Regulation and function of angiogenic factors in chronic lymphocytic leukemia

Abstract

Progression of chronic lymphocytic leukemia (CLL) is determined by the localization of malignant cells in lymphoid tissues, where they receive growth and survival signals. CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease. Stromal cellular and molecular components in CLL niches disturb the balance of pro- and antiangiogenic molecules in CLL cells and induce an angiogenic switch. Additionally, CLL cells also influence the behavior of microenvironmental cells, inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages, neutrophils, and other cells present in CLL niches. As a result of these reciprocal functional interactions, bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease. Besides their role in regulating angiogenesis, angiogenic factors are also involved in CLL cell migration and survival, all contributing to disease progression. Angiogenic factors, particularly vascular endothelial growth factor, have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years. However, the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.

Keywords

Chronic lymphocytic leukemia / angiogenic factors / CLL microenvironment / CLL migration and survival / antiangiogenic therapy

References

[1] Zenz T,Küppers R,Stilgenbauer S.From pathogenesis to treatment of chronic lymphocytic leukaemia.Nat Rev Cancer2010;10:37-50

[2] Gaidano G,Dalla-Favera R.Molecular pathogenesis of chronic lymphocytic leukemia.J Clin Invest2012;122:3432-8 PMCID:PMC3461921

[3] Hallek M,Eichhorst B.Chronic lymphocytic leukaemia.Lancet2018;391:1524-37

[4] Delgado J,Colomer D.Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies.Haematologica2020;105:2205-17 PMCID:PMC7556519

[5] Rai KR,Cronkite EP,Levy RN.Clinical staging of chronic lymphocytic leukemia.Blood1975;46:219-34

[6] Binet JL,Dighiero G.A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.Cancer1981;48:198-206

[7] Eichhorst B,Montserrat E.ESMO Guidelines CommitteeChronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol2021;32:23-33

[8] Fürstenau M.Novel agents in chronic lymphocytic leukemia: new combination therapies and strategies to overcome resistance.Cancers (Basel)2021;13:1336 PMCID:PMC8002361

[9] Seifert M,Bloehdorn J.Cellular origin and pathophysiology of chronic lymphocytic leukemia.J Exp Med2012;209:2183-98 PMCID:PMC3501361

[10] Bulian P,Fegan C.CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia.J Clin Oncol2014;32:897-904 PMCID:PMC4876311

[11] Burgler S.Role of CD38 expression in diagnosis and pathogenesis of chronic lymphocytic leukemia and its potential as therapeutic target.Crit Rev Immunol2015;35:417-32

[12] Puente XS,Quesada V.Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.Nature2011;475:101-5 PMCID:PMC3322590

[13] Benedetti D,Pozzo F.NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways.Leukemia2018;32:654-62

[14] Davids MS.Cell trafficking in chronic lymphocytic leukemia.Open J Hematol2012;3:1 PMCID:PMC3404599

[15] Redondo-Muñoz J,Teixidó J.Molecular players in hematologic tumor cell trafficking.Front Immunol2019;10:156 PMCID:PMC6372527

[16] Malavasi F,Damle R,Ferrarini M.CD38 and chronic lymphocytic leukemia: a decade later.Blood2011;118:3470-8 PMCID:PMC3574275

[17] Gutjahr JC,Hartmann TN.The role of CD44 in the pathophysiology of chronic lymphocytic leukemia.Front Immunol2015;6:177 PMCID:PMC4403525

[18] Burger JA.The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies.Semin Cancer Biol2014;24:71-81

[19] Aguayo A,Manshouri T.Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes.Blood2000;96:2240-5

[20] Shanafelt TD.The clinical and biologic importance of neovascularization and angiogenic signaling pathways in chronic lymphocytic leukemia.Semin Oncol2006;33:174-85

[21] Letilovic T,Verstovsek S,Ferrajoli A.Role of angiogenesis in chronic lymphocytic leukemia.Cancer2006;107:925-34

