在腫瘤微環境中，腫瘤相關纖維母細胞(cancer-associated fibroblasts，CAFs)對於供養腫瘤生成扮演重要的角色。CAFs透過分泌多種分子作用幫助腫瘤細胞生長、入侵以及爬行。本研究擬鑑定由CAFs所分泌的因子，並分析其對腫瘤細胞爬行及入侵能力的影響。首先我們利用老鼠胚胎纖維母細胞的條件培養液(NIH-3T3CM)促進老鼠黑色素瘤細胞的爬行。同時，相較於正常的人類纖維母細胞，腫瘤相關纖維母細胞的條件培養液(CAFCM)更能增加人類黑色素瘤細胞的爬行能力。我們進一步證明分子量大於50kDa的NIH-3T3CM以及CAFCM 才具有促進黑色素瘤細胞爬行的能力，但其不會影響細胞增生能力。藉由質譜儀的分析，我們鑑定出一個新穎因子-胎球蛋白A(fetuin-A，Fet-A)。在CAFCM中Fet-A的表現量增高，並且Fet-A會藉由結合膜連蛋白A2(annexin A2，ANXA2)使黑色素瘤細胞的爬行能力增加。而降低ANXA2的表現就能降低Fet-A所引起的黑色素瘤細胞爬行。在腫瘤樣本中我們進一步觀察到Fet-A的表現位置和CAF有一致性。而且不論利用Fet-A抗體抑制NIH-3T3CM中的Fet-A作用或是降低Fet-A在NIH-3T3中的表現量都會明顯的降低黑色素瘤細胞的爬行。此外，表面等離子體共振技術以及遠端西方點墨法都可以顯示凝血酶調節素第一功能區塊重組蛋白(recombinant thrombomodulin domain 1，rTMD1)與Fet-A有直接的交互作用。最後我們發現rTMD1可以有效抑制由Fet-A所引起的黑色素瘤細胞爬行。總括而言，本論文結果顯示由CAFs所分泌的Fet-A可增加黑色素瘤細胞的爬行能力，且rTMD1可能拮抗由Fet-A所媒介的細胞爬行。

Cancer-associated fibroblasts (CAFs) are the most important components for supporting tumorigenesis in tumor microenvironment. CAFs promote the growth, invasion and migration of cancer cells through a variety of paracrine mechanisms. In this study, we intend to identify the factor from CAFs and to analyze its paracrine effect on cancer cell migration and invasion. The conditioned medium from NIH-3T3 (NIH-3T3CM), the mouse embryonic fibroblast, induced B16F10 melanoma cell migration. In addition, the conditioned medium from CAF (CAFCM) also increased the ability of human melanoma cell migration compared to that of normal human fibroblasts. We further demonstrated that the fractions above 50 kilodalton of NIH-3T3CM and CAFCM induced melanoma cell migration but not affected its proliferation. By using mass spectrometry, we identified a novel factor, fetuin-A (Fet-A). The expression of Fet-A was up-regulated in CAFCM, and it increased the ability of melanoma cell migration via binding to annexin A2 (ANXA2). The knockdown of ANXA2 expression in melanoma cells reduced the migration of melanoma cells induced by Fet-A. We also observed that Fet-A colocalized with CAFs in tumor specimen. Moreover, the depletion of Fet-A in NIH-3T3CM with specific Fet-A antibody and knockdown of Fet-A expression in NIH-3T3 dramatically reduced melanoma cell migration. In addition, the surface plasmon resonance and Far Western experiments revealed that recombinant thrombomodulin domain 1 (rTMD1) protein directly interacted with Fet-A. Finally, we found that rTMD1 significantly inhibited Fet-A-induced melanoma cell migration. In conclusion, our results suggested that Fet-A from CAFs increases the ability of melanoma cell migration, and rTMD1 might antagonize Fet-A-mediated cell migration.

