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07.05.2024 | Original Article

Inflammation mediated angiogenesis in chronic lymphocytic leukemia

verfasst von: Olivera Mitrović-Ajtić, Emilija Živković, Tijana Subotički, Miloš Diklić, Dragoslava Đikić, Milica Vukotić, Teodora Dragojević, Vojin Vuković, Darko Antić, Vladan P. Čokić

Erschienen in: Annals of Hematology

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Abstract

Chronic inflammation has been identified in leukemias as an essential regulator of angiogenesis. B-chronic lymphocytic leukemia (CLL) cells secrete high levels of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 alpha (HIF1α). The aim was to assess the role of inflammation in activation of angiogenic factors: endothelial nitric oxide synthase (eNOS), HIF1α and VEGF via proliferation related signaling pathways and VEGF autocrine control. We isolated mononuclear cells (MNC) and CD19⁺ cells from peripheral blood of 60 patients with CLL. MNC were treated with pro-inflammatory interleukin-6 (IL-6) and VEGF, in combination with inhibitors of JAK1/2 (Ruxolitinib), mTOR (Rapamycin), NF-κB (JSH23), SMAD (LDN-193189) and PI3K/AKT (Ly294002) signaling pathways, to evaluate eNOS, VEGF and HIF1α expression by immunoblotting, immunocytochemistry and RT-qPCR. Also, we investigated IL-6 dependent neovascularization in human microvascular endothelial cells (HMEC-1) in co-culture with MNC of CLL. The angiogenic factors eNOS, VEGF and HIF1α had significantly higher frequencies in MNC of CLL in comparison to healthy controls (p < 0.001) and CD19⁺ cells of CLL. IL-6 increased the quantity of HIF1α (p < 0.05) and VEGF positive cells in the presence of JSH23 (p < 0.01). VEGF increased HIF1α (p < 0.05), and decreased eNOS gene expression (p < 0.01) in MNC of CLL. VEGF significantly (p < 0.001) increased the number of HIF1α positive MNC of CLL, prevented by inhibitors of JAK1/2, PI3K and mTOR signaling pathways. VEGF stimulation of SMAD (p < 0.05) and STAT5 (p < 0.01) signaling has been prevented by inhibitors of JAK1/2, mTOR, PI3K and SMAD signaling, individually (p < 0.01) or mutually (p < 0.001). Also, we showed that MNC of CLL and IL-6 individually stimulate neovascularization in co-culture with HMEC-1, without a cumulative effect. We demonstrated elevated angiogenic factors in CLL, while VEGF and IL-6 independently stimulated HIF1α. VEGF stimulation of HIF1α was mostly mTOR dependent, while IL-6 stimulation was NF-κB dependent.

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Darwiche W, Gubler B, Marolleau JP (2018) Ghamlouch H (2018) Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues from a Functional Perspective. Front Immunol 9:683. https://doi.org/10.3389/fimmu.2018.00683CrossRefPubMedPubMedCentral

Strati P, Shanafelt TD (2015) Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 126(4):454–462. https://doi.org/10.1182/blood-2015-02-585059CrossRefPubMedPubMedCentral

Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS (2019) Contribution of Angiogenesis to Inflammation and Cancer. Front Oncol 9:1399. https://doi.org/10.3389/fonc.2019.01399CrossRefPubMedPubMedCentral

MitrovićAjtić O, Subotički T, Diklić M, Đikić D, Vukotić M, Dragojević T, Živković E, Antić D, Čokić V (2022) Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia. Int J Mol Sci 23(13):6952. https://doi.org/10.3390/ijms23136952CrossRef

Han Y, Wang X, Wang B, Jiang G (2016) The progress of angiogenic factors in the development of leukemias. Intractable Rare Dis Res 5(1):6–16. https://doi.org/10.5582/irdr.2015.01048CrossRefPubMedPubMedCentral

Montemagno C, Pagès G (2020) Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs. Front Cell Dev Biol 8:584. https://doi.org/10.3389/fcell.2020.00584CrossRefPubMedPubMedCentral

Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ, Cairnduff F, Selby PJ, Perren TJ, Lansdown M, Banks RE (2000) Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 60:2898–2905PubMed

