Skip to main content

Maspin and Suppression of Tumor Metastasis

  • Chapter
  • First Online:
Genetically Engineered Mice for Cancer Research
  • 1326 Accesses

Abstract

Maspin is a member of the family of Serine Protease Inhibitors or serpins. Since its discovery in 1994, considerable amount of information has been gathered regarding its role in normal tissue development and pathological processes, such as tumorigenesis and metastasis. It is now well recognized that maspin is unique serpin with tumor suppressing activities. Like many of its serpin family members, maspin possesses multiple functions, including antimigration, anti-invasion, induction of apoptosis, and anti-angiogenesis. Its functions are dependent on its cellular locations: extracellular, intracellular, mitochondria, and nucleus. This chapter covers three major topics on maspin research: biological functions of maspin, regulation of maspin gene expression, and modeling breast cancers in mice with maspin as a paradigm. Our goal is to provide readers with a comprehensive analysis of maspin study by many maspin researchers in the past few years and also with unique insights on our study of maspin functions in mouse model in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Affara NI, Coussens LM (2007) IKKalpha at the crossroads of inflammation and metastasis. Cell 129:25–26

    Article  PubMed  CAS  Google Scholar 

  • Al-Ayyoubi M, Gettins PG, Volz K (2004) Crystal structure of human maspin, a serpin with antitumor properties: reactive center loop of maspin is exposed but constrained. J Biol Chem 279:55540–55544

    Article  PubMed  CAS  Google Scholar 

  • Amir S, Margaryan NV, Odero-Marah V, Khalkhali-Ellis Z, Hendrix MJ (2005) Maspin regulates hypoxia-mediated stimulation of uPA/uPAR complex in invasive breast cancer cells. Cancer Biol Ther 4:400–406

    Article  PubMed  CAS  Google Scholar 

  • Bailey CM, Khalkhali-Ellis Z, Kondo S, Margaryan N, Seftor RE, Wheaton WW, Amir S, Pins MR, Schutte BC, Hendrix MJ (2005) Maspin binds directly to interferon regulatory factor 6: identification of a novel serpin partnership. J Biol Chem 280(40):34210–34217

    Article  PubMed  CAS  Google Scholar 

  • Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJ (2006) Biological functions of maspin. J Cell Physiol 209:617–624

    Article  PubMed  CAS  Google Scholar 

  • Biliran H Jr, Sheng S (2001) Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin. Cancer Res 61:8676–8682

    PubMed  CAS  Google Scholar 

  • Blacque OE, Worrall DM (2002) Evidence for a direct interaction between the tumour suppressor serpin maspin, and types I and III collagen. J Biol Chem 277(13):10783–10788

    Article  PubMed  CAS  Google Scholar 

  • Brouillet JP, Dufour F, Lemamy G, Garcia M, Schlup N, Grenier J, Mani JC, Rochefort H (1997) Increased cathepsin D level in the serum of patients with metastatic breast carcinoma detected with a specific pro-cathepsin D immunoassay. Cancer 79:2132–2136

    Article  PubMed  CAS  Google Scholar 

  • Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H (1989) Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res 49:3904–3909

    PubMed  CAS  Google Scholar 

  • Cella N, Contreras A, Latha K, Rosen JM, Zhang M (2006) Maspin is physically associated with [beta]1 integrin regulating cell adhesion in mammary epithelial cells. FASEB J 20:1510–1512

    Article  PubMed  CAS  Google Scholar 

  • Costello JF, Vertino PM (2002) Methylation matters: a new spin on maspin. Nat Genet 31:123–124

    Article  PubMed  CAS  Google Scholar 

  • de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37

    Article  PubMed  Google Scholar 

  • Domann FE, Rice JC, Hendrix MJ, Futscher BW (2000) Epigenetic silencing of maspin gene expression in human breast cancers. Int J Cancer 85:805–810

    Article  PubMed  CAS  Google Scholar 

  • Dyson N, Buchkovich K, Whyte P, Harlow E (1989) The cellular 107 K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell 58:249–255

    Article  PubMed  CAS  Google Scholar 

  • Ferrucci PF, Rabascio C, Gigli F, Corsini C, Giordano G, Bertolini F, Martinelli G (2007) A new comprehensive gene expression panel to study tumor micrometastasis in patients with high-risk breast cancer. Int J Oncol 30:955–962

    PubMed  CAS  Google Scholar 

  • Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, Domann FE (2002) Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet 31:175–179

    Article  PubMed  CAS  Google Scholar 

  • Hall DC, Johnson-Pais TL, Grubbs B, Bernal R, Leach RJ, Padalecki SS (2008) Maspin reduces prostate cancer metastasis to bone. Urol Oncol 26(6):652–658

