Acute Lymphoid Leukemia Cells with Greater Stem Cell Antigen-1 (Ly6a/Sca-1) Expression Exhibit Higher Levels of Metalloproteinase Activity and Are More Aggressive In Vivo
Stem cell antigen-1 (Ly6a/Sca-1) is a gene that is expressed in activated lymphocytes, hematopoietic stem cells and stem cells of a variety of tissues in mice. Despite decades of study its functions remain poorly defined. These studies explored the impact of expression of this stem cell associated gene in acute lymphoid leukemia. Higher levels of Ly6a/Sca-1 expression led to more aggressive leukemia growth in vivo and earlier death of hosts. Leukemias expressing higher levels of Ly6a/Sca-1 exhibited higher levels of matrix metalloproteinases. The results suggest the hypothesis that the more aggressive behavior of Ly6a/Sca-1 expressing leukemias is due at least in part to greater capacity to degrade microenvironmental stroma and invade tissues.
References
[1]
Shand JC, Jansson J, Hsu YC, Campbell A, Mullen CA (2010) Differential gene expression in acute lymphoblastic leukemia cells surviving allogeneic transplant. Cancer Immunol Immunother 59: 1633–1644. doi: 10.1007/s00262-010-0889-y
[2]
Ortega G, Korty PE, Shevach EM, Malek TR (1986) Role of Ly-6 in lymphocyte activation. I. Characterization of a monoclonal antibody to a nonpolymorphic Ly-6 specificity. J Immunol 137: 3240–3246.
[3]
Malek TR, Ortega G, Chan C, Kroczek RA, Shevach EM (1986) Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies. J Exp Med 164: 709–722. doi: 10.1084/jem.164.3.709
[4]
Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, et al. (1992) In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood 80: 3044–3050.
[5]
Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241: 58–62. doi: 10.1126/science.2898810
[6]
van de Rijn M, Heimfeld S, Spangrude GJ, Weissman IL (1989) Mouse hematopoietic stem-cell antigen Sca-1 is a member of the Ly-6 antigen family. Proc Natl Acad Sci U S A 86: 4634–4638. doi: 10.1073/pnas.86.12.4634
[7]
LeClair KP, Palfree RG, Flood PM, Hammerling U, Bothwell A (1986) Isolation of a murine Ly-6 cDNA reveals a new multigene family. EMBO J 5: 3227–3234.
[8]
Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells.[erratum appears in Science 1989 Jun 2;244(4908): 1030]. Science 241: 58–62. doi: 10.1126/science.2898810
[9]
Rock KL, Reiser H, Bamezai A, McGrew J, Benacerraf B (1989) The LY-6 locus: a multigene family encoding phosphatidylinositol-anchored membrane proteins concerned with T-cell activation. Immunol Rev 111: 195–224. doi: 10.1111/j.1600-065x.1989.tb00547.x
[10]
Epting CL, King FW, Pedersen A, Zaman J, Ritner C, et al. (2008) Stem cell antigen-1 localizes to lipid microdomains and associates with insulin degrading enzyme in skeletal myoblasts. Journal of Cellular Physiology 217: 250–260. doi: 10.1002/jcp.21500
[11]
Pflugh DL, Maher SE, Bothwell ALM (2002) Ly-6 superfamily members Ly-6A/E, Ly-6C, and Ly-6I recognize two potential ligands expressed by B lymphocytes. Journal of Immunology 169: 5130–5136. doi: 10.4049/jimmunol.169.9.5130
[12]
English A, Kosoy R, Pawlinski R, Bamezai A (2000) A monoclonal antibody against the 66-kDa protein expressed in mouse spleen and thymus inhibits Ly-6A.2-dependent cell-cell adhesion. Journal of Immunology 165: 3763–3771. doi: 10.4049/jimmunol.165.7.3763
[13]
Bamezai A, Rock KL (1995) Overexpressed Ly-6A.2 mediates cell-cell adhesion by binding a ligand expressed on lymphoid cells. Proc Natl Acad Sci U S A 92: 4294–4298. doi: 10.1073/pnas.92.10.4294
LaBelle JL, Truitt RL (2002) Characterization of a murine NKT cell tumor previously described as an acute myelogenous leukemia. Leukemia & Lymphoma 43: 1637–1644. doi: 10.1080/1042819021000002974
[16]
Young FM, Campbell A, Emo KL, Jansson J, Wang P-Y, et al. (2008) High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells. Biology of Blood & Marrow Transplantation 14: 622–630. doi: 10.1016/j.bbmt.2008.02.015
[17]
Mitchell PO, Mills T, O’Connor RS, Kline ER, Graubert T, et al. (2005) Sca-1 negatively regulates proliferation and differentiation of muscle cells. Dev Biol 283: 240–252. doi: 10.1016/j.ydbio.2006.10.031
[18]
Mori S, El-Baki H, Mullen CA (2003) An analysis of immunodominance among minor histocompatibility antigens in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 31: 865–875. doi: 10.1038/sj.bmt.1704021
[19]
Korngold R, Sprent J (1987) Variable capacity of L3T4+ T cells to cause lethal graft-versus-host disease across minor histocompatibility barriers in mice. The Journal of Experimental Medicine 165: 1552–1564. doi: 10.1084/jem.165.6.1552
[20]
Kafadar KA, Yi L, Ahmad Y, So L, Rossi F, et al. (2009) Sca-1 expression is required for efficient remodeling of the extracellular matrix during skeletal muscle regeneration. Dev Biol 326: 47–59. doi: 10.1016/j.ydbio.2008.10.036
[21]
Franco GC, Kajiya M, Nakanishi T, Ohta K, Rosalen PL, et al. (2011) Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo. Exp Cell Res 317: 1454–1464. doi: 10.1016/j.yexcr.2011.03.014
[22]
Perez-Caro M, Cobaleda C, Gonzalez-Herrero I, Vicente-Duenas C, Bermejo-Rodriguez C, et al. (2009) Cancer induction by restriction of oncogene expression to the stem cell compartment. EMBO J 28: 8–20. doi: 10.1038/emboj.2008.253
[23]
Grange C, Lanzardo S, Cavallo F, Camussi G, Bussolati B (2008) Sca-1 identifies the tumor-initiating cells in mammary tumors of BALB-neuT transgenic mice. Neoplasia 10: 1433–1443.