1. Kanavy, H. E., and Gerstenblith, M. R. (2011) Ultraviolet radiation and melanoma. Seminars in cutaneous medicine and surgery 30, 222-228
2. Thompson, J. F., Scolyer, R. A., and Kefford, R. F. (2005) Cutaneous melanoma. Lancet 365, 687-701
3. Jerant, A. F., Johnson, J. T., Sheridan, C. D., and Caffrey, T. J. (2000) Early detection and treatment of skin cancer. American family physician 62, 357-368, 375-356, 381-352
4. Miller, A. J., and Mihm, M. C., Jr. (2006) Melanoma. The New England journal of medicine 355, 51-65
5. Gray-Schopfer, V., Wellbrock, C., and Marais, R. (2007) Melanoma biology and new targeted therapy. Nature 445, 851-857
6. Rodemann, H. P., and Muller, G. A. (1991) Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. American journal of kidney diseases : the official journal of the National Kidney Foundation 17, 684-686
7. Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C., and Brown, R. A. (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature reviews. Molecular cell biology 3, 349-363
8. Chang, H. Y., Chi, J. T., Dudoit, S., Bondre, C., van de Rijn, M., Botstein, D., and Brown, P. O. (2002) Diversity, topographic differentiation, and positional memory in human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 99, 12877-12882
9. Kalluri, R. (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nature reviews. Cancer 3, 422-433
10. Ronnov-Jessen, L., Petersen, O. W., and Bissell, M. J. (1996) Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiological reviews 76, 69-125
11. Mishra, P., Banerjee, D., and Ben-Baruch, A. (2011) Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy. Journal of leukocyte biology 89, 31-39
12. Park, C. C., Bissell, M. J., and Barcellos-Hoff, M. H. (2000) The influence of the microenvironment on the malignant phenotype. Molecular medicine today 6, 324-329
13. Dimanche-Boitrel, M. T., Vakaet, L., Jr., Pujuguet, P., Chauffert, B., Martin, M. S., Hammann, A., Van Roy, F., Mareel, M., and Martin, F. (1994) In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of tumor-associated myofibroblasts. International journal of cancer. Journal international du cancer 56, 512-521
14. Bucala, R., Ritchlin, C., Winchester, R., and Cerami, A. (1991) Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. The Journal of experimental medicine 173, 569-574
15. Li, H., Fan, X., and Houghton, J. (2007) Tumor microenvironment: the role of the tumor stroma in cancer. Journal of cellular biochemistry 101, 805-815
16. Garin-Chesa, P., Old, L. J., and Rettig, W. J. (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proceedings of the National Academy of Sciences of the United States of America 87, 7235-7239
17. De Wever, O., Demetter, P., Mareel, M., and Bracke, M. (2008) Stromal myofibroblasts are drivers of invasive cancer growth. International journal of cancer. Journal international du cancer 123, 2229-2238
18. Giannoni, E., Bianchini, F., Masieri, L., Serni, S., Torre, E., Calorini, L., and Chiarugi, P. (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer research 70, 6945-6956
19. Xing, F., Saidou, J., and Watabe, K. (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Frontiers in bioscience 15, 166-179
20. Kalluri, R., and Zeisberg, M. (2006) Fibroblasts in cancer. Nature reviews. Cancer 6, 392-401
21. Orimo, A., and Weinberg, R. A. (2006) Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell cycle 5, 1597-1601
22. Micke, P., and Ostman, A. (2004) Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung cancer 45 Suppl 2, S163-175
23. Loeffler, M., Kruger, J. A., Niethammer, A. G., and Reisfeld, R. A. (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. The Journal of clinical investigation 116, 1955-1962
24. Cornil, I., Theodorescu, D., Man, S., Herlyn, M., Jambrosic, J., and Kerbel, R. S. (1991) Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression. Proceedings of the National Academy of Sciences of the United States of America 88, 6028-6032
25. Ruiter, D., Bogenrieder, T., Elder, D., and Herlyn, M. (2002) Melanoma-stroma interactions: structural and functional aspects. The lancet oncology 3, 35-43