Kay NE, Bone ND, Tschumper RC, Howell KH, Geyer SM, Dewald GW, Hanson CA, Jelinek DF (2002) B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 16:911–919. https://doi.org/10.1038/sj.leu.2402467CrossRefPubMed

Griggio V, Vitale C, Todaro M, Riganti C, Kopecka J, Salvetti C, Bomben R, Bo MD, Magliulo D, Rossi D, Pozzato G, Bonello L, Marchetti M, Omedè P, Kodipad AA, Laurenti L, Del Poeta G, Mauro FR, Bernardi R, Zenz T, Gattei V, Gaidano G, Foà R, Massaia M, Boccadoro M, Coscia M (2020) HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia. Haematologica 105(4):1042–1054. https://doi.org/10.3324/haematol.2019.217430CrossRefPubMedPubMedCentral

10.

Ghosh AK, Shanafelt TD, Cimmino A, Taccioli C, Volinia S, Liu CG, Calin GA, Croce CM, Chan DA, Giaccia AJ, Secreto C, Wellik LE, Lee YK, Mukhopadhyay D, Kay NE (2009) Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood 113(22):5568–5574. https://doi.org/10.1182/blood-2008-10-185686CrossRefPubMedPubMedCentral

11.

Lopes-Coelho F, Martins F, Pereira SA, Serpa J (2021) Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 22(7):3765. https://doi.org/10.3390/ijms22073765CrossRefPubMedPubMedCentral

12.

Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2:826–835. https://doi.org/10.1038/nrc925CrossRefPubMed

13.

Subotički T, MitrovićAjtić O, Živković E, Diklić M, Đikić D, Tošić M, Beleslin-Čokić B, Dragojević T, Gotić M, Santibanez JF, Čokić V (2021) VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms. Int J Mol Sci 22(13):6671. https://doi.org/10.3390/ijms22136671CrossRefPubMedPubMedCentral

14.

Darwiche W, Gubler B, Marolleau JP, Ghamlouch H (2018) Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective. Front Immunol 9:683. https://doi.org/10.3389/fimmu.2018.00683CrossRefPubMedPubMedCentral

15.

Hoermann G, Greiner G, Valent P (2015) Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms. Mediat Inflamm 2015:869242. https://doi.org/10.1155/2015/869242CrossRef

16.

Zhu F, McCaw L, Spaner DE, Gorczynski RM (2018) Targeting the IL-17/IL-6 axis can alter growth of Chronic Lymphocytic Leukemia in vivo/in vitro. Leuk Res 66:28–38. https://doi.org/10.1016/j.leukres.2018.01.006CrossRefPubMed

17.

Maffei R, Martinelli S, Castelli I, Santachiara R, Zucchini P, Fontana M, Fiorcari S, Bonacorsi G, Ilariucci F, Torelli G, Marasca R (2010) Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia derived Ang2 and VEGF. Leuk Res 34(3):312–321. https://doi.org/10.1016/j.leukres.2009.06.023CrossRefPubMed

18.

Frater JL, Kay NE, Goolsby CL, Crawford SE, Dewald GW, Peterson LC (2008) Dysregulated angiogenesis in B-chronic lymphocytic leukemia: morphologic, immunohistochemical, and flow cytometric evidence. Diagn Pathol 3:16. https://doi.org/10.1186/1746-1596-3-16CrossRefPubMedPubMedCentral

19.

Ribatti D, Vacca A, De Falco G, Ria R, Roncali L, Damacco F (2001) Role of hematopoietic growth factors in angiogenesis. Acta Haematol 106:157–161. https://doi.org/10.1159/000046611CrossRefPubMed

20.

Kay NE, Strati P, LaPlant BR, Leis JF, Nikcevich D, Call TG, Pettinger AM, Lesnick CE, Hanson CA, Shanafelt TD (2016) A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia. Oncotarget 7(48):78269–78280. https://doi.org/10.18632/oncotarget.13412CrossRefPubMedPubMedCentral

21.