[24]
Berman SD, Calo E, Landman AS, Danielian PS, Miller ES, et al. (2008) Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proceedings of the National Academy of Sciences of the United States of America 105: 11851–11856. doi: 10.1073/pnas.0805462105
[25]
Treister A, Sagi-Assif O, Meer M, Smorodinsky NI, Anavi R, et al. (1998) Expression of Ly-6, a marker for highly malignant murine tumor cells, is regulated by growth conditions and stress. International Journal of Cancer 77: 306–313. doi: 10.1002/(sici)1097-0215(19980717)77:2<306::aid-ijc22>3.0.co;2-7
[26]
Kim RJ, Kim SR, Roh KJ, Park SB, Park JR, et al. (2010) Ras activation contributes to the maintenance and expansion of Sca-1pos cells in a mouse model of breast cancer. Cancer Lett 287: 172–181. doi: 10.1016/j.canlet.2009.06.010
[27]
Seigel GM, Campbell LM, Narayan M, Gonzalez-Fernandez F (2005) Cancer stem cell characteristics in retinoblastoma. Mol Vis 11: 729–737.
[28]
Xin L, Lawson DA, Witte ON (2005) The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 102: 6942–6947. doi: 10.1073/pnas.0502320102
[29]
Redondo-Munoz J, Jose Terol M, Garcia-Marco JA, Garcia-Pardo A (2008) Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. Blood 111: 383–386. doi: 10.1182/blood-2007-08-107300
[30]
Nieborowska-Skorska M, Hoser G, Rink L, Malecki M, Kossev P, et al. (2006) Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells. Cancer Res 66: 4108–4116. doi: 10.1158/0008-5472.can-05-1584
[31]
Redondo-Munoz J, Ugarte-Berzal E, Terol MJ, Van den Steen PE, Hernandez del Cerro M, et al. (2010) Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. Cancer Cell 17: 160–172. doi: 10.1016/j.ccr.2009.12.044
[32]
Stefanidakis M, Karjalainen K, Jaalouk DE, Gahmberg CG, O’Brien S, et al. (2009) Role of leukemia cell invadosome in extramedullary infiltration. Blood 114: 3008–3017. doi: 10.1182/blood-2008-04-148643
[33]
Fayard B, Bianchi F, Dey J, Moreno E, Djaffer S, et al. (2009) The serine protease inhibitor protease nexin-1 controls mammary cancer metastasis through LRP-1-mediated MMP-9 expression. Cancer Res 69: 5690–5698. doi: 10.1158/0008-5472.can-08-4573
[34]
Hofmann UB, Eggert AA, Blass K, Brocker EB, Becker JC (2003) Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation. Cancer Res 63: 8221–8225.
[35]
Littlepage LE, Sternlicht MD, Rougier N, Phillips J, Gallo E, et al. (2010) Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res 70: 2224–2234. doi: 10.1158/0008-5472.can-09-3515
[36]
Barker HE, Chang J, Cox TR, Lang G, Bird D, et al. (2011) LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res 71: 1561–1572. doi: 10.1158/0008-5472.can-10-2868
[37]
Epting CL, Lopez JE, Shen X, Liu L, Bristow J, et al. (2004) Stem cell antigen-1 is necessary for cell-cycle withdrawal and myoblast differentiation in C2C12 cells. J Cell Sci 117: 6185–6195. doi: 10.1242/jcs.01548
[38]
Mallya M, Campbell RD, Aguado B (2006) Characterization of the five novel Ly-6 superfamily members encoded in the MHC, and detection of cells expressing their potential ligands. Protein Sci 15: 2244–2256. doi: 10.1110/ps.062242606
[39]
de Nooij-van Dalen AG, van Dongen GA, Smeets SJ, Nieuwenhuis EJ, Stigter-van Walsum M, et al. (2003) Characterization of the human Ly-6 antigens, the newly annotated member Ly-6K included, as molecular markers for head-and-neck squamous cell carcinoma. Int J Cancer 103: 768–774. doi: 10.1002/ijc.10903
[40]
Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, et al. (2007) Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res 67: 11601–11611. doi: 10.1158/0008-5472.can-07-3243
[41]
Brakenhoff RH, Gerretsen M, Knippels EM, van Dijk M, van Essen H, et al. (1995) The human E48 antigen, highly homologous to the murine Ly-6 antigen ThB, is a GPI-anchored molecule apparently involved in keratinocyte cell-cell adhesion. J Cell Biol 129: 1677–1689. doi: 10.1083/jcb.129.6.1677