    Article  PubMed  CAS  Google Scholar 

  • Hellgren I, Drvota V, Pieper R, Enoksson S, Blomberg P, Islam KB, Sylven C (2000) Highly ­efficient cell-mediated gene transfer using non-viral vectors and FuGene6: in vitro and in vivo studies. Cell Mol Life Sci 57:1326–1333

    Article  PubMed  CAS  Google Scholar 

  • Huntington JA, Read RJ, Carrell RW (2000) Structure of a serpin-protease complex shows inhibition by deformation. Nature 407:923–926

    Article  PubMed  CAS  Google Scholar 

  • Jiang N, Meng Y, Zhang S, Mensah-Osman E, Sheng S (2002) Maspin sensitizes breast carcinoma cells to induced apoptosis. Oncogene 21:4089–4098

    Article  PubMed  CAS  Google Scholar 

  • Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    Article  PubMed  CAS  Google Scholar 

  • Kelly WK, Marks PA (2005) Drug insight: histone deacetylase inhibitors – development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2:150–157

    Article  PubMed  CAS  Google Scholar 

  • Khalkhali-Ellis Z, Christian AL, Kirschmann DA, Edwards EM, Rezaie-Thompson M, Vasef MA, Gruman LM, Seftor RE, Norwood LE, Hendrix MJ (2004) Regulating the tumor suppressor gene maspin in breast cancer cells: a potential mechanism for the anticancer properties of tamoxifen. Clin Cancer Res 10:449–454

    Article  PubMed  CAS  Google Scholar 

  • Khalkhali-Ellis Z, Hendrix MJ (2003) Nitric oxide regulation of maspin expression in normal mammary epithelial and breast cancer cells. Am J Pathol 162:1411–1417

    Article  PubMed  CAS  Google Scholar 

  • Khalkhali-Ellis Z, Hendrix MJ (2007) Elucidating the function of secreted maspin: inhibiting cathepsin D-mediated matrix degradation. Cancer Res 67:3535–3539

    Article  PubMed  CAS  Google Scholar 

  • Koblinski JE, Kaplan-Singer BR, VanOsdol SJ, Wu M, Engbring JA, Wang S, Goldsmith CM, Piper JT, Vostal JG, Harms JF et al (2005) Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Res 65:7370–7377

    Article  PubMed  CAS  Google Scholar 

  • Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A et al (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285–289

    Article  PubMed  CAS  Google Scholar 

  • Latha K, Zhang W, Cella N, Shi HY, Zhang M (2005) Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition. Mol Cell Biol 25:1737–1748

    Article  PubMed  CAS  Google Scholar 

  • Law RH, Irving JA, Buckle AM, Ruzyla K, Buzza M, Bashtannyk-Puhalovich TA, Beddoe TC, Nguyen K, Margaret Worrall D, Bottomley SP et al (2005) The high resolution crystal structure of the human tumour suppressor maspin reveals a novel conformational switch in the G-helix. J Biol Chem 280(23):22356–22364

    Article  PubMed  CAS  Google Scholar 

  • Li M, Hu J, Heermeier K, Hennighausen L, Furth PA (1996) Expression of a viral oncoprotein during mammary gland development alters cell fate and function: induction of p53-independent apoptosis is followed by impaired milk protein production in surviving cells. Cell Growth Differ 7:3–11

    PubMed  CAS  Google Scholar 

  • Li M, Lewis B, Capuco AV, Laucirica R, Furth PA (2000) WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis. Oncogene 19:1010–1019

    Article  PubMed  CAS  Google Scholar 

  • Li X, Yin S, Meng Y, Sakr W, Sheng S (2006) Endogenous inhibition of histone deacetylase 1 by tumor-suppressive maspin. Cancer Res 66:9323–9329

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Schem C, Shi YH, Medina D, Zhang M (2008) Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis. Clin Exp Metastasis 25(4):389–400

    Article  PubMed  Google Scholar 

  • Li Z, Shi HY, Zhang M (2005) Targeted expression of maspin in tumor vasculatures induces endothelial cell apoptosis. Oncogene 24(12):2008–2019

    Article  PubMed  CAS  Google Scholar 

  • Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prebois C, Rochefort H, Vignon F (2006) Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett 237:167–179

    Article  PubMed  CAS  Google Scholar 

  • Liotta LA, Rao CN, Barsky SH (1983) Tumor invasion and the extracellular matrix. Lab Invest 49:636–649

