DOCSLIB.ORG

HIF-2A Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1 Kate Vandyke1,2,3, Mara N

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
HIF-2A Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1 Kate Vandyke1,2,3, Mara N Published OnlineFirst August 30, 2017; DOI: 10.1158/0008-5472.CAN-17-0115 Cancer Molecular and Cellular Pathobiology Research HIF-2a Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1 Kate Vandyke1,2,3, Mara N. Zeissig1,2, Duncan R. Hewett1,2, Sally K. Martin1,2, Krzysztof M. Mrozik1,2, Chee Man Cheong1,2, Peter Diamond1, L. Bik To3,4, Stan Gronthos2,5, Daniel J. Peet6, Peter I. Croucher7,8, and Andrew C.W. Zannettino1,2,3,9 Abstract Disease progression and relapse in multiple myeloma is chemokine receptor CCR1 in multiple myeloma PCs. CCR1 dependent on the ability of the multiple myeloma plasma activation potently induces multiple myeloma PC migration cells (PC) to reenter the circulation and disseminate through- toward CCL3 while abrogating the multiple myeloma PC out the bone marrow. Increased bone marrow hypoxia is migratory response to CXCL12. In addition, increased CCR1 associated with increased recirculation of multiple myeloma expression by multiple myeloma PCs conferred poor prognosis PCs. Accordingly, we hypothesized that during chronic hyp- in newly diagnosed multiple myeloma patients and was asso- oxia, activation of HIF-2a may overcome the bone marrow ciated with an increase in circulating multiple myeloma PCs in retention signal provided by stromal-derived CXCL12, thereby these patients. Taken together, our results suggest a role for enabling dissemination of multiple myeloma PCs. Here we hypoxia-mediated CCR1 upregulation in driving the egress of demonstrate that HIF-2a upregulates multiple myeloma PC multiple myeloma PCs from the bone marrow. Targeting CXCL12 expression, decreasing migration toward CXCL12 and CCR1 may represent a novel strategy to prevent dissemination reducing adhesion to mesenchymal stromal cells in vitro.We and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. also found that HIF-2a strongly induced expression of the Ó2017 AACR. Introduction development of the asymptomatic precursor disease monoclonal gammopathy of undetermined significance (MGUS; ref. 2). In a Multiple myeloma is an incurable hematologic cancer that is small proportion of MGUS patients (1% per year), intrinsic responsible for an estimated 80,000 deaths worldwide, each year genetic changes, coupled with extrinsic factors, lead to the pro- (1). Multiple myeloma is characterized by the clonal proliferation liferation of the multiple myeloma PCs and their dissemination to of malignant plasma cells (PC) within the bone marrow. While, in sites throughout the skeleton (3). Ultimately, multiple myeloma some cases, malignant PCs establish at a single site, forming a PC proliferation and dissemination results in hypercalcemia, solitary plasmacytoma, in the majority of cases, the transformed renal insufficiency, anemia, and osteolytic bone disease, features PC will disseminate throughout the bone marrow, leading to the characteristic of progressive disease (4). Dissemination and repopulation throughout the bone marrow 1Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and is key, not only during multiple myeloma disease progression, but Medical Sciences, University of Adelaide, Adelaide, Australia. 2Cancer Theme, also in the outgrowth of resistant multiple myeloma PCs during South Australian Health and Medical Research Institute, Adelaide, Australia. 3SA relapse following therapy. Evidence suggest that in most, if not all Pathology, Adelaide, Australia. 4Haematology and Bone Marrow Transplant multiple myeloma patients, malignant PCs continually migrate 5 Unit, Royal Adelaide Hospital, Adelaide, Australia. Mesenchymal Stem Cell and repopulate multiple sites throughout the bone marrow (2). Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, Circulating multiple myeloma PCs are observed in over two- University of Adelaide, Adelaide, Australia. 6School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, Australia. 7Bone Biology thirds of newly diagnosed multiple myeloma patients and are Division, Garvan Institute of Medical Research, Sydney, Australia. 8St Vincent's a predictor of response to therapy, with increased numbers of Clinical School, Faculty of Medicine, University of New South Wales, Sydney, circulating multiple myeloma PCs representing an independent Australia. 