Simultaneous Inhibition of CXCR4 and VLA-4 Exhibits Combinatorial Effect in Overcoming Stroma-Mediated Chemotherapy Resistance in Mantle Cell Lymphoma Cells
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
There is growing evidence that crosstalk between mantle celllymphoma (MCL) cells and stromal microenvironments, suchas bone marrow and secondary lymphoid tissues, promotestumor progression by enhancing survival and growth as wellas drug resistance of MCL cells. Recent advances in the understandingof lymphoma microenvironment have led to theidentification of crucial factors involved in the crosstalk andsubsequent generation of their targeted agents. In the presentstudy, we evaluated the combinatory effect of blockingantibodies (Ab) targeting CXCR4 and VLA-4, both of whichwere known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line,Jeko-1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells intothe protective stromal cells, but also enhanced sensitivityof Jeko-1 to a chemotherapeutic agent to a greater degreethan with either Ab alone. These combinatorial effects wereassociated with decreased phosphorylation of ERK1/2, AKTand NF-κB. Importantly, drug resistance could not be overcomeonce the adhesion of Jeko-1 to the stromal occurreddespite the combined use of Abs, suggesting that the effortsto mitigate migration of MCLs should be attempted as muchas possible. Our results provide a basis for a future developmentof therapeutic strategies targeting both CXCR4 andVLA-4, such as Ab combinations or bispecific antibodies, toimprove treatment outcomes of MCL with grave prognosis.
Abstract
There is growing evidence that crosstalk between mantle celllymphoma (MCL) cells and stromal microenvironments, suchas bone marrow and secondary lymphoid tissues, promotestumor progression by enhancing survival and growth as wellas drug resistance of MCL cells. Recent advances in the understandingof lymphoma microenvironment have led to theidentification of crucial factors involved in the crosstalk andsubsequent generation of their targeted agents. In the presentstudy, we evaluated the combinatory effect of blockingantibodies (Ab) targeting CXCR4 and VLA-4, both of whichwere known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line,Jeko-1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells intothe protective stromal cells, but also enhanced sensitivityof Jeko-1 to a chemotherapeutic agent to a greater degreethan with either Ab alone. These combinatorial effects wereassociated with decreased phosphorylation of ERK1/2, AKTand NF-κB. Importantly, drug resistance could not be overcomeonce the adhesion of Jeko-1 to the stromal occurreddespite the combined use of Abs, suggesting that the effortsto mitigate migration of MCLs should be attempted as muchas possible. Our results provide a basis for a future developmentof therapeutic strategies targeting both CXCR4 andVLA-4, such as Ab combinations or bispecific antibodies, toimprove treatment outcomes of MCL with grave prognosis.
참고문헌 (25)
- The Non-Hodgkin's Lymphoma Classification Project, "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma", Blood, 89, pp.3909~3918 (1997)
- Matsunaga, T, "Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia", Nat. Med, 9, pp.1158~1165 (2003)
- Kurtova, A. V., "Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting", Blood, 113, pp.4604~4613 (2009)
- Lwin, T., "Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas", Blood, 110, pp.1631~1638 (2007)
- Mohle, R., "Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1)", Leukemia, 13, pp.1954~1959 (1999)
- Bradstock, K. F, "Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers", Leukemia, 14, pp.882~888 (2000)
- Dialynas, D. P, "Engraftment of human T-cell acute lymphoblastic leukemia in immunodeficient NOD", SCID mice which have been preconditioned by injection of human cord blood, 2001, pp.19, 443~452
- Hideshima, T., "Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat. Rev", Cancer, 2, pp.927~937 (2002)
- Tavor, S, "CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD", SCID mice, 2004, pp.64, 2817~2824
- Beider, K., "Targeting the CD20 and CXCR4 pathways in non-hodgkin lymphoma with rituximab and high-affinity CXCR4 antagonist BKT140", Clin. Cancer Res, 19, pp.3495~3507 (2013)
- Lavrovsky, Y, "CXCR4 receptor as a promising target for oncolytic drugs", Mini Rev. Med. Chem, 8, pp.1075~1087 (2008)
- Burger, J. A., "CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers", Leukemia, 23, pp.43~52 (2009)
- Shishido, S., "Role of integrin alpha4 in drug resistance of leukemia", Front. Oncol, 4, pp.99~ (2014)
- Podar, K., "Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation", J. Biol. Chem, 277, pp.7875~7881 (2002)
- Peled, A, "The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial", stromal migration and engraftment of NOD, Blood, pp.2000, 95[DOI]
- Ding, Z., "L-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: implications for cellular activation during adhesion and migration", Blood, 101, pp.4245~4252 (2003)
- Ngo, H. T., "SDF-1", CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia, 2008, pp.112, 150~158
- Meads, M. B., "The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance", Clin. Cancer Res, 14, pp.2519~2526 (2008)
- Damiano, J. S., "Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines", Blood, 93, pp.1658~1667 (1999)
- Zeng, Z., "Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML", Blood, 113, pp.6215~6224 (2009)
- Rizzatti, E. G., "Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways", Br. J. Haematol, 130, pp.516~526 (2005)
- Perez-Galan, P, "Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation", Blood, 117, pp.542~552 (2011)
- Bleul, C. C., "A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)", J. Exp. Med, 184, pp.1101~1109 (1996)
- Nagasawa, T, "Molecular cloning and structure of a pre-B-cell growth-stimulating factor", Proc. Natl. Acad. Sci. U. S. A, 91, pp.2305~2309 (1994)
- Felsher, D. W., "Reversible tumorigenesis by MYC in hematopoietic lineages", Mol. Cell, 4, pp.199~207 (1999)