritoneal cells. Our studies suggest that annexin A2 is part of a tumor-host signal pathway between ovarian cancer and peritoneal cells which promotes ovarian cancer metastasis. Accumulating evidence suggest that interactions between annexin A2 and its binding proteins play an important role in the tumor microenvironment and act together to enhance cancer metastasis. This article reviews the current knowledge on the biological role of annexin A2 and its binding proteins in solid malignancies including ovarian cancer.

[1]  P. Oh,et al.  Endothelial Caveolae Have the Molecular Transport Machinery for Vesicle Budding, Docking, and Fusion Including VAMP, NSF, SNAP, Annexins, and GTPases (*) , 1995, The Journal of Biological Chemistry.

[2]  M. Miyazaki,et al.  Annexin II Overexpression Predicts Rapid Recurrence after Surgery in Pancreatic Cancer Patients Undergoing Gemcitabine-Adjuvant Chemotherapy , 2008, Annals of surgical oncology.

[3]  R. Layfield,et al.  Annexins in human breast cancer: Possible predictors of pathological response to neoadjuvant chemotherapy. , 2009, European journal of cancer.

[4]  Y. Cho,et al.  Two-dimensional gel analysis of protein expression profile in squamous cervical cancer patients. , 2005, Gynecologic oncology.

[5]  L. Wei,et al.  Annexin A2 Regulates the Levels of Plasmin, S100A10 and Fascin in L5178Y Cells , 2008, Cancer investigation.

[6]  A. Mes-Masson,et al.  Comparative proteome analysis of human epithelial ovarian cancer , 2007, Proteome Science.

[7]  Y. Nakajima,et al.  Annexin II overexpression correlates with stromal tenascin‐C overexpression , 2001, Cancer.

[8]  G. Tuszynski,et al.  Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. , 2006, Experimental and molecular pathology.

[9]  U. Rescher,et al.  Tyrosine phosphorylation of annexin A2 regulates Rho-mediated actin rearrangement and cell adhesion , 2008, Journal of Cell Science.

[10]  K. Hajjar,et al.  An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation. , 1994, The Journal of biological chemistry.

[11]  R. Schwartz-Albiez,et al.  Collagen‐Binding proteins of mammary epithelial cells are related to Ca2+‐and phospholipid‐binding annexins , 1990, Journal of cellular physiology.

[12]  T. Yeatman,et al.  Expression of annexins on the surfaces of non-metastatic and metastatic human and rodent tumor cells , 2004, Clinical & Experimental Metastasis.

[13]  G. Tuszynski,et al.  Angiostatin binds to tyrosine kinase substrate annexin II through the lysine-binding domain in endothelial cells. , 2002, Microvascular research.

[14]  T. Enomoto,et al.  Targeting annexin A4 to counteract chemoresistance in clear cell carcinoma of the ovary , 2010, Expert opinion on therapeutic targets.

[15]  K. Hajjar,et al.  Interaction of the Fibrinolytic Receptor, Annexin II, with the Endothelial Cell Surface , 1996, The Journal of Biological Chemistry.

[16]  G. Murray,et al.  Characterisation and protein expression profiling of annexins in colorectal cancer , 2007, British Journal of Cancer.

[17]  T. Yeatman,et al.  Extracellular annexin II is associated with divalent cation‐dependent tumor cell–endothelial cell adhesion of metastatic RAW117 large‐cell lymphoma cells , 1993, Journal of cellular biochemistry.

[18]  F. Real,et al.  New Insights into the tPA-Annexin A2 Interaction , 2003, The Journal of Biological Chemistry.

[19]  J. Ramser,et al.  Chromosomal region 15q21.1 is a frequent target of allelic imbalance in advanced breast carcinomas , 2003, International journal of cancer.

[20]  Bihui Huang,et al.  Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2* , 2010, The Journal of Biological Chemistry.

[21]  H. Erickson,et al.  Mitogenesis, cell migration, and loss of focal adhesions induced by tenascin-C interacting with its cell surface receptor, annexin II. , 1996, Molecular biology of the cell.

[22]  Qing‐Yu He,et al.  Proteomic identification of malignant transformation‐related proteins in esophageal squamous cell carcinoma , 2008, Journal of cellular biochemistry.

[23]  M. Tachibana,et al.  Annexin II represents metastatic potential in clear-cell renal cell carcinoma , 2009, British Journal of Cancer.

[24]  M. Weinfeld,et al.  Expression of a releasable form of annexin II by human keratinocytes , 2002, Journal of cellular biochemistry.