9Centre for Cancer Biology, University of South Australia, Adelaide, indicator of poor prognosis and rapid progression (5–8). Australia. The homing of multiple myeloma PCs from the peripheral Note: Supplementary data for this article are available at Cancer Research circulation to the bone marrow is critically dependent on the Online (http://cancerres.aacrjournals.org/). chemokine (C-X-C motif) ligand CXCL12 (also known as stromal Corresponding Author: Andrew C.W. Zannettino, Myeloma Research Labora- cell–derived factor-1; SDF-1), the ligand for CXCR4. CXCL12 is tory, Adelaide Medical School, Faculty of Health and Medical Sciences, University highly expressed by bone marrow mesenchymal stromal cells of Adelaide, North Terrace, Adelaide, SA 5000, Australia. Phone: 618-812-8490; (BMSC; refs. 9, 10) and acts as potent attractor for the homing of Fax: 618-8222-3139; E-mail: [email protected] both normal and malignant PCs into the bone marrow (11, 12). doi: 10.1158/0008-5472.CAN-17-0115 In addition, CXCL12 is crucial in the subsequent retention of Ó2017 American Association for Cancer Research. multiple myeloma PCs in the bone marrow, stimulating increased 5452 Cancer Res; 77(20) October 15, 2017 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 30, 2017; DOI: 10.1158/0008-5472.CAN-17-0115 CCR1, CXCL12, and Hypoxia in MM Dissemination adhesion of multiple myeloma PCs to bone marrow stromal cells marrow aspirates isolated from the posterior iliac crest of healthy and promoting multiple myeloma PC survival and resistance to adult human donors and were used at passage 6. Survival was therapeutics (13, 14). calculated from the date of bone marrow or blood collection until While the mechanisms involved in multiple myeloma PC death, by any cause. Patients who were lost to follow up were homing to the bone marrow are relatively well characterized, the censored at the date of last contact. mechanisms responsible for driving multiple myeloma PCs egress from the bone marrow remain to be elucidated. Emerging data Cell culture suggest that the elevated bone marrow hypoxia observed in Unless otherwise specified, all cell culture reagents were multiple myeloma (15–17) is a potential microenvironmental sourced from Sigma-Aldrich and all media were supplemented stimulus that drives multiple myeloma PC dissemination (18). with 2 mol/L L-glutamine, 100 U/mL penicillin, 100 mg/mL Recent studies suggest bone marrow hypoxia strongly correlates streptomycin, 1 mmol/L sodium pyruvate, and 10 mmol/L with both tumor burden and numbers of circulating multiple HEPES buffer. BMSCs were maintained as described previously myeloma PCs in mouse models of multiple myeloma, suggesting (21). HMCLs RPMI-8226, LP-1, and U266 were obtained from the that hypoxic multiple myeloma PCs may be preferentially mobi- ATCC between 2000 and 2003; STR authentication was not lized to the peripheral blood (18). This may, at least in part, be due conducted on these lines as they were obtained directly from the to decreased adhesion and a reduced chemotactic response to ATCC. OPM2 cells were provided by Prof. Andrew Spencer bone marrow stromal cells under hypoxia (18). A similar asso- (Monash University, Melbourne, Australia) in 2004; this cell line ciation between tumor hypoxia and increased metastasis has also was authenticated in 2016 using STR analysis performed by the been seen in patients with solid tumors and in animal models of Molecular Genetics Laboratory, SA Pathology, using an metastasis (17). AmpFLSTR Identifiler PCR Amplification Kit (Thermo Fisher Exposure to hypoxia induces gene expression through the Scientific). HMCLs were last mycoplasma tested in May 2016 stabilization and increased expression of the hypoxia-inducible using a MycoAlert Mycoplasma Detection Kit (Lonza). HMCLs transcription factors HIF-1a and HIF-2a (17). Our previous were maintained in RPMI1640 medium with 10% FCS (Thermo studies suggest that HIF-2a plays a critical role in multiple Fisher Scientific) and supplements. All experiments were con- myeloma disease progression, through binding to the promoter ducted within 4 weeks of thawing of cells. Cell lines were routinely and driving expression of CXCL12 (15). In addition to being cultured in a humidified environment with 5% carbon dioxide at highly expressed by bone marrow stromal cells, CXCL12 is highly 37C. Hypoxic culture conditions (<1% oxygen) were established expressed by multiple myeloma PCs (19) and multiple myeloma using an anaerobic sachet (Oxoid). Where indicated, cells were PC–derived CXCL12 plays an important role in driving osteolysis treated with the CCR1 inhibitor BX471 (Sigma Aldrich) in (19, 20) and angiogenesis (15) in myeloma patients. 0.0004% DMSO, or 0.0004% DMSO alone, or with recombinant In the studies presented here, we investigated whether upre- human (rh)CXCL12 (100 ng/mL; R&D Systems) or rhCCL3 gulation of CXCL12 expression in multiple myeloma PCs, in (100 ng/mL; PeproTech). Generation of RPMI-8226 and LP-1 response to HIF-2a expression, abrogates the chemoattraction cell lines overexpressing CXCL12, HIF-1a, or HIF-2a is described