Lu J, Cannizzaro E, Meier-Abt F, Scheinost S, Bruch PM, Giles HA, Lütge A, Hüllein J, Wagner L, Giacopelli B, Nadeu F, Delgado J, Campo E, Mangolini M, Ringshausen I, Böttcher M, Mougiakakos D, Jacobs A, Bodenmiller B, Dietrich S, Oakes CC, Zenz T, Huber W (2021) Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia. Nat Cancer 2(8):853–864. https://doi.org/10.1038/s43018-021-00216-6CrossRefPubMedPubMedCentral

22.

Zent CS, LaPlant BR, Johnston PB, Call TG, Habermann TM, Micallef IN, Witzig TE (2010) The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer 116:2201–2207. https://doi.org/10.1002/cncr.25005CrossRefPubMed

23.

Blunt MD, Carter MJ, Larrayoz M, Smith LD, Aguilar-Hernandez M, Cox KL, Tipton T, Reynolds M, Murphy S, Lemm E, Dias S, Duncombe A, Strefford JC, Johnson PW, Forconi F, Stevenson FK, Packham G, Cragg MS, Steele AJ (2015) The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eμ-TCL1 mouse model. Blood 25:4032–4041. https://doi.org/10.1182/blood-2014-11-610329CrossRef

24.

Chen Y, Chen L, Yu J, Ghia EM, Choi MY, Zhang L, Zhang S, Sanchez-Lopez E, Widhopf GF 2nd, Messer K, Rassenti LZ, Jamieson C, Kipps TJ (2019) Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia. Blood 134(13):1084–1094. https://doi.org/10.1182/blood.2019001366CrossRefPubMedPubMedCentral

25.

Farahani M, Treweeke AT, Toh CH, Till KJ, Harris RJ, Cawley JC, Zuzel M, Chen H (2005) Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells. Leukemia 19(4):524–530. https://doi.org/10.1038/sj.leu.2403631CrossRefPubMed

26.

Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S (2012) PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis. Adv Hematol 843085. https://doi.org/10.1155/2012/843085

27.

Ellis L, Hammers H, Pili R (2009) Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 280(2):145–153. https://doi.org/10.1016/j.canlet.2008.11.012CrossRefPubMed

28.

Li Q, Michaud M, Canosa S, Kuo A, Madri JA (2011) GSK-3β: a signaling pathway node modulating neural stem cell and endothelial cell interactions. Angiogenesis 14(2):173–185. https://doi.org/10.1007/s10456-011-9201-9CrossRefPubMed

29.

Khodashenas M, Rajabian A, Attaranzadeh A, Lavi Arab F, Allahyari N (1992) Allahyari A (2022) Evaluation of cytokine levels as possible predicting elements in patients with chronic lymphocytic leukemia. Rev Assoc Med Bras 68(10):1364–1368. https://doi.org/10.1590/1806-9282.20220260CrossRef

30.

Bibi S, Arslanhan MD, Langenfeld F, Jeanningros S, Cerny-Reiterer S, Hadzijusufovic E, Tchertanov L, Moriggl R, Valent P, Arock M (2014) Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy. Haematologica 99(3):417–429. https://doi.org/10.3324/haematol.2013.098442CrossRefPubMedPubMedCentral

31.

Matvieieva AS, Kovalevska LM, Ivanivska TS, Klein E, Kashuba EV (2019) The STAT5 transcription factor in B-cells of patients with chronic lymphocytic leukemia. Biopolym Cell 30–38. https://doi.org/10.7124/bc.000993

32.

Witkowska M, Majchrzak A, Cebula-Obrzut B, Wawrzyniak E, Robak T, Smolewski P (2017) The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia. Tumour Biol 39(3):1010428317694551. https://doi.org/10.1177/1010428317694551CrossRefPubMed

Titel: Inflammation mediated angiogenesis in chronic lymphocytic leukemia
verfasst von: Olivera Mitrović-Ajtić
Emilija Živković
Tijana Subotički
Miloš Diklić
Dragoslava Đikić
Milica Vukotić
Teodora Dragojević
Vojin Vuković
Darko Antić
Vladan P. Čokić
Publikationsdatum: 07.05.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-024-05781-1

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Inflammation mediated angiogenesis in chronic lymphocytic leukemia

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Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

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GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

Update Innere Medizin