With the recognition that WASP/WAVE proteins are intrinsically involved in cell motility through regulation of actin polymerization, there has come the realization that this family could be involved in the motility of cancer cells and their invasive and metastatic potential.
There have since been numerous investigations into the role of the WASP/WAVE family proteins in development of cancer.
The evidence presented here confirms that WASP/WAVE proteins are linked to the migratory, invasive, and metastatic behavior of numerous cell types, including breast cancer cells, which have been the main focus of this review.
A link between WASP/WAVE activity and the clinical outcome for breast cancer patients has also been described. Although recent studies have started to implicate the activators and pathways through which WASP/WAVEs may act to influence the behavior of cancer cells, further studies are required to fully elucidate which of the factors that regulate this family may be responsible for their role in cancer progression.
Through doing so, we can target the WASP/WAVE family or the pathways that they are a part of in the hope of controlling the invasive and metastatic cell behavior that they have been implicated in.
Many reports have highlighted the potential of targeting the WASP/WAVE family as a therapy for cancer progression, in particular breast cancer.
It is important to determine the molecular mechanisms of WASP/WAVE activity and their exact contributions to the stages of cancer progression, thereby opening the door for development of anticancer drugs targeting the WASP/WAVE family and related pathways.
This work was supported by two sponsors, ie, the Life Science Research Network Wales, an initiative funded through Welsh Government’s Sêr Cymru programme, and Cancer Research Wales.
The authors report that they have no conflicts of interest associated with this work.
Bethan Frugtniet, Wen G. Jiang, Tracey A. Martin
Cardiff-China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
Correspondence: Tracey A MartinCardiff-China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK.
Tel +44 29 2068 7209
E-mail: [email protected]
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
- Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014;64:9–29.
- Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12:895–904.
- Ridley AJ, Schwartz MA, Burridge K, et al. Cell migration: integrating signals from front to back. Science. 2003;302:1704–1709.
- Linder S, Wiesner C, Himmel M. Degrading devices: invadosomes in proteolytic cell invasion. Annu Rev Cell Dev Biol. 2011;27:185–211.
- Ridley AJ. Life at the leading edge. Cell. 2011;145:1012–1022.
- Insall RH, Machesky LM. Actin dynamics at the leading edge: from simple machinery to complex networks. Dev Cell. 2009;17:310–322.
- Raftopoulou M, Hall A. Cell migration: Rho GTPases lead the way. Dev Biol. 2004;265:23–32.
- Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol. 2007;8: 37–48.
- Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773: 642–652.
- Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 1994;78:635–644.
- Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954;13:133–139.
- Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125: 876–885.
- Orange JS, Stone KD, Turvey SE, Krzewski K. The Wiskott-Aldrich syndrome. Cell Mol Life Sci. 2004;61:2361–2385.
- Zhu Q, Watanabe C, Liu T, et al. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood. 1997;90:2680–2689.
- Miki H, Miura K, Takenawa T. N-WASP, a novel actin-depolymerizing protein, regulates the cortical cytoskeletal rearrangement in a PIP2-dependent manner downstream of tyrosine kinases. EMBO J. 1996;15: 5326–5335.
- Miki H, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J. 1998;17:6932–6941.
- Machesky LM, Insall RH. Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr Biol. 1998;8:1347–1356.
- Suetsugu S, Miki H, Takenawa T. Identification of two human WAVE/SCAR homologues as general actin regulatory molecules which associate with the Arp2/3 complex. Biochem Biophys Res Commun. 1999;260: 296–302.
- Linardopoulou EV, Parghi SS, Friedman C, Osborn GE, Parkhurst SM, Trask BJ. Human subtelomeric WASH genes encode a new subclass of the WASP family. PLoS Genet. 2007;3:e237.
- Campellone KG, Webb NJ, Znameroski EA, Welch MD. WHAMM is an Arp2/3 complex activator that binds microtubules and functions in ER to Golgi transport. Cell. 2008;134:148–161.
