دورية أكاديمية
CXCR4 mediates leukemic cell migration and survival in the testicular microenvironment.
العنوان: | CXCR4 mediates leukemic cell migration and survival in the testicular microenvironment. |
---|---|
المؤلفون: | Skroblyn T; Department of Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.; Department of Pediatric Oncology, Charité-University Medicine, Campus Virchow Klinikum, Berlin, Germany., Joedicke JJ; Department of Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany., Pfau M; Department of Pediatric Oncology, Charité-University Medicine, Campus Virchow Klinikum, Berlin, Germany., Krüger K; Department of Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany., Bourquin JP; Department of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland., Izraeli S; Schneider Children's Medical Center of Israel, Petach Tiqva, Israel.; Tel Aviv University, Tel Aviv, Israel., Eckert C; Department of Pediatric Oncology, Charité-University Medicine, Campus Virchow Klinikum, Berlin, Germany.; German Cancer Consortium, and German Cancer Research Center, Heidelberg, Germany., Höpken UE; Department of Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. |
المصدر: | The Journal of pathology [J Pathol] 2022 Sep; Vol. 258 (1), pp. 12-25. Date of Electronic Publication: 2022 Jun 06. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Chichester : John Wiley And Sons Original Publication: London, Oliver & Boyd. |
مواضيع طبية MeSH: | Precursor Cell Lymphoblastic Leukemia-Lymphoma*/pathology , Testis*/chemistry , Testis*/metabolism , Testis*/pathology, Animals ; Cell Movement ; Chemokine CXCL12/metabolism ; Child ; Humans ; Male ; Mice ; Receptors, CXCR4/metabolism ; Recurrence ; Signal Transduction ; Tumor Microenvironment |
مستخلص: | The testis is the second most frequent extramedullary site of relapse in pediatric acute lymphoblastic leukemia (ALL). The mechanism for B-cell (B) ALL cell migration towards and survival within the testis remains elusive. Here, we identified CXCL12-CXCR4 as the leading signaling axis for B-ALL cell migration and survival in the testicular leukemic niche. We combined analysis of primary human ALL with a novel patient-derived xenograft (PDX)-ALL mouse model with testicular involvement. Prerequisites for leukemic cell infiltration in the testis were prepubertal age of the recipient mice, high surface expression of CXCR4 on PDX-ALL cells, and CXCL12 secretion from the testicular stroma. Analysis of primary pediatric patient samples revealed that CXCR4 was the only chemokine receptor being robustly expressed on B-ALL cells both at the time of diagnosis and relapse. In affected patient testes, leukemic cells localized within the interstitial space in close proximity to testicular macrophages. Mouse macrophages isolated from affected testes, in the PDX model, revealed a macrophage polarization towards a M2-like phenotype in the presence of ALL cells. Therapeutically, blockade of CXCR4-mediated functions using an anti-CXCR4 antibody treatment completely abolished testicular infiltration of PDX-ALL cells and strongly impaired the overall development of leukemia. Collectively, we identified a prepubertal condition together with high CXCR4 expression as factors affecting the leukemia permissive testicular microenvironment. We propose CXCR4 as a promising target for therapeutic prevention of testicular relapses in childhood B-ALL. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.) |