Load more

Recommended publications
  • Chemokine Receptor CXCR3 Promotes Colon Cancer Metastasis to Lymph Nodes
    Oncogene (2007) 26, 4679–4688 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes K Kawada1,2,5, H Hosogi1,2,5, M Sonoshita1, H Sakashita3, T Manabe3, Y Shimahara2, Y Sakai2, A Takabayashi4, M Oshima1 and MM Taketo1 1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Department of Clinical Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and 4Kitano Hospital Medical Institute, Osaka, Japan Chemokines and their receptors are essential for leuko- inflammatory cytokines, growth factors and/or patho- cyte trafficking, and also implicated in cancer metastasis genic stimuli. Important roles of chemokines and their to specific organs. We have recently demonstrated that receptors have been demonstrated in inflammation, CXCR3 plays a critical role in metastasis of mouse infection, tissue injury, allergy and cardiovascular melanoma cells to lymph nodes. Here, we show that some diseases as well as in malignant tumors. Chemokine human colon cancer cell lines express CXCR3 constitu- receptor CXCR3 is essential for the physiologic and tively. We constructed cells that expressed CXCR3 cDNA pathologic recruitment of plasmacytoid dendritic cell (‘DLD-1-CXCR3’), and compared with nonexpressing precursors, monocytes and natural killer cells to controls by rectal transplantation in nude mice. Although inflamed lymph nodes (LNs) (Cella et al., 1999; both cell lines disseminated to lymph nodes at similar Janatpour et al., 2001; Martin-Fontecha et al., 2004), frequencies at 2 weeks, DLD-1-CXCR3 expanded more and for retention of Th1 lymphocytes within LNs rapidly than the control in 4 weeks.
    [Show full text]
  • Role of Chemokines and Chemokine Receptors in Shaping the Effector Phase of the Antitumor Immune Response
    Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027 Cancer Review Research Role of Chemokines and Chemokine Receptors in Shaping the Effector Phase of the Antitumor Immune Response Katarzyna Franciszkiewicz1, Alexandre Boissonnas2, Marie Boutet1, Christophe Combadiere 2, and Fathia Mami-Chouaib1 Abstract Immune system–mediated eradication of neoplastic cells requires induction of a strong long-lasting antitumor T-cell response. However, generation of tumor-specific effector T cells does not necessarily result in tumor clearance. CTL must firstbeabletomigratetothetumorsite,infiltrate the tumor tissue, and interact with the target to finally trigger effector functions indispensable for tumor destruction. Chemokines are involved in circulation, homing, retention, and activation of immunocompetent cells. Although some of them are known to contribute to tumor growth and metastasis, others are responsible for changes in the tumor microenvironment that lead to extensive infiltration of lymphocytes, resulting in tumor eradication. Given their chemoattractive and activating properties, a role for chemokines in the development of the effector phase of the antitumor immune response has been suggested. Here, we emphasize the role of the chemokine–chemokine receptor network at multiple levels of the T-cell–mediated antitumor immune response. The identification of chemokine-dependent molecular mechanisms implicated in tumor-specific CTL trafficking, retention, and regulation of their in situ effector functions may offer new perspectives for development of innovative immunotherapeutic approaches to cancer treatment. Cancer Res; 72(24); 1–8. Ó2012 AACR. Introduction critical step in optimization of current cancer immunotherapy The identification of tumor-associated antigens (TAA) and protocols. the isolation of tumor-specific cytotoxic T cells have led to Chemokines coordinate circulation, homing, and retention great efforts in developing immunotherapeutic approaches to of immune cells.