- Zuchero JB, Coutts AS, Quinlan ME, Thangue NB, Mullins RD. p53-cofactor JMY is a multifunctional actin nucleation factor. Nat Cell Biol. 2009;11:451–459.
- Takenawa T, Miki H. WASP and WAVE family proteins. key molecules for rapid rearrangement of cortical actin filaments and cell movement. J Cell Sci. 2001;114:1801–1809.
- Eden S, Rohatgi R, Podtelejnikov AV, Mann M, Kirschner MW. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature. 2002;418:790–793.
- Gautreau A, Ho HY, Li J, Steen H, Gygi SP, Kirschner MW. Purification and architecture of the ubiquitous Wave complex. Proc Natl Acad Sci U S A. 2004;101:4379–4383.
- Stovold CF, Millard TH, Machesky LM. Inclusion of Scar/WAVE3 in a similar complex to Scar/WAVE1 and 2. BMC Cell Biol. 2005;6:11.
- Innocenti M, Zucconi A, Disanza A, et al. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol. 2004;6:319–327.
- Rohatgi R, Ma L, Miki H, et al. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell. 1999;97:221–231.
- Yarar D, To W, Abo A, Welch MD. The Wiskott-Aldrich syndrome protein directs actin-based motility by stimulating actin nucleation with the Arp2/3 complex. Curr Biol. 1999;9:555–558.
- Kim AS, Kakalis LT, Abdul-Manan N, Liu GA, Rosen MK. Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature. 2000;404:151–158.
- Miki H, Sasaki T, Takai Y, Takenawa T. Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP. Nature. 1998;391:93–96.
- Prehoda KE, Scott JA, Mullins RD, Lim WA. Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. Science. 2000;290:801–806.
- Rohatgi R, Ho HY, Kirschner MW. Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate. J Cell Biol. 2000;150:1299–1310.
- Derivery E, Lombard B, Loew D, Gautreau A. The Wave complex is intrinsically inactive. Cell Motil Cytoskeleton. 2009;66:777–790.
- Ismail AM, Padrick SB, Chen B, Umetani J, Rosen MK. The WAVE regulatory complex is inhibited. Nat Struct Mol Biol. 2009;16:561–563.
- Lebensohn AM, Kirschner MW. Activation of the WAVE complex by coincident signals controls actin assembly. Mol Cell. 2009;36: 512–524.
- Oikawa T, Yamaguchi H, Itoh T, et al. PtdIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia. Nat Cell Biol. 2004;6:420–426.
- Suetsugu S, Kurisu S, Oikawa T, Yamazaki D, Oda A, Takenawa T. Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac. J Cell Biol. 2006;173: 571–585.
- Derivery E, Gautreau A. Generation of branched actin networks: assembly and regulation of the N-WASP and WAVE molecular machines. Bioessays. 2010;32:119–131.
- Euteneuer U, Schliwa M. Persistent, directional motility of cells and cytoplasmic fragments in the absence of microtubules. Nature. 1984;310:58–61.
- Nemethova M, Auinger S, Small JV. Building the actin cytoskeleton: filopodia contribute to the construction of contractile bundles in the lamella. J Cell Biol. 2008;180:1233–1244.
- Galbraith CG, Yamada KM, Galbraith JA. Polymerizing actin fibers position integrins primed to probe for adhesion sites. Science. 2007;315: 992–995.
- Welch MD, Mullins RD. Cellular control of actin nucleation. Annu Rev Cell Dev Biol. 2002;18:247–288.
- Chhabra ES, Higgs HN. The many faces of actin: matching assembly factors with cellular structures. Nat Cell Biol. 2007;9:1110–1121.
- Lommel S, Benesch S, Rottner K, Franz T, Wehland J, Kuhn R. Actin pedestal formation by enteropathogenic Escherichia coli and intracellular motility of Shigella flexneri are abolished in N-WASP-defective cells. EMBO Rep. 2001;2:850–857.