[25]  Qing‐Yu He,et al.  Characterization of phosphoproteins in gastric cancer secretome. , 2011, Omics : a journal of integrative biology.

[26]  Yili Yang,et al.  Increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. , 2010, Cancer research.

[27]  Bonnie F. Sloane,et al.  Cell surface complex of cathepsin B/annexin II tetramer in malignant progression. , 2000, Biochimica et biophysica acta.

[28]  P. Hoffmann,et al.  Transforming growth factor‐beta‐induced protein secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells , 2011, International journal of cancer.

[29]  J. Frangioni,et al.  Annexin A2 Is a Molecular Target for TM601, a Peptide with Tumor-targeting and Anti-angiogenic Effects , 2009, The Journal of Biological Chemistry.

[30]  R. Ownbey,et al.  Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation. , 2010, Experimental and molecular pathology.

[31]  D. Waisman,et al.  Tyrosine Phosphorylation of Annexin II Tetramer Is Stimulated by Membrane Binding* , 1997, The Journal of Biological Chemistry.

[32]  A. Puisieux,et al.  Annexin II up-regulates cellular levels of p11 protein by a post-translational mechanisms. , 1996, The Biochemical journal.

[33]  Donald R Schwartz,et al.  Comprehensive proteome analysis of ovarian cancers using liquid phase separation, mass mapping and tandem mass spectrometry: A strategy for identification of candidate cancer biomarkers , 2004, Proteomics.

[34]  Mi Young Park,et al.  Evaluation of annexin II as a potential serum marker for hepatocellular carcinoma using a developed sandwich ELISA method. , 2009, International journal of molecular medicine.

[35]  P. Singh,et al.  Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells , 2007, Oncogene.

[36]  Pomila Singh.  Role of Annexin-II in GI cancers: interaction with gastrins/progastrins. , 2007, Cancer letters.

[37]  M. Henry,et al.  2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines. , 2011, Journal of proteomics.

[38]  F. Real,et al.  The plasminogen activator system in pancreas cancer: role of t-PA in the invasive potential in vitro , 1998, Oncogene.

[39]  S. Olwill,et al.  Annexin II cell surface and mRNA expression in human acute myeloid leukaemia cell lines. , 2005, Thrombosis research.

[40]  T. Tomonaga,et al.  Identification of Altered Protein Expression and Post-Translational Modifications in Primary Colorectal Cancer by Using Agarose Two-Dimensional Gel Electrophoresis , 2004, Clinical Cancer Research.

[41]  U. Hellman,et al.  Differential tissue-specific protein markers of vaginal carcinoma , 2009, British Journal of Cancer.

[42]  G. Tuszynski,et al.  Antibody-directed targeting of angiostatin's receptor annexin II inhibits Lewis Lung Carcinoma tumor growth via blocking of plasminogen activation: possible biochemical mechanism of angiostatin's action. , 2006, Experimental and molecular pathology.

[43]  S. Hanash,et al.  Proteomic Analysis of Ovarian Cancer Cells Reveals Dynamic Processes of Protein Secretion and Shedding of Extra-Cellular Domains , 2008, PloS one.

[44]  F. Zhong,et al.  Neuritogenesis and the Nerve Growth Factor-induced Differentiation of PC-12 Cells Requires Annexin II-mediated Plasmin Generation* , 2001, The Journal of Biological Chemistry.

[45]  V. Gerke,et al.  The tight association of the tyrosine kinase substrate annexin II with the submembranous cytoskeleton depends on intact p11- and Ca(2+)-binding sites. , 1992, Journal of cell science.

[46]  Qing‐Yu He,et al.  Proteomics of buccal squamous cell carcinoma: The involvement of multiple pathways in tumorigenesis , 2004, Proteomics.

[47]  T. Teratani,et al.  Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma , 2007, Cancer science.

[48]  Eithne Costello,et al.  S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility , 2009, British Journal of Cancer.

[49]  D. Chan,et al.  Secretion of extracellular hsp90α via exosomes increases cancer cell motility: a role for plasminogen activation , 2010, BMC Cancer.

[50]  M. Israel,et al.  Annexin II marks astrocytic brain tumors of high histologic grade. , 1994, Oncology research.

[51]  Lei Zhang,et al.  Increased expression of Annexin A2 in oral squamous cell carcinoma. , 2009, Archives of oral biology.

[52]  J. Ruan,et al.  Overexpression of Annexin II affects the proliferation, apoptosis, invasion and production of proangiogenic factors in multiple myeloma , 2009, International journal of hematology.