[22] Kini AR,Peterson LC.Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia.Leukemia2000;14:1414-8

[23] Peterson L.Angiogenesis is increased in B-cell chronic lymphocytic leukemia.Blood2001;97:2529

[24] Frater JL,Goolsby CL,Dewald GW.Dysregulated angiogenesis in B-chronic lymphocytic leukemia: morphologic, immunohistochemical, and flow cytometric evidence.Diagn Pathol2008;3:16 PMCID:PMC2362108

[25] Negaard HF,Bowitz-Lothe IM.Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors.Leukemia2009;23:162-9

[26] Molica S,Ribatti D.Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia.Blood2002;100:3344-51

[27] Molica S,Vitelli G.Markers of increased angiogenesis and their correlation with biological parameters identifying high-risk patients in early B-cell chronic lymphocytic leukemia.Leuk Res2007;31:1575-8

[28] Ding W,Knox TR.Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression.Br J Haematol2009;147:471-83 PMCID:PMC2783570

[29] Attekum MH, Eldering E, Kater AP. Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk.Haematologica2017;102:1469-76 PMCID:PMC5685246

[30] Dubois N,Meuleman N,Lagneaux L.Importance of crosstalk between chronic lymphocytic leukemia cells and the stromal microenvironment: direct contact, soluble factors, and extracellular vesicles.Front Oncol2020;10:1422 PMCID:PMC7466743

[31] Kay NE,Strege AK,Bone ND.Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an "angiogenic switch".Leuk Res2007;31:899-906 PMCID:PMC2505044

[32] Edelmann J,Carpinteiro A.Bone marrow fibroblasts induce expression of PI3K/NF-kappaB pathway genes and a pro-angiogenic phenotype in CLL cells.Leuk Res2008;32:1565-72

[33] Maffei R,Bulgarelli J.Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells.Haematologica2012;97:952-60 PMCID:PMC3366665

[34] Xia Y,Li J.Angiogenic factors in chronic lymphocytic leukemia.Leuk Res2012;36:1211-7

[35] Aguirre Palma LM,Kreuzer KA.Angiogenic factors in chronic lymphocytic leukaemia (CLL): where do we stand?.Crit Rev Oncol Hematol2015;93:225-36

[36] Kay NE,Tschumper RC.B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules.Leukemia2002;16:911-9

[37] Baban D,Earl H,Seymour L.Quantitative analysis of vascular endothelial growth factor expression in chronic lymphocytic leukaemia.Int J Oncol1996:8:29-34

[38] Chen H,West DC.In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells.Blood2000;96:3181-7

[39] Ho CL,Phyliky RL.Autocrine expression of platelet-derived growth factor B in B cell chronic lymphocytic leukemia.Acta Haematol2005;114:133-40

[40] Bauvois B,Mathiot C.Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons.Leukemia2002;16:791-8

[41] Kamiguti AS,Till KJ.The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia.Br J Haematol2004;125:128-40

[42] Redondo-Muñoz J,Samaniego R,García-Marco JA.MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha4beta1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration.Blood2006;108:3143-51

[43] Duensing S.Increased intracellular and plasma levels of basic fibroblast growth factor in B-cell chronic lymphocytic leukemia.Blood1995;85:1978-80

[44] Menzel T,Calleja E.Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine.Blood1996;87:1056-63

[45] Gora-Tybor J,Robak T.Circulating proangiogenic cytokines and angiogenesis inhibitor endostatin in untreated patients with chronic lymphocytic leukemia.Mediators Inflamm2003;12:167-71 PMCID:PMC1781611

[46] Takahashi H.The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions.Clin Sci (Lond)2005;109:227-41

[47] Olsson AK,Kreuger J.VEGF receptor signalling - in control of vascular function.Nat Rev Mol Cell Biol2006;7:359-71

[48] Shibuya M.Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies.Genes Cancer2011;2:1097-105 PMCID:PMC3411125