    [Show full text]
  • Polyclonal Anti-CCR1 Antibody
    FabGennix International, Inc. 9191 Kyser Way Bldg. 4 Suite 402 Frisco, TX 75033 Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Polyclonal Anti-CCR1 antibody Catalog Number: CCR1-112AP General Information Product CCR1 Antibody Affinity Purified Description Chemokine (C-C motif) receptor 1 Antibody Affinity Purified Accession # Uniprot: P32246 GenBank: AAH64991 Verified Applications ELISA, WB Species Cross Reactivity Human Host Rabbit Immunogen Synthetic peptide taken within amino acid region 1-50 on human CCR1 protein. Alternative Nomenclature C C chemokine receptor type 1 antibody, C C CKR 1 antibody, CCR1 antibody, CD191 antibody, CMKBR 1 antibody, CMKR1 antibody, HM145 antibody, LD78 receptor antibody, Macrophage inflammatory protein 1 alpha /Rantes receptor antibody, MIP-1alpha-R antibody, MIP1aR antibody, RANTES receptor antibody, SCYAR1 antibody Physical Properties Quantity 100 µg Volume 200 µl Form Affinity Purified Immunoglobulins Immunoglobulin & Concentration 0.65-0.75 mg/ml IgG in antibody stabilization buffer Storage Store at -20⁰C for long term storage. Recommended Dilutions DOT Blot 1:10,000 ELISA 1:10,000 Western Blot 1:500 Related Products Catalog # FITC-Conjugated CCR1.112-FITC Antigenic Blocking Peptide P-CCR1.112 Western Blot Positive Control PC-CCR1.112 Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Overview: Chemokine receptors represent a subfamily of ~20 GPCRs that were originally identified by their roles in immune cell trafficking. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and RANTES, members of the beta chemokine family of leukocyte chemo- attractants, bind to a common seven-transmembrane-domain human receptor.
    [Show full text]
  • CCR5 in T Cell-Mediated Liver Diseases: What's Going On? Maureen N
    CCR5 in T Cell-Mediated Liver Diseases: What's Going On? Maureen N. Ajuebor, Jillian A. Carey and Mark G. Swain This information is current as J Immunol 2006; 177:2039-2045; ; of September 29, 2021. doi: 10.4049/jimmunol.177.4.2039 http://www.jimmunol.org/content/177/4/2039 Downloaded from References This article cites 62 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/177/4/2039.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?1 Maureen N. Ajuebor, Jillian A. Carey, and Mark G. Swain2 The chemokine receptor CCR5 came into worldwide Over the past 10 years, chemokines have been the focus of a prominence a decade ago when it was identified as one of great deal of research pertaining to their role in promoting leu- the major coreceptors for HIV infectivity.