    PubMed  CAS  Google Scholar 

  • Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446:690–694

    Article  PubMed  CAS  Google Scholar 

  • Maass N, Hojo T, Zhang M, Sager R, Jonat W, Nagasaki K (2000) Maspin – a novel protease inhibitor with tumor-suppressing activity in breast cancer. Acta Oncol 39:931–934

    Article  PubMed  CAS  Google Scholar 

  • Maekawa T, Sano Y, Shinagawa T, Rahman Z, Sakuma T, Nomura S, Licht JD, Ishii S (2008) ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors. Oncogene 27:1045–1054

    Article  PubMed  CAS  Google Scholar 

  • McCormick F (2001) Cancer gene therapy: fringe or cutting edge? Nat Rev Cancer 1:130–141

    Article  PubMed  CAS  Google Scholar 

  • Medina D (1996) The mammary gland: a unique organ for the study of development and tumorigenesis. J Mammary Gland Biol Neoplasia 1:5–19

    Article  PubMed  CAS  Google Scholar 

  • Medina D, Daniel C (1996) Experimental models of development, function, and neoplasia. J Mammary Gland Biol Neoplasia 1:3–4

    Article  PubMed  CAS  Google Scholar 

  • Mietz JA, Unger T, Huibregtse JM, Howley PM (1992) The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J 11:5013–5020

    PubMed  CAS  Google Scholar 

  • Ng IO, Lai EC, Ng MM, Fan ST (1992) Tumor encapsulation in hepatocellular carcinoma. A pathologic study of 189 cases. Cancer 70:45–49

    Article  PubMed  CAS  Google Scholar 

  • O’Brien T, Karlsen AE, Andersen HU, Mandrup-Poulsen T, Nerup J (1999) Absence of toxicity associated with adenoviral-mediated transfer of the beta-galactosidase reporter gene to neonatal rat islets in vitro. Diabetes Res Clin Pract 44:157–163

    Article  PubMed  Google Scholar 

  • Odero-Marah VA, Khalkhali-Ellis Z, Chunthapong J, Amir S, Seftor RE, Seftor EA, Hendrix MJ (2003) Maspin regulates different signaling pathways for motility and adhesion in aggressive breast cancer cells. Cancer Biol Ther 2:398–403

    PubMed  CAS  Google Scholar 

  • Pemberton PA, Wong DT, Gibson HL, Kiefer MC, Fitzpatrick PA, Sager R, Barr PJ (1995) The tumor suppressor maspin does not undergo the stressed to relaxed transition or inhibit trypsin-like serine proteases. Evidence that maspin is not a protease inhibitory serpin. J Biol Chem 270:15832–15837

    Article  PubMed  CAS  Google Scholar 

  • Pierson CR, McGowen R, Grignon D, Sakr W, Dey J, Sheng S (2002) Maspin is up-regulated in premalignant prostate epithelia. Prostate 53:255–262

    Article  PubMed  CAS  Google Scholar 

  • Pillai R, Coverdale LE, Dubey G, Martin CC (2004) Histone deacetylase 1 (HDAC-1) required for the normal formation of craniofacial cartilage and pectoral fins of the zebrafish. Dev Dyn 231:647–654

    Article  PubMed  CAS  Google Scholar 

  • Rahman Q, Abidi P, Afaq F, Schiffmann D, Mossman BT, Kamp DW, Athar M (1999) Glutathione redox system in oxidative lung injury. Crit Rev Toxicol 29:543–568

    Article  PubMed  CAS  Google Scholar 

  • Ren WP, Sloane BF (1996) Cathepsins D and B in breast cancer. Cancer Treat Res 83:325–352

    Article  PubMed  CAS  Google Scholar 

  • Rochlitz CF (2001) Gene therapy of cancer. Swiss Med Wkly 131:4–9

    PubMed  CAS  Google Scholar 

  • Roth JA, Cristiano RJ (1997) Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 89:21–39

    Article  PubMed  CAS  Google Scholar 

  • Sager R, Sheng S, Anisowicz A, Sotiropoulou G, Zou Z, Stenman G, Swisshelm K, Chen Z, Hendrix MJ, Pemberton P et al (1994) RNA genetics of breast cancer: maspin as paradigm. Cold Spring Harb Symp Quant Biol 59:537–546

    PubMed  CAS  Google Scholar 

  • Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R (1996) Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci USA 93:11669–11674

    Article  PubMed  CAS  Google Scholar 

  • Sherman JM, Stone EM, Freeman-Cook LL, Brachmann CB, Boeke JD, Pillus L (1999) The conserved core of a human SIR2 homologue functions in yeast silencing. Mol Biol Cell 10:3045–3059