[49] Ferrara N,LeCouter J.The biology of VEGF and its receptors.Nat Med2003;9:669-76

[50] Molica S,Levato D,Liso V.Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia.Br J Haematol1999;107:605-10

[51] Molica S,Levato D,Digiesi G.Clinicoprognostic implications of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in early B-cell chronic lymphocytic leukaemia.Br J Cancer2002;86:31-5 PMCID:PMC2746542

[52] Ding W,Tschumper RC.Platelet-derived growth factor (PDGF)-PDGF receptor interaction activates bone marrow-derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch.Blood2010;116:2984-93 PMCID:PMC2974606

[53] Maffei R,Martinelli S.Angiopoietin-2 expression in B-cell chronic lymphocytic leukemia: association with clinical outcome and immunoglobulin heavy-chain mutational status.Leukemia2007;21:1312-5

[54] Maffei R,Santachiara R.Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia.Blood2010;116:584-92

[55] Vrbacky F,Vroblova V.Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features.Hematology2010;15:210-4

[56] Molica S,Levato D.Increased serum levels of matrix metalloproteinase-9 predict clinical outcome of patients with early B-cell chronic lymphocytic leukaemia.Eur J Haematol2003;70:373-8

[57] Gusella M,Paolini R.Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia.Tumour Biol2017;39:1010428317694325

[58] Lopez-Dee Z,Gutierrez LS.Thrombospondin-1: multiple paths to inflammation.Mediators Inflamm2011;2011:296069 PMCID:PMC3134184

[59] Rosenwald A,Widhopf G.Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.J Exp Med2001;194:1639-47 PMCID:PMC2193523

[60] Sinha S,Nelson M.Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells.Leukemia2016;30:1431-6 PMCID:PMC4879100

[61] Ferrajoli A,Estrov Z.High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.Clin Cancer Res2001;7:795-9

[62] Bairey O,Kaganovsky E,Shaklai M.All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells.Leuk Res2004;28:243-8

[63] Nowakowski GS,Wu X.Neuropilin-1 is expressed by chronic lymphocytic leukemia B cells.Leuk Res2008;32:1634-6 PMCID:PMC3440870

[64] Piechnik A,Omiotek M.The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients.Int J Cancer2013;133:1489-96

[65] Gutiérrez-González A,Ugarte-Berzal E.α4β1 integrin associates with VEGFR2 in CLL cells and contributes to VEGF binding and intracellular signaling.Blood Adv2019;3:2144-8 PMCID:PMC6650728

[66] Saharinen P,Santoyo MM,Alitalo K.The TIE receptor family. In: Wheeler DL, Yarden Y, editors. Receptor tyrosine kinases: family and subfamilies. Cham: Springer International Publishing; 2015. p. 743-75.

[67] Aguayo A,O'brien S.Clinical relevance of Flt1 and Tie1 angiogenesis receptors expression in B-cell chronic lymphocytic leukemia (CLL).Leuk Res2001;25:279-85

[68] Palma LM, Flamme H, Gerke I, Kreuzer KA. Angiopoietins modulate survival, migration, and the components of the Ang-Tie2 pathway of chronic lymphocytic leukaemia (CLL) cells in vitro.Cancer Microenviron2016;9:13-26 PMCID:PMC4842182

[69] Pötzsch B,Poll-Wolbeck S,Kreuzer KA.Angiopoietin-2/Tie2 signaling in the microenvironment of chronic lymphocytic leukemia (CLL).Res Cancer Tumor2014;3:6-18

[70] Maffei R,Martinelli S.Angiopoietin-2 acts as a survival factor for chronic lymphocytic leukemia B cells throughout Tie-2 receptor engagement.Hematol Oncol2018;36:372-5

[71] Bogdanovic E,Dumont DJ.Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization.J Cell Sci2006;119:3551-60

[72] Rutella S,Puggioni P,Di Mario A.Expression of thrombospondin receptor (CD36) in B-cell chronic lymphocytic leukemia as an indicator of tumor cell dissemination.Haematologica1999;84:419-24