[53]  M. Bailly,et al.  Regulation of actin dynamics by annexin 2 , 2006, The EMBO journal.

[54]  Amit K Dinda,et al.  Expression of biomarkers modulating prostate cancer angiogenesis: Differential expression of annexin II in prostate carcinomas from India and USA , 2003, Molecular Cancer.

[55]  M. Kapoor,et al.  Evidence for Annexin II-S100A10 Complex and Plasmin in Mobilization of Cytokine Activity of Human TrpRS* , 2008, Journal of Biological Chemistry.

[56]  P. Mullen,et al.  Regulation and function of the extracellular matrix protein tenascin-C in ovarian cancer cell lines , 1999, British Journal of Cancer.

[57]  K. Miyazaki,et al.  Matrilysin (matrix metalloprotease‐7) cleaves membrane‐bound annexin II and enhances binding of tissue‐type plasminogen activator to cancer cell surfaces , 2008, The FEBS journal.

[58]  J. Bai,et al.  Involvement of Annexin A2 in p53 induced apoptosis in lung cancer , 2008, Molecular and Cellular Biochemistry.

[59]  E. Diamandis,et al.  Comprehensive analysis of conditioned media from ovarian cancer cell lines identifies novel candidate markers of epithelial ovarian cancer. , 2009, Journal of proteome research.

[60]  Graeme I Murray,et al.  Current and emerging concepts in tumour metastasis , 2010, The Journal of pathology.

[61]  D. Waisman,et al.  The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. , 1998, Biochemistry.

[62]  V. Díaz,et al.  Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro , 2004, Gut.

[63]  Mahesh C Sharma,et al.  The role of annexin II in angiogenesis and tumor progression: a potential therapeutic target. , 2007, Current pharmaceutical design.

[64]  Wei Xin,et al.  Dysregulation of the annexin family protein family is associated with prostate cancer progression. , 2003, The American journal of pathology.

[65]  S. Moss,et al.  Annexins: from structure to function. , 2002, Physiological reviews.

[66]  M. Hollingsworth,et al.  Enhanced expression of annexin II in human pancreatic carcinoma cells and primary pancreatic cancers. , 1993, Carcinogenesis.

[67]  J. Gillette,et al.  Annexin 2 expression is reduced in human osteosarcoma metastases , 2004, Journal of cellular biochemistry.

[68]  W. Paulus,et al.  Knockdown of annexin 2 decreases migration of human glioma cells in vitro , 2006, Neuropathology and applied neurobiology.

[69]  K. Pienta,et al.  Annexin II/Annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer , 2008, Journal of cellular biochemistry.

[70]  J. Vishwanatha,et al.  Signal transducer and activator of transcription 6 (STAT6) is a novel interactor of annexin A2 in prostate cancer cells. , 2010, Biochemistry.

[71]  H. Friess,et al.  Tenascin C and annexin II expression in the process of pancreatic carcinogenesis , 2006, The Journal of pathology.

[72]  Bonnie F. Sloane,et al.  Human Procathepsin B Interacts with the Annexin II Tetramer on the Surface of Tumor Cells* , 2000, The Journal of Biological Chemistry.

[73]  H. Schwarz,et al.  Analysis of Cd44-Containing Lipid Rafts , 1999, The Journal of cell biology.

[74]  O. Tysnes,et al.  Expression of annexin II in glioma cell lines and in brain tumor biopsies , 1998, Journal of Neuro-Oncology.

[75]  Y. Yang,et al.  Anxa2 plays a critical role in enhanced invasiveness of the multidrug resistant human breast cancer cells. , 2009, Journal of proteome research.

[76]  T. Ahlering,et al.  Reduced annexin II protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer. , 2007, Archives of pathology & laboratory medicine.

[77]  H. Usuki,et al.  Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma. , 2008, International journal of oncology.

[78]  T. Syrovets,et al.  Identification of the annexin A2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. , 2006, Blood.

[79]  K. Hajjar,et al.  An endothelial cell receptor for plasminogen/tissue plasminogen activator. I. Identity with annexin II. , 1994, The Journal of biological chemistry.

[80]  H. Kwaan.  The plasminogen-plasmin system in malignancy , 1992, Cancer and Metastasis Reviews.

[81]  G. Kreitzer,et al.  An Annexin 2 Phosphorylation Switch Mediates p11-dependent Translocation of Annexin 2 to the Cell Surface* , 2004, Journal of Biological Chemistry.