    [Show full text]
  • B-Cell Development, Activation, and Differentiation
    B-Cell Development, Activation, and Differentiation Sarah Holstein, MD, PhD Nov 13, 2014 Lymphoid tissues • Primary – Bone marrow – Thymus • Secondary – Lymph nodes – Spleen – Tonsils – Lymphoid tissue within GI and respiratory tracts Overview of B cell development • B cells are generated in the bone marrow • Takes 1-2 weeks to develop from hematopoietic stem cells to mature B cells • Sequence of expression of cell surface receptor and adhesion molecules which allows for differentiation of B cells, proliferation at various stages, and movement within the bone marrow microenvironment • Immature B cell leaves the bone marrow and undergoes further differentiation • Immune system must create a repertoire of receptors capable of recognizing a large array of antigens while at the same time eliminating self-reactive B cells Overview of B cell development • Early B cell development constitutes the steps that lead to B cell commitment and expression of surface immunoglobulin, production of mature B cells • Mature B cells leave the bone marrow and migrate to secondary lymphoid tissues • B cells then interact with exogenous antigen and/or T helper cells = antigen- dependent phase Overview of B cells Hematopoiesis • Hematopoietic stem cells (HSCs) source of all blood cells • Blood-forming cells first found in the yolk sac (primarily primitive rbc production) • HSCs arise in distal aorta ~3-4 weeks • HSCs migrate to the liver (primary site of hematopoiesis after 6 wks gestation) • Bone marrow hematopoiesis starts ~5 months of gestation Role of bone
    [Show full text]
  • Hiv Coreceptors: from Discovery and Designation to New Paradigms and Promise
    October 15, 2007 EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH 375 Eur J Med Res (2007) 12: 375-384 © I. Holzapfel Publishers 2007 HIV CORECEPTORS: FROM DISCOVERY AND DESIGNATION TO NEW PARADIGMS AND PROMISE Ghalib Alkhatib1 and Edward A. Berger2 1Department of Microbiology and Immunology and the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN, 2Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA Abstract which engages target cell receptors, and the gp41 sub- Just over a decade ago, the specific chemokine recep- unit, which promotes the membrane fusion reaction tors CXCR4 and CCR5 were identified as the essential [5, 6]. coreceptors that function along with CD4 to enable Despite the rapid identification of CD4 as the “pri- human immunodeficiency virus (HIV) entry into tar- mary receptor” for HIV, it soon became clear that the get cells. The coreceptor discoveries immediately pro- complexities of virus entry and tropism could not be vided a molecular explanation for the distinct tropisms explained by CD4 expression alone; several lines of of different HIV-1 isolates for different CD4-positive evidence suggested that additional molecular compo- target cell types, and revealed fundamentally new in- nents of the entry process were yet to be uncovered. sights into host and viral factors influencing HIV For one, expression of recombinant human CD4 on transmission and disease. The sequential 2-step mech- otherwise CD4-negative human cell types rendered anism by which the HIV envelope glycoprotein (Env) them permissive for HIV infection; however efficient interacts first with CD4, then with coreceptor, re- human CD4 expression on murine cells failed to con- vealed a major mechanism by which conserved Env fer infection permissiveness, apparently due to a block epitopes are protected from antibody-mediated neu- at a very early step in the replication cycle [7].
    [Show full text]
  • Association of CXCR4 Expression with Metastasis and Survival Among Patients with Non-Small Cell Lung Cancer
    The Korean Journal of Pathology 2008; 42: 358-64 Association of CXCR4 Expression with Metastasis and Survival among Patients with Non-small Cell Lung Cancer Joon Seon Song∙Jin Kyung Jung Background : Expression of CXCR4 chemokine receptor, initially described to be involved Jong Chul Park∙Dong Kwan Kim1 in the homing of lymphocytes in inflammatory tissue, on breast cancer cell lines is associated Se Jin Jang with the development of lung metastases. In the present study, we evaluated CXCR4 expres- sion in patients with non-small cell lung cancer (NSCLC). Methods : Tissue microarray blocks Departments of Pathology and 1Thoracic were constructed from 408 formalin-fixed, paraffin-embedded NSCLC samples and analyzed and Cardiovascular Surgery, University via immunohistochemical staining. Results : We observed CXCR4 expression in 214 (66.3%) of Ulsan College of Medicine, Asan of the 323 tumors with cytoplasmic or nuclear staining patterns. These tumors were then divid- Medical Center, Seoul, Korea ed into 109 negative, 166 weak-positive and 48 strong-positive expression groups. Strong expression of CXCR4 correlated with NSCLC recurrence (p=0.047) and distant metastasis Received : August 21, 2008 (p=0.035). However, lymph node metastasis (p=0.683) and locoregional recurrence (p=0.856) Accepted : October 22, 2008 were not associated with CXCR4 expression. Interestingly, the median overall survival times Corresponding Author relative to CXCR4 expression were 71 months in the CXCR4-negative group, 43 months in Se Jin Jang, M.D. the weakly positive CXCR4 group and 23 months in the strongly positive CXCR4 group. Strong- Department of Pathology, University of Ulsan College ly positive CXCR4 staining was associated with significantly worse outcomes (p=0.005, log- of Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea rank test).