- Lorenz M, Yamaguchi H, Wang Y, Singer RH, Condeelis J. Imaging sites of N-wasp activity in lamellipodia and invadopodia of carcinoma cells. Curr Biol. 2004;14:697–703.
- Kawamura K, Takano K, Suetsugu S, et al. N-WASP and WAVE2 acting downstream of phosphatidylinositol 3-kinase are required for myogenic cell migration induced by hepatocyte growth factor. J Biol Chem. 2004;279:54862–54871.
- Le Clainche C, Schlaepfer D, Ferrari A, et al. IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway. J Biol Chem. 2007;282:426–435.
- Snapper SB, Takeshima F, Anton I, et al. N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility. Nat Cell Biol. 2001;3:897–904.
- Innocenti M, Gerboth S, Rottner K, et al. Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nat Cell Biol. 2005;7:969–976.
- Rogers SL, Wiedemann U, Stuurman N, Vale RD. Molecular requirements for actin-based lamella formation in Drosophila S2 cells. J Cell Biol. 2003;162:1079–1088.
- Suetsugu S, Yamazaki D, Kurisu S, Takenawa T. Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev Cell. 2003;5:595–609.
- Krause M, Gautreau A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol. 2014;15:577–590.
- Yamazaki D, Suetsugu S, Miki H, et al. WAVE2 is required for directed cell migration and cardiovascular development. Nature. 2003;424: 452–456.
- Kurisu S, Suetsugu S, Yamazaki D, Yamaguchi H, Takenawa T. Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene. 2005;24: 1309–1319.
- Kheir WA, Gevrey JC, Yamaguchi H, Isaac B, Cox D. A WAVE2-Abi1 complex mediates CSF-1-induced F-actin-rich membrane protrusions and migration in macrophages. J Cell Sci. 2005;118:5369–5379.
- Friedl P, Wolf K. Tumor-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–374.
- Tang H, Li A, Bi J, et al. Loss of Scar/WAVE complex promotes N-WASP- and FAK-dependent invasion. Curr Biol. 2013;23:107–117.
- Buccione R, Orth JD, McNiven MA. Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol. 2004;5: 647–657.
- Yamaguchi H, Lorenz M, Kempiak S, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol. 2005;168:441–452.
- Oser M, Yamaguchi H, Mader CC, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol. 2009;186:571–587.
- Mizutani K, Miki H, He H, Maruta H, Takenawa T. Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer Res. 2002;62:669–674.
- Gligorijevic B, Wyckoff J, Yamaguchi H, Wang Y, Roussos ET, Condeelis J. N-WASP-mediated invadopodium formation is involved in intravasation and lung metastasis of mammary tumors. J Cell Sci. 2012;125:724–734.
- Coopman PJ, Do MT, Thompson EW, Mueller SC. Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. Clin Cancer Res. 1998;4:507–515.
- Yang LY, Tao YM, Ou DP, Wang W, Chang ZG, Wu F. Increased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 correlated with poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2006;12:5673–5679.
- Semba S, Iwaya K, Matsubayashi J, et al. Coexpression of actin-related protein 2 and Wiskott-Aldrich syndrome family verproline-homologous protein 2 in adenocarcinoma of the lung. Clin Cancer Res. 2006;12:2449–2454.
- Iwaya K, Oikawa K, Semba S, et al. Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma. Cancer Sci. 2007;98:992–999.
- Fernando HS, Sanders AJ, Kynaston HG, Jiang WG. WAVE3 is associated with invasiveness in prostate cancer cells. Urol Oncol. 2010;28: 320–327.
- Fernando HS, Sanders AJ, Kynaston HG, Jiang WG. WAVE1 is associated with invasiveness and growth of prostate cancer cells. J Urol. 2008;180:1515–1521.
- Teng Y, Ren MQ, Cheney R, Sharma S, Cowell JK. Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases. Br J Cancer. 2010;103:1066–1075.