26. Lazar-Molnar, E., Hegyesi, H., Toth, S., and Falus, A. (2000) Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12, 547-554
27. Berking, C., Takemoto, R., Schaider, H., Showe, L., Satyamoorthy, K., Robbins, P., and Herlyn, M. (2001) Transforming growth factor-beta1 increases survival of human melanoma through stroma remodeling. Cancer research 61, 8306-8316
28. Lee, J. T., and Herlyn, M. (2007) Microenvironmental influences in melanoma progression. Journal of cellular biochemistry 101, 862-872
29. Villanueva, J., and Herlyn, M. (2008) Melanoma and the tumor microenvironment. Current oncology reports 10, 439-446
30. Li, L., Dragulev, B., Zigrino, P., Mauch, C., and Fox, J. W. (2009) The invasive potential of human melanoma cell lines correlates with their ability to alter fibroblast gene expression in vitro and the stromal microenvironment in vivo. International journal of cancer. Journal international du cancer 125, 1796-1804
31. Dziegielewska, K. M., Brown, W. M., Casey, S. J., Christie, D. L., Foreman, R. C., Hill, R. M., and Saunders, N. R. (1990) The complete cDNA and amino acid sequence of bovine fetuin. Its homology with alpha 2HS glycoprotein and relation to other members of the cystatin superfamily. The Journal of biological chemistry 265, 4354-4357
32. Schafer, C., Heiss, A., Schwarz, A., Westenfeld, R., Ketteler, M., Floege, J., Muller-Esterl, W., Schinke, T., and Jahnen-Dechent, W. (2003) The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. The Journal of clinical investigation 112, 357-366
33. Denecke, B., Graber, S., Schafer, C., Heiss, A., Woltje, M., and Jahnen-Dechent, W. (2003) Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. The Biochemical journal 376, 135-145
34. Olivier, E., Soury, E., Ruminy, P., Husson, A., Parmentier, F., Daveau, M., and Salier, J. P. (2000) Fetuin-B, a second member of the fetuin family in mammals. The Biochemical journal 350 Pt 2, 589-597
35. Dziegielewska, K. M., Mollgard, K., Reynolds, M. L., and Saunders, N. R. (1987) A fetuin-related glycoprotein (alpha 2HS) in human embryonic and fetal development. Cell and tissue research 248, 33-41
36. Brown, W. M., Saunders, N. R., Mollgard, K., and Dziegielewska, K. M. (1992) Fetuin--an old friend revisited. BioEssays : news and reviews in molecular, cellular and developmental biology 14, 749-755
37. Ochieng, J., and Chaudhuri, G. (2010) Cystatin superfamily. Journal of health care for the poor and underserved 21, 51-70
38. Yoshioka, Y., Gejyo, F., Marti, T., Rickli, E. E., Burgi, W., Offner, G. D., Troxler, R. F., and Schmid, K. (1986) The complete amino acid sequence of the A-chain of human plasma alpha 2HS-glycoprotein. The Journal of biological chemistry 261, 1665-1676
39. Haglund, A. C., Ek, B., and Ek, P. (2001) Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein (human fetuin) in vivo. The Biochemical journal 357, 437-445
40. Gejyo, F., Chang, J. L., Burgi, W., Schmid, K., Offner, G. D., Troxler, R. F., Van Halbeek, H., Dorland, L., Gerwig, G. J., and Vliegenthart, J. F. (1983) Characterization of the B-chain of human plasma alpha 2HS-glycoprotein. The complete amino acid sequence and primary structure of its heteroglycan. The Journal of biological chemistry 258, 4966-4971
41. Guillory, B., Sakwe, A. M., Saria, M., Thompson, P., Adhiambo, C., Koumangoye, R., Ballard, B., Binhazim, A., Cone, C., Jahanen-Dechent, W., and Ochieng, J. (2010) Lack of fetuin-A (alpha2-HS-glycoprotein) reduces mammary tumor incidence and prolongs tumor latency via the transforming growth factor-beta signaling pathway in a mouse model of breast cancer. The American journal of pathology 177, 2635-2644
42. Demetriou, M., Binkert, C., Sukhu, B., Tenenbaum, H. C., and Dennis, J. W. (1996) Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist. The Journal of biological chemistry 271, 12755-12761
43. Pal, D., Dasgupta, S., Kundu, R., Maitra, S., Das, G., Mukhopadhyay, S., Ray, S., Majumdar, S. S., and Bhattacharya, S. (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nature medicine 18, 1279-1285