    [Show full text]
  • Chemokines Upon Activation CXCL12 And
    The Journal of Immunology ● Cutting Edge: IFN-Producing Cells Respond to CXCR3 Ligands in the Presence of CXCL12 and Secrete Inflammatory Chemokines upon Activation1 Anne Krug,* Ravindra Uppaluri,† Fabio Facchetti,‡ Brigitte G. Dorner,* Kathleen C. F. Sheehan,* Robert D. Schreiber,* Marina Cella,* and Marco Colonna2* from the blood to inflamed lymph nodes through HEV. Consistent Human natural IFN-producing cells (IPC) circulate in the with this hypothesis, human blood IPC express L-selectin and blood and cluster in chronically inflamed lymph nodes around CXCR3, the receptor for the inflammatory chemokines CXCL9 high endothelial venules (HEV). Although L-selectin, CXCR4, (monokine induced by IFN-␥), CXCL10 (IFN-␥-inducible protein and CCR7 are recognized as critical IPC homing mediators, 10), and CXCL11 (IFN-␥-inducible T cell ␣ chemoattractant) (4). the role of CXCR3 is unclear, since IPC do not respond to However, it has been shown that human IPC do not migrate in CXCR3 ligands in vitro. In this study, we show that migration vitro in response to CXCR3 ligands (5). Similarly, IPC do not of murine and human IPC to CXCR3 ligands in vitro requires respond in vitro to CCL3 (macrophage-inflammatory protein 1 engagement of CXCR4 by CXCL12. We also demonstrate that (MIP-1␣)), CCL4 (MIP-1␤), and CCL5 (RANTES) despite the CXCL12 is present in human HEV in vivo. Moreover, after expression of CCR5 (5). Human IPC also express CXCR4 and interaction with pathogenic stimuli, murine and human IPC respond to the CXCR4 ligand CXCL12 in vitro (5, 6). Importantly, secrete high levels of inflammatory chemokines. Thus, IPC CXCL12 secreted by some tumors attracts IPC and protects them migration into inflamed lymph nodes may be initially me- from IL-10-induced apoptosis in vivo (6).
    [Show full text]
  • Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but Not Decreased Promoter Methylation in Colorectal Cancer
    cancers Article Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer Alexei J. Stuckel 1, Wei Zhang 2, Xu Zhang 3, Shuai Zeng 4,5, Urszula Dougherty 6, Reba Mustafi 6, Qiong Zhang 1, Elsa Perreand 1, Tripti Khare 1 , Trupti Joshi 4,7,8 , Diana C. West-Szymanski 6, 6, 1,9, , Marc Bissonnette y and Sharad Khare * y 1 Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; [email protected] (A.J.S.); [email protected] (Q.Z.); [email protected] (E.P.); [email protected] (T.K.) 2 Department of Preventive Medicine and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; [email protected] 3 Department of Medicine, University of Illinois, Chicago, IL 60607, USA; [email protected] 4 Bond Life Sciences Center, University of Missouri, Columbia, MO 65201, USA; [email protected] (S.Z.); [email protected] (T.J.) 5 Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO 65201, USA 6 Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; [email protected] (U.D.); rmustafi@uchicago.edu (R.M.); [email protected] (D.C.W.-S.); [email protected] (M.B.) 7 Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211, USA 8 Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MO 65212, USA 9 Harry S.