    PubMed  CAS  Google Scholar 

  • Shi HY, Liang R, Templeton NS, Zhang M (2002) Inhibition of breast tumor progression by systemic delivery of the maspin gene in a syngeneic tumor model. Mol Ther 5:755–761

    Article  PubMed  CAS  Google Scholar 

  • Shi HY, Stafford LJ, Liu Z, Liu M, Zhang M (2007) Maspin controls mammary tumor cell migration through inhibiting Rac1 and Cdc42, but not the RhoA GTPase. Cell Motil Cytoskeleton 64:338–346

    Article  PubMed  CAS  Google Scholar 

  • Shi HY, Zhang W, Liang R, Abraham S, Kittrell FS, Medina D, Zhang M (2001) Blocking tumor growth, invasion, and metastasis by maspin in a syngeneic breast cancer model. Cancer Res 61:6945–6951

    PubMed  CAS  Google Scholar 

  • Shi HY, Zhang W, Liang R, Kittrell F, Templeton NS, Medina D, Zhang M (2003) Modeling human breast cancer metastasis in mice: maspin as a paradigm. Histol Histopathol 18:201–206

    PubMed  CAS  Google Scholar 

  • Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59:271–278

    Article  PubMed  CAS  Google Scholar 

  • Solomon LA, Munkarah AR, Schimp VL, Arabi MH, Morris RT, Nassar H, Ali-Fehmi R (2006) Maspin expression and localization impact on angiogenesis and prognosis in ovarian cancer. Gynecol Oncol 101:385–389

    Article  PubMed  CAS  Google Scholar 

  • Tanaka N, Ishihara M, Kitagawa M, Harada H, Kimura T, Matsuyama T, Lamphier MS, Aizawa S, Mak TW, Taniguchi T (1994) Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell 77:829–839

    Article  PubMed  CAS  Google Scholar 

  • Tsujimura H, Tamura T, Kong HJ, Nishiyama A, Ishii KJ, Klinman DM, Ozato K (2004) Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells. J Immunol 172:6820–6827

    PubMed  CAS  Google Scholar 

  • Tzeng YJ, Guhl E, Graessmann M, Graessmann A (1993) Breast cancer formation in transgenic animals induced by the whey acidic protein SV40 T antigen (WAP-SV-T) hybrid gene. Oncogene 8:1965–1971

    PubMed  CAS  Google Scholar 

  • Xia W, Lau YK, Hu MC, Li L, Johnston DA, Sheng S, El-Naggar A, Hung MC (2000) High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma. Oncogene 19:2398–2403

    Article  PubMed  CAS  Google Scholar 

  • Yin S, Li X, Meng Y, Finley RL Jr, Sakr W, Yang H, Reddy N, Sheng S (2005) Tumor suppressive maspin regulates cell response to oxidative stress by direct interaction with glutathione S-transferase. J Biol Chem 280(41):34985–34996

    Article  PubMed  CAS  Google Scholar 

  • Yin S, Lockett J, Meng Y, Biliran H Jr, Blouse GE, Li X, Reddy N, Zhao Z, Lin X, Anagli J et al (2006) Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system. Cancer Res 66:4173–4181

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Maass N, Magit D, Sager R (1997a) Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. Cell Growth Differ 8:179–186

    PubMed  CAS  Google Scholar 

  • Zhang M, Magit D, Botteri F, Shi Y, He K, Li M, Furth P, Sager R (1999) Maspin plays an important role in mammary gland development. Dev Biol 215:278–287

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Magit D, Sager R (1997b) Expression of maspin in prostate cells is regulated by a positive ets element and a negative hormonal responsive element site recognized by androgen receptor. Proc Natl Acad Sci USA 94:5673–5678

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Shi Y, Magit D, Furth PA, Sager R (2000a) Reduced mammary tumor progression in WAP-TAg/WAP-maspin bitransgenic mice. Oncogene 19:6053–6058

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Volpert O, Shi YH, Bouck N (2000b) Maspin is an angiogenesis inhibitor. Nat Med 6:196–199

    Article  PubMed  Google Scholar 

  • Zhang W, Shi HY, Zhang M (2005) Maspin overexpression modulates tumor cell apoptosis through the regulation of Bcl-2 family proteins. BMC Cancer 5:50

    Article  PubMed  Google Scholar 

  • Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R (1994) Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells [see comments]. Science 263:526–529

    Article  PubMed  CAS  Google Scholar 

  • Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S (2000) p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem 275:6051–6054

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ming Zhang .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Reinke, L., Zhang, M. (2012). Maspin and Suppression of Tumor Metastasis. In: Green, J., Ried, T. (eds) Genetically Engineered Mice for Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69805-2_17

Download citation

Publish with us

Policies and ethics