44. Rasul, S., Wagner, L., and Kautzky-Willer, A. (2012) Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus. Endocrine 42, 496-505
45. Kundranda, M. N., Ray, S., Saria, M., Friedman, D., Matrisian, L. M., Lukyanov, P., and Ochieng, J. (2004) Annexins expressed on the cell surface serve as receptors for adhesion to immobilized fetuin-A. Biochimica et biophysica acta 1693, 111-123
46. Sakwe, A. M., Koumangoye, R., Goodwin, S. J., and Ochieng, J. (2010) Fetuin-A ({alpha}2HS-glycoprotein) is a major serum adhesive protein that mediates growth signaling in breast tumor cells. The Journal of biological chemistry 285, 41827-41835
47. Kundranda, M. N., Henderson, M., Carter, K. J., Gorden, L., Binhazim, A., Ray, S., Baptiste, T., Shokrani, M., Leite-Browning, M. L., Jahnen-Dechent, W., Matrisian, L. M., and Ochieng, J. (2005) The serum glycoprotein fetuin-A promotes Lewis lung carcinoma tumorigenesis via adhesive-dependent and adhesive-independent mechanisms. Cancer research 65, 499-506
48. Yi, J. K., Chang, J. W., Han, W., Lee, J. W., Ko, E., Kim, D. H., Bae, J. Y., Yu, J., Lee, C., Yu, M. H., and Noh, D. Y. (2009) Autoantibody to tumor antigen, alpha 2-HS glycoprotein: a novel biomarker of breast cancer screening and diagnosis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 18, 1357-1364
49. Nangami, G. N., Watson, K., Parker-Johnson, K., Okereke, K. O., Sakwe, A., Thompson, P., Frimpong, N., and Ochieng, J. (2013) Fetuin-A (alpha2HS-glycoprotein) is a serum chemo-attractant that also promotes invasion of tumor cells through Matrigel. Biochemical and biophysical research communications 438, 660-665
50. Esmon, C. T. (1993) Molecular events that control the protein C anticoagulant pathway. Thrombosis and haemostasis 70, 29-35
51. Conway, E. M. (2012) Thrombomodulin and its role in inflammation. Seminars in immunopathology 34, 107-125
52. Tracy, P. B. (1988) Regulation of thrombin generation at cell surfaces. Seminars in thrombosis and hemostasis 14, 227-233
53. Kim, S. J., Shiba, E., Ishii, H., Inoue, T., Taguchi, T., Tanji, Y., Kimoto, Y., Izukura, M., and Takai, S. (1997) Thrombomodulin is a new biological and prognostic marker for breast cancer: an immunohistochemical study. Anticancer research 17, 2319-2323
54. Hanly, A. M., Redmond, M., Winter, D. C., Brophy, S., Deasy, J. M., Bouchier-Hayes, D. J., and Kay, E. W. (2006) Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival. British journal of cancer 94, 1320-1325
55. Tabata, M., Sugihara, K., Yonezawa, S., Yamashita, S., and Maruyama, I. (1997) An immunohistochemical study of thrombomodulin in oral squamous cell carcinoma and its association with invasive and metastatic potential. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 26, 258-264
56. Suehiro, T., Shimada, M., Matsumata, T., Taketomi, A., Yamamoto, K., and Sugimachi, K. (1995) Thrombomodulin inhibits intrahepatic spread in human hepatocellular carcinoma. Hepatology 21, 1285-1290
57. Tezuka, Y., Yonezawa, S., Maruyama, I., Matsushita, Y., Shimizu, T., Obama, H., Sagara, M., Shirao, K., Kusano, C., Natsugoe, S., and et al. (1995) Expression of thrombomodulin in esophageal squamous cell carcinoma and its relationship to lymph node metastasis. Cancer research 55, 4196-4200
58. Appleton, M. A., Attanoos, R. L., and Jasani, B. (1996) Thrombomodulin as a marker of vascular and lymphatic tumours. Histopathology 29, 153-157
59. Lindahl, A. K., Boffa, M. C., and Abildgaard, U. (1993) Increased plasma thrombomodulin in cancer patients. Thrombosis and haemostasis 69, 112-114
60. Furuta, J., Kaneda, A., Umebayashi, Y., Otsuka, F., Sugimura, T., and Ushijima, T. (2005) Silencing of the thrombomodulin gene in human malignant melanoma. Melanoma research 15, 15-20
61. Zhang, Y., Weiler-Guettler, H., Chen, J., Wilhelm, O., Deng, Y., Qiu, F., Nakagawa, K., Klevesath, M., Wilhelm, S., Bohrer, H., Nakagawa, M., Graeff, H., Martin, E., Stern, D. M., Rosenberg, R. D., Ziegler, R., and Nawroth, P. P. (1998) Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity. The Journal of clinical investigation 101, 1301-1309