    [Show full text]
  • CCR9 Homes Metastatic Melanoma Cells to the Small Bowel 55 Commentary on Amersi Et Al., P
    The Biology Behind CCR9 Homes Metastatic Melanoma Cells to the Small Bowel 55 Commentary on Amersi et al., p. 638 Ann Richmond The question of why certain types of tumors often metastasize Chemokine/chemokine receptor engagement results in acti- to the same organs has intrigued scientists for over a century. In vation of downstream signals, including phosphatidylino- 1889, Paget put forth the ‘‘seed and soil’’ concept that cancer sitol 3-kinase; ras/raf/mitogen-activated protein kinase; small cells (seed) spread in a nonrandom fashion to distant target GTPases such as Rac, Rho,Cdc42, and others; pAKT; src kinases; organs where they are drawn based on a conducive micro- DOCK/ELMO; p130Cas; FAK; machinery involved in the orga- environmental milieu (soil; ref. 1). A second concept that has nization of the actin cytoskeleton; and PKC-mediated signals been around for sometime is that tumor cells express ‘‘homing that lead to mobilization of intracellular free calcium (3). These signals’’ to direct their movement to appropriate microenviron- events occur in a cyclic fashion that involves local excitation ments for growth of metastatic lesions. A homing signal acts followed by global inhibition, allowing for modulation of the like a lighthouse to allow the ship to move toward the land. We actin cytoskeleton to facilitate extension of pseudopods and have recently come to understand that chemokine receptors retraction of uropods in a continuously cycling manner such displayed on tumor cells allow the tumor cell (seed) to follow a that the end result is directed migration up the chemokine gradient of chemokine to its target organ milieu (soil) that gradient.
    [Show full text]
  • Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3
    1521-0111/96/6/753–764$35.00 https://doi.org/10.1124/mol.119.116954 MOLECULAR PHARMACOLOGY Mol Pharmacol 96:753–764, December 2019 Copyright ª 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Special Section: From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function – Minireview Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3 Vladimir Bobkov, Marta Arimont, Aurélien Zarca, Timo W.M. De Groof, Bas van der Woning, Hans de Haard, and Martine J. Smit Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.) Downloaded from Received April 22, 2019; accepted July 3, 2019 ABSTRACT Dysregulation of the chemokine system is implicated in a number CXCR4 and ACKR3, formerly referred to as CXCR7. We of autoimmune and inflammatory diseases, as well as cancer. discuss their unique properties and advantages over small- molpharm.aspetjournals.org Modulation of chemokine receptor function is a very promising molecule compounds, and also refer to the molecules in approach for therapeutic intervention. Despite interest from preclinical and clinical development. We focus on single- academic groups and pharmaceutical companies, there are domain antibodies and scaffolds and their utilization in GPCR currently few approved medicines targeting chemokine recep- research. Additionally, structural analysis of antibody binding tors. Monoclonal antibodies (mAbs) and antibody-based mole- to CXCR4 is discussed. cules have been successfully applied in the clinical therapy of cancer and represent a potential new class of therapeutics SIGNIFICANCE STATEMENT targeting chemokine receptors belonging to the class of G Modulating the function of GPCRs, and particularly chemokine protein–coupled receptors (GPCRs).
    [Show full text]
  • Macrophages Confer Survival Signals Via CCR1-Dependent Translational MCL-1 Induction in Chronic Lymphocytic Leukemia
    OPEN Oncogene (2017) 36, 3651–3660 www.nature.com/onc ORIGINAL ARTICLE Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia MHA van Attekum1,2, S Terpstra1,2, E Slinger1,2, M von Lindern3, PD Moerland4, A Jongejan4, AP Kater1,5,6 and E Eldering2,5,6 Protective interactions with bystander cells in micro-environmental niches, such as lymph nodes (LNs), contribute to survival and therapy resistance of chronic lymphocytic leukemia (CLL) cells. This is caused by a shift in expression of B-cell lymphoma 2 (BCL-2) family members. Pro-survival proteins B-cell lymphoma-extra large (BCL-XL), BCL-2-related protein A1 (BFL-1) and myeloid leukemia cell differentiation protein 1 (MCL-1) are upregulated by LN-residing T cells through CD40L interaction, presumably via nuclear factor (NF)-κB signaling. Macrophages (Mϕs) also reside in the LN, and are assumed to provide important supportive functions for CLL cells. However, if and how Mϕs are able to induce survival is incompletely known. We first established that Mϕs induced survival because of an exclusive upregulation of MCL-1. Next, we investigated the mechanism underlying MCL-1 induction by Mϕs in comparison with CD40L. Genome-wide expression profiling of in vitro Mϕ- and CD40L-stimulated CLL cells indicated activation of the phosphoinositide 3-kinase (PI3K)-V-Akt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which was confirmed in ex vivo CLL LN material. Inhibition of PI3K-AKT-mTOR signaling abrogated MCL-1 upregulation and survival by Mϕs, as well as CD40 stimulation.
    [Show full text]