References: | Miranda-Filho A, Piñeros M, Ferlay J, et al. Epidemiological patterns of leukaemia in 184 countries: a population-based study. Lancet Haematol 2018; 5: e14-e24. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol 2015; 33: 2938-2948. Henze G, Stackelberg A. Relapsed acute lymphoblastic leukemia. In Childhood Leukemias (3rd edn), Pui C-H (ed). Cambridge University Press: Cambridge, 2012; 367-382. Chen-Santel C, Ulrike T, van Schewick C, et al. Bilateral involvement is an independent risk factor in testicular relapse of childhood ALL: results of the trials ALL-REZ BFM 83 - 2002. Blood 2014; 124: 66. Gandemer V, Chevret S, Petit A, et al. Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol. Haematologica 2012; 97: 1743-1750. Jayakrishnan T, Shaikh H, Samhouri Y, et al. Isolated testicular recurrence of B cell acute lymphoblastic leukaemia in an adult: rare case. BMJ Case Rep 2019; 12: e232286. Locatelli F, Schrappe M, Bernardo ME, et al. How I treat relapsed childhood acute lymphoblastic leukemia. Blood 2012; 120: 2807-2816. Tokoyoda K, Egawa T, Sugiyama T, et al. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 2004; 20: 707-718. Burger JA, Bürkle A. The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. Br J Haematol 2007; 137: 288-296. Méndez-Ferrer S, Bonnet D, Steensma DP, et al. Bone marrow niches in haematological malignancies. Nat Rev Cancer 2020; 20: 285-298. Crazzolara R, Kreczy A, Mann G, et al. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol 2001; 115: 545-553. Guo F, Wang Y, Liu J, et al. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene 2016; 35: 816-826. Gilbert DC, Chandler I, McIntyre A, et al. Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents. J Pathol 2009; 217: 94-102. McIver SC, Loveland KL, Roman SD, et al. The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis. Andrology 2013; 1: 517-529. Westernströer B, Langenstroth D, Kliesch S, et al. Developmental expression patterns of chemokines CXCL11, CXCL12 and their receptor CXCR7 in testes of common marmoset and human. Cell Tissue Res 2015; 361: 885-898. Fijak M, Meinhardt A. The testis in immune privilege. Immunol Rev 2006; 213: 66-81. Winnall WR, Hedger MP. Phenotypic and functional heterogeneity of the testicular macrophage population: a new regulatory model. J Reprod Immunol 2013; 97: 147-158. Lokka E, Lintukorpi L, Cisneros-Montalvo S, et al. Generation, localization and functions of macrophages during the development of testis. Nat Commun 2020; 11: 4375. Mossadegh-Keller N, Gentek R, Gimenez G, et al. Developmental origin and maintenance of distinct testicular macrophage populations. J Exp Med 2017; 214: 2829-2841. Shalapour S, Eckert C, Seeger K, et al. Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia. J Mol Med (Berl) 2010; 88: 249-265. Bluhm J, Kieback E, Marino SF, et al. CAR T cells with enhanced sensitivity to B cell maturation antigen for the targeting of B cell non-Hodgkin's lymphoma and multiple myeloma. Mol Ther 2018; 26: 1906-1920. Höpken UE, Rehm A. Homeostatic chemokines guide lymphoma cells to tumor growth-promoting niches within secondary lymphoid organs. J Mol Med (Berl) 2012; 90: 1237-1245. Höpken UE, Rehm A. Targeting the tumor microenvironment of leukemia and lymphoma. Trends Cancer 2019; 5: 351-364. Alsadeq A, Lenk L, Vadakumchery A, et al. IL7R is associated with CNS infiltration and relapse in pediatric B-cell precursor acute lymphoblastic leukemia. Blood 2018; 132: 1614-1617. Pal D, Blair HJ, Elder A, et al. Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia. Leukemia 2016; 30: 1691-1700. de Rooij B, Polak R, van den Berk LCJ, et al. Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis. Haematologica 2017; 102: e389-e393. Griswold MD. The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998; 9: 411-416. Zirkin BR, Papadopoulos V. Leydig cells: formation, function, and regulation. Biol Reprod 2018; 99: 101-111. Maekawa M, Kamimura K, Nagano T. Peritubular myoid cells in the testis: their structure and function. Arch Histol Cytol 1996; 59: 1-13. Kanai Y, Hiramatsu R, Matoba S, et al. From SRY to SOX9: mammalian testis differentiation. J Biochem 2005; 138: 13-19. Velázquez-Avila M, Balandrán JC, Ramírez-Ramírez D, et al. High cortactin expression in B-cell acute lymphoblastic leukemia is associated with increased transendothelial migration and bone marrow relapse. Leukemia 2019; 33: 1337-1348. Jackson H, Jackson NC, Bock M, et al. Testicular relapse in acute lymphoblastic leukaemia: studies with an experimental mouse model. Br J Cancer 1984; 49: 73-78. Arnaud MP, Vallée A, Robert G, et al. CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling. Blood 2015; 126: 1802-1812. Pals ST, de Gorter DJ, Spaargaren M. Lymphoma dissemination: the other face of lymphocyte homing. Blood 2007; 110: 3102-3111. Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 2009; 23: 43-52. Abdelrasoul H, Vadakumchery A, Werner M, et al. Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Nat Commun 2020; 11: 3194. Bhushan S, Tchatalbachev S, Lu Y, et al. Differential activation of inflammatory pathways in testicular macrophages provides a rationale for their subdued inflammatory capacity. J Immunol 2015; 194: 5455-5464. Winnall WR, Muir JA, Hedger MP. Rat resident testicular macrophages have an alternatively activated phenotype and constitutively produce interleukin-10 in vitro. J Leukoc Biol 2011; 90: 133-143. Bhushan S, Theas MS, Guazzone VA, et al. Immune cell subtypes and their function in the testis. Front Immunol 2020; 11: 583304. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549-555. Chen SY, Yang X, Feng WL, et al. Organ-specific microenvironment modifies diverse functional and phenotypic characteristics of leukemia-associated macrophages in mouse T cell acute lymphoblastic leukemia. J Immunol 2015; 194: 2919-2929. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283: 845-848. van den Berk LC, van der Veer A, Willemse ME, et al. Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia. Br J Haematol 2014; 166: 240-249. Yang QE, Kim D, Kaucher A, et al. CXCL12-CXCR4 signaling is required for the maintenance of mouse spermatogonial stem cells. J Cell Sci 2013; 126: 1009-1020. Gaudichon J, Jakobczyk H, Debaize L, et al. Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: reconciling biological concepts and clinical issues. Blood Rev 2019; 36: 40-56. Green CD, Ma Q, Manske GL, et al. A comprehensive roadmap of murine spermatogenesis defined by single-cell RNA-Seq. Dev Cell 2018; 46: 651-667.e10. Gandemer V, Aubry M, Roussel M, et al. CD9 expression can be used to predict childhood TEL/AML1-positive acute lymphoblastic leukemia: proposal for an accelerated diagnostic flowchart. Leuk Res 2010; 34: 430-437. Orecchioni M, Ghosheh Y, Pramod AB, et al. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front Immunol 2019; 10: 1084. Gätjen M, Brand F, Grau M, et al. Splenic marginal zone granulocytes acquire an accentuated neutrophil B-cell helper phenotype in chronic lymphocytic leukemia. Cancer Res 2016; 76: 5253-5265. Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol 2020; 10: 1672. Zhang Y, Saavedra E, Tang R, et al. Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143). Sci Rep 2017; 7: 7305. Li L, Chai Y, Wu C, et al. Chemokine receptor CXCR4: an important player affecting the molecular-targeted drugs commonly used in hematological malignancies. Expert Rev Hematol 2020; 13: 1387-1396. Pham H, Tonai R, Wu M, et al. CD73, CD90, CD105 and Cadherin-11 RT-PCR screening for mesenchymal stem cells from cryopreserved human cord tissue. Int J Stem Cells 2018; 11: 26-38. Harkness L, Zaher W, Ditzel N, et al. CD146/MCAM defines functionality of human bone marrow stromal stem cell populations. Stem Cell Res Ther 2016; 7: 4. Kauerhof AC, Nicolas N, Bhushan S, et al. Investigation of activin A in inflammatory responses of the testis and its role in the development of testicular fibrosis. Hum Reprod 2019; 34: 1536-1550. Bhushan S, Aslani F, Zhang Z, et al. Isolation of Sertoli cells and peritubular cells from rat testes. J Vis Exp 2016: (108): e53389. |
فهرسة مساهمة: | Keywords: B cell acute lymphoblastic leukemia; chemokine receptor CXCR4; macrophages; testis relapse; tumor microenvironment |
المشرفين على المادة: | 0 (CXCR4 protein, human) 0 (Chemokine CXCL12) 0 (Receptors, CXCR4) |
تواريخ الأحداث: | Date Created: 20220506 Date Completed: 20220815 Latest Revision: 20221019 |
رمز التحديث: | 20231215 |
DOI: | 10.1002/path.5924 |
PMID: | 35522562 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1096-9896 |
---|---|
DOI: | 10.1002/path.5924 |