62. Nakano, M., Furutani, M., Hiraishi, S., and Ishii, H. (1998) Characterization of soluble thrombomodulin fragments in human urine. Thrombosis and haemostasis 79, 331-337
63. Ishii, H., and Majerus, P. W. (1985) Thrombomodulin is present in human plasma and urine. The Journal of clinical investigation 76, 2178-2181
64. Hosaka, Y., Higuchi, T., Tsumagari, M., and Ishii, H. (2000) Inhibition of invasion and experimental metastasis of murine melanoma cells by human soluble thrombomodulin. Cancer letters 161, 231-240
65. Wang, C. Y., and Lin, C. F. (2014) Annexin A2: its molecular regulation and cellular expression in cancer development. Disease markers 2014, 308976
66. Jahnen-Dechent, W., Heiss, A., Schafer, C., and Ketteler, M. (2011) Fetuin-A regulation of calcified matrix metabolism. Circulation research 108, 1494-1509
67. Chen, N. X., O'Neill, K. D., Chen, X., Duan, D., Wang, E., Sturek, M. S., Edwards, J. M., and Moe, S. M. (2007) Fetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins. American journal of physiology. Renal physiology 292, F599-606
68. Sharma, M. R., Koltowski, L., Ownbey, R. T., Tuszynski, G. P., and Sharma, M. C. (2006) Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Experimental and molecular pathology 81, 146-156
69. Sharma, M., Blackman, M. R., and Sharma, M. C. (2012) Antibody-directed neutralization of annexin II (ANX II) inhibits neoangiogenesis and human breast tumor growth in a xenograft model. Experimental and molecular pathology 92, 175-184
70. Ohno, Y., Izumi, M., Kawamura, T., Nishimura, T., Mukai, K., and Tachibana, M. (2009) Annexin II represents metastatic potential in clear-cell renal cell carcinoma. British journal of cancer 101, 287-294
71. Emoto, K., Sawada, H., Yamada, Y., Fujimoto, H., Takahama, Y., Ueno, M., Takayama, T., Uchida, H., Kamada, K., Naito, A., Hirao, S., and Nakajima, Y. (2001) Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer research 21, 1339-1345
72. Jia, J. W., Li, K. L., Wu, J. X., and Guo, S. L. (2013) Clinical significance of annexin II expression in human non-small cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 34, 1767-1771
73. Wang, Y. X., Lv, H., Li, Z. X., Li, C., and Wu, X. Y. (2012) Effect of shRNA mediated down-regulation of Annexin A2 on biological behavior of human lung adencarcinoma cells A549. Pathology oncology research : POR 18, 183-190
74. Rodrigo, J. P., Lequerica-Fernandez, P., Rosado, P., Allonca, E., Garcia-Pedrero, J. M., and de Vicente, J. C. (2011) Clinical significance of annexin A2 downregulation in oral squamous cell carcinoma. Head & neck 33, 1708-1714
75. Vishwanatha, J. K., Chiang, Y., Kumble, K. D., Hollingsworth, M. A., and Pour, P. M. (1993) Enhanced expression of annexin II in human pancreatic carcinoma cells and primary pancreatic cancers. Carcinogenesis 14, 2575-2579
76. Spijkers-Hagelstein, J. A., Mimoso Pinhancos, S., Schneider, P., Pieters, R., and Stam, R. W. (2013) Src kinase-induced phosphorylation of annexin A2 mediates glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia 27, 1063-1071
77. Zheng, L., Foley, K., Huang, L., Leubner, A., Mo, G., Olino, K., Edil, B. H., Mizuma, M., Sharma, R., Le, D. T., Anders, R. A., Illei, P. B., Van Eyk, J. E., Maitra, A., Laheru, D., and Jaffee, E. M. (2011) Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer. PloS one 6, e19390
78. Nedjadi, T., Kitteringham, N., Campbell, F., Jenkins, R. E., Park, B. K., Navarro, P., Ashcroft, F., Tepikin, A., Neoptolemos, J. P., and Costello, E. (2009) S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility. British journal of cancer 101, 1145-1154
79. Roda, O., Valero, M. L., Peiro, S., Andreu, D., Real, F. X., and Navarro, P. (2003) New insights into the tPA-annexin A2 interaction. Is annexin A2 CYS8 the sole requirement for this association? The Journal of biological chemistry 278, 5702-5709
80. Madureira, P. A., Hill, R., Lee, P. W., and Waisman, D. M. (2012) Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage. PloS one 7, e50591