- Ishihara D, Dovas A, Hernandez L, et al. Wiskott-Aldrich syndrome protein regulates leukocyte-dependent breast cancer metastasis. Cell Rep. 2013;4:429–436.
- Goswami S, Sahai E, Wyckoff JB, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005;65: 5278–5283.
- Wyckoff J, Wang W, Lin EY, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 2004;64:7022–7029.
- Zicha D, Allen WE, Brickell PM, et al. Chemotaxis of macrophages is abolished in the Wiskott-Aldrich syndrome. Br J Haematol. 1998;101: 659–665.
- Escudero-Esparza A, Jiang WG, Martin TA. Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways. J Exp Clin Cancer Res. 2012;31:43.
- Peterson JR, Bickford LC, Morgan D, et al. Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol. 2004;11:747–755.
- Martin TA, Pereira G, Watkins G, Mansel RE, Jiang WG. N-WASP is a putative tumor suppressor in breast cancer cells, in vitro and in vivo, and is associated with clinical outcome in patients with breast cancer. Clin Exp Metastasis. 2008;25:97–108.
- Pichot CS, Arvanitis C, Hartig SM, et al. Cdc42-interacting protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASp. Cancer Res. 2010;70:8347–8356.
- Sanchez AM, Flamini MI, Baldacci C, Goglia L, Genazzani AR, Simoncini T. Estrogen receptor-alpha promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP. Mol Endocrinol. 2010;24:2114–2125.
- 80. Fernando HS, Davies SR, Chhabra A, et al. Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer. Oncology. 2007;73:376–383.
- Kim JS, Kang CG, Kim SH, Lee EO. Rhapontigenin suppresses cell migration and invasion by inhibiting the PI3K-dependent Rac1 signaling pathway in MDA-MB-231 human breast cancer cells. J Nat Prod. 2014;77:1135–1139.
- Ko HS, Kim JS, Cho SM, et al. Urokinase-type plasminogen activator expression and Rac1/WAVE-2/Arp2/3 pathway are blocked by pterostilbene to suppress cell migration and invasion in MDA-MB-231 cells. Bioorg Med Chem Lett. 2014;24:1176–1179.
- Takahashi K, Suzuki K. WAVE2, N-WASP, and Mena facilitate cell invasion via phosphatidylinositol 3-kinase-dependent local accumulation of actin filaments. J Cell Biochem. 2011;112:3421–3429.
- Sossey-Alaoui K, Su G, Malaj E, Roe B, Cowell JK. WAVE3, an actin-polymerization gene, is truncated and inactivated as a result of a constitutional t(1;13)(q21;q12) chromosome translocation in a patient with ganglioneuroblastoma. Oncogene. 2002;21:5967–5974.
- Sossey-Alaoui K, Safina A, Li X, et al. Down-regulation of WAVE3, a metastasis promoter gene, inhibits invasion and metastasis of breast cancer cells. Am J Pathol. 2007;170:2112–2121.
- Kulkarni S, Augoff K, Rivera L, et al. Increased expression levels of WAVE3 are associated with the progression and metastasis of triple negative breast cancer. PLoS One. 2012;7:e42895.
- Sossey-Alaoui K, Ranalli TA, Li X, Bakin AV, Cowell JK. WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. Exp Cell Res. 2005;308:135–145.
- Taylor MA, Davuluri G, Parvani JG, et al. Upregulated WAVE3 expression is essential for TGF-beta-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat. 2013;142: 341–353.
- Spence HJ, Timpson P, Tang HR, Insall RH, Machesky LM. Scar/WAVE3 contributes to motility and plasticity of lamellipodial dynamics but not invasion in three dimensions. Biochem J. 2012;448:35–42.
- Sossey-Alaoui K. Surfing the big WAVE: insights into the role of WAVE3 as a driving force in cancer progression and metastasis. Semin Cell Dev Biol. 2013;24:287–297.
- Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK. HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem. 2012;287:10051–10059.
Source: Breast Cancer: Targets and Therapy.