[82]  Bonnie F. Sloane,et al.  Live-cell imaging demonstrates extracellular matrix degradation in association with active cathepsin B in caveolae of endothelial cells during tube formation. , 2009, Experimental cell research.

[83]  Ahmed H. Tewfik,et al.  Early detection of ovarian cancer using group biomarkers , 2008, Molecular Cancer Therapeutics.

[84]  Li Mao,et al.  Identification and validation of metastasis-associated proteins in head and neck cancer cell lines by two-dimensional electrophoresis and mass spectrometry , 2004, Clinical & Experimental Metastasis.

[85]  S. Clark,et al.  Loss of annexin II heavy and light chains in prostate cancer and its precursors. , 2001, Cancer research.

[86]  J. Vishwanatha,et al.  Detection of secreted and intracellular annexin II by a radioimmunoassay. , 1995, Journal of immunological methods.

[87]  R. Chiquet‐Ehrismann,et al.  Tenascin-C induced signaling in cancer. , 2006, Cancer letters.

[88]  W. Su,et al.  Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. , 2009, Molecular biology of the cell.

[89]  G. Shen,et al.  Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator. , 2002, Thrombosis research.

[90]  Maria D Person,et al.  Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration , 2003, Oncogene.

[91]  Juan Tang,et al.  Annexin II promotes invasion and migration of human hepatocellular carcinoma cells in vitro via its interaction with HAb18G/CD147 , 2010, Cancer science.

[92]  Daniel W Chan,et al.  Suppression of annexin A11 in ovarian cancer: implications in chemoresistance. , 2009, Neoplasia.

[93]  Jianhua Wang,et al.  Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. , 2007, Blood.

[94]  M. Ranson,et al.  Plasminogen binding and cancer: promises and pitfalls. , 2003, Frontiers in bioscience : a journal and virtual library.

[95]  M. Fresno,et al.  Annexin A2 localizes to the basal epithelial layer and is down-regulated in dysplasia and head and neck squamous cell carcinoma. , 2008, Cancer Letters.

[96]  D. Alkon,et al.  Secretion of Annexin II via Activation of Insulin Receptor and Insulin-like Growth Factor Receptor* , 2003, The Journal of Biological Chemistry.

[97]  I. Ekiel,et al.  Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation* , 2005, Journal of Biological Chemistry.

[98]  M. Ohnishi,et al.  Involvement of annexin I and annexin II in hepatocyte proliferation: Can annexins I and II be markers for proliferative hepatocytes? , 1994, Hepatology.

[99]  J. Vishwanatha,et al.  Polymeric nanoparticles for sustained down-regulation of annexin A2 inhibit prostate tumor growth. , 2009, Journal of nanoscience and nanotechnology.

[100]  Tingmei Chen,et al.  Silencing of the annexin II gene down-regulates the levels of S100A10, c-Myc, and plasmin and inhibits breast cancer cell proliferation and invasion. , 2010, Saudi medical journal.

[101]  F. Hecht,et al.  Chromosomal localization of the human genes for lipocortin I and lipocortin II. , 1988, Oncogene research.

[102]  S. Mussunoor,et al.  The role of annexins in tumour development and progression , 2008, The Journal of pathology.

[103]  S. Reddy,et al.  Cloning and Characterization of the Annexin II Receptor on Human Marrow Stromal Cells* , 2006, Journal of Biological Chemistry.

[104]  J. Brooks,et al.  Angiostatin receptor annexin II in vascular tumors including angiosarcoma. , 2007, Human pathology.

[105]  D. Waisman.  Annexin II tetramer: structure and function , 1995, Molecular and Cellular Biochemistry.

[106]  M. Rosenblum,et al.  Developmental regulation of annexin II (Lipocortin 2) in human brain and expression in high grade glioma. , 1992, Cancer research.

[107]  D. Skarecky,et al.  Annexin A2 positively contributes to the malignant phenotype and secretion of IL‐6 in DU145 prostate cancer cells , 2009, International journal of cancer.

[108]  K. Hajjar,et al.  Annexin II: a mediator of the plasmin/plasminogen activator system. , 1999, Trends in cardiovascular medicine.

[109]  S. Pietschmann,et al.  Expression of annexin II in conventional renal cell carcinoma is correlated with Fuhrman grade and clinical outcome , 2004, Virchows Archiv.

[110]  A. Kazlauskas,et al.  Heat Shock Protein 90&agr;–Dependent Translocation of Annexin II to the Surface of Endothelial Cells Modulates Plasmin Activity in the Diabetic Rat Aorta , 2004, Circulation research.