81. Deora, A. B., Kreitzer, G., Jacovina, A. T., and Hajjar, K. A. (2004) An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. The Journal of biological chemistry 279, 43411-43418
82. de Graauw, M., Tijdens, I., Smeets, M. B., Hensbergen, P. J., Deelder, A. M., and van de Water, B. (2008) Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin Activation. Molecular and cellular biology 28, 1029-1040
83. Shetty, P. K., Thamake, S. I., Biswas, S., Johansson, S. L., and Vishwanatha, J. K. (2012) Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer. PloS one 7, e44299
84. Mohammad, H. S., Kurokohchi, K., Yoneyama, H., Tokuda, M., Morishita, A., Jian, G., Shi, L., Murota, M., Tani, J., Kato, K., Miyoshi, H., Deguchi, A., Himoto, T., Usuki, H., Wakabayashi, H., Izuishi, K., Suzuki, Y., Iwama, H., Deguchi, K., Uchida, N., Sabet, E. A., Arafa, U. A., Hassan, A. T., El-Sayed, A. A., and Masaki, T. (2008) Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma. International journal of oncology 33, 1157-1163
85. Wang, Y. Q., Zhang, F., Tian, R., Ji, W., Zhou, Y., Sun, X. M., Liu, Y., Wang, Z. Y., and Niu, R. F. (2012) Tyrosine 23 Phosphorylation of Annexin A2 Promotes Proliferation, Invasion, and Stat3 Phosphorylation in the Nucleus of Human Breast Cancer SK-BR-3 Cells. Cancer biology & medicine 9, 248-253
86. Domoto, T., Miyama, Y., Suzuki, H., Teratani, T., Arai, K., Sugiyama, T., Takayama, T., Mugiya, S., Ozono, S., and Nozawa, R. (2007) Evaluation of S100A10, annexin II and B-FABP expression as markers for renal cell carcinoma. Cancer science 98, 77-82
87. Reeves, S. A., Chavez-Kappel, C., Davis, R., Rosenblum, M., and Israel, M. A. (1992) Developmental regulation of annexin II (Lipocortin 2) in human brain and expression in high grade glioma. Cancer research 52, 6871-6876
88. Zhang, Q., Ye, Z., Yang, Q., He, X., Wang, H., and Zhao, Z. (2012) Upregulated expression of annexin II is a prognostic marker for patients with gastric cancer. World journal of surgical oncology 10, 103
89. Cardone, A., Tolino, A., Zarcone, R., Borruto Caracciolo, G., and Tartaglia, E. (1997) Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva medica 39, 174-177
90. Maeshima, A. M., Niki, T., Maeshima, A., Yamada, T., Kondo, H., and Matsuno, Y. (2002) Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer 95, 2546-2554
91. Bhola, N. E., Balko, J. M., Dugger, T. C., Kuba, M. G., Sanchez, V., Sanders, M., Stanford, J., Cook, R. S., and Arteaga, C. L. (2013) TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. The Journal of clinical investigation 123, 1348-1358
92. Ferrara, N., Hillan, K. J., Gerber, H. P., and Novotny, W. (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature reviews. Drug discovery 3, 391-400
93. Hu-Lowe, D. D., Zou, H. Y., Grazzini, M. L., Hallin, M. E., Wickman, G. R., Amundson, K., Chen, J. H., Rewolinski, D. A., Yamazaki, S., Wu, E. Y., McTigue, M. A., Murray, B. W., Kania, R. S., O'Connor, P., Shalinsky, D. R., and Bender, S. L. (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 7272-7283
94. Cecchi, F., Rabe, D. C., and Bottaro, D. P. (2012) Targeting the HGF/Met signaling pathway in cancer therapy. Expert opinion on therapeutic targets 16, 553-572
95. Dezube, B. J., Krown, S. E., Lee, J. Y., Bauer, K. S., and Aboulafia, D. M. (2006) Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS Malignancy Consortium Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24, 1389-1394
96. Saftig, P., Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W., Moritz, J. D., Schu, P., and von Figura, K. (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 95, 13453-13458
97. Reardon, D. A., Quinn, J. A., Akabani, G., Coleman, R. E., Friedman, A. H., Friedman, H. S., Herndon, J. E., 2nd, McLendon, R. E., Pegram, C. N., Provenzale, J. M., Dowell, J. M., Rich, J. N., Vredenburgh, J. J., Desjardins, A., Sampson, J. H., Gururangan, S., Wong, T. Z., Badruddoja, M. A., Zhao, X. G., Bigner, D. D., and Zalutsky, M. R. (2006) Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 47, 912-918