[73] Mateo V,Bron D.CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia.Nat Med1999;5:1277-84

[74] Mateo V,Biron G.Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization.Blood2002;100:2882-90

[75] Redondo-Muñoz J,García-Marco JA.Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells.Blood2008;112:169-78

[76] Amigo-Jiménez I,Ugarte-Berzal E,García-Marco JA.Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide.PLoS One2014;9:e99993 PMCID:PMC4067296

[77] Bailón E,Amigo-Jiménez I.Overexpression of progelatinase B/proMMP-9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen.J Leukoc Biol2014;96:185-99

[78] Aguilera-Montilla N,Uceda-Castro R.MMP-9 affects gene expression in chronic lymphocytic leukemia revealing CD99 as an MMP-9 target and a novel partner in malignant cell migration/arrest.Oncogene2019;38:4605-19

[79] Aguilera-Montilla N,Ugarte-Berzal E.Matrix metalloproteinase-9 induces a pro-angiogenic profile in chronic lymphocytic leukemia cells.Biochem Biophys Res Commun2019;520:198-204

[80] Cohen JA,Pozzo F.An updated perspective on current prognostic and predictive biomarkers in chronic lymphocytic leukemia in the context of chemoimmunotherapy and novel targeted therapy.Cancers (Basel)2020;12:894 PMCID:PMC7226446

[81] Redondo-Muñoz J,Terol MJ.Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.Cancer Cell2010;17:160-72

[82] Tissino E,Benedetti D.CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression.Blood2020;135:1244-54 PMCID:PMC7228464

[83] Maffei R,Castelli I.Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF.Leuk Res2010;34:312-21

[84] Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.Biochim Biophys Acta2016;1863:401-13 PMCID:PMC4715999

[85] Schulz A,Zenz T,Lichter P.Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2.Haematologica2011;96:408-16 PMCID:PMC3046272

[86] Do HTT,Cho J.Chemokines and their receptors: multifaceted roles in cancer progression and potential value as cancer prognostic markers.Cancers (Basel)2020;12:287 PMCID:PMC7072521

[87] Ugarte-Berzal E,Eroles P.VEGF/VEGFR2 interaction down-regulates matrix metalloproteinase-9 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration.Blood2010;115:846-9

[88] Ma Z,Benveniste EN.Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-gamma and IFN-beta: critical role of STAT-1alpha.J Immunol2001;167:5150-9

[89] Niu G,Huang M.Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.Oncogene2002;21:2000-8

[90] Chen Z.STAT3: a critical transcription activator in angiogenesis.Med Res Rev2008;28:185-200

[91] Badoux X,Harris D.Cross-talk between chronic lymphocytic leukemia cells and bone marrow endothelial cells: role of signal transducer and activator of transcription 3.Hum Pathol2011;42:1989-2000 PMCID:PMC4085742

[92] Gao P,Wei T.The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis.Oncotarget2017;8:69139-61 PMCID:PMC5620326

[93] Lozano-Santos C,Fernandez-Cuevas B.Vascular endothelial growth factor A (VEGFA) gene polymorphisms have an impact on survival in a subgroup of indolent patients with chronic lymphocytic leukemia.PLoS One2014;9:e101063 PMCID:PMC4074164

[94] Góra-Tybor J,Robak T.Clinical relevance of vascular endothelial growth factor type A (VEGFA) and VEGF receptor type 2 (VEGFR2) gene polymorphism in chronic lymphocytic leukemia.Blood Cells Mol Dis2015;54:139-43

[95] Ballester S,Rodrigues P,Terol MJ.Clinical relevance of +936 C>T VEGFA and c.233C>T bFGF polymorphisms in chronic lymphocytic leukemia.Genes (Basel)2020;11:686 PMCID:PMC7349122

[96] Martinelli S,Maffei R.ANGPT2 promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia.Epigenetics2013;8:720-9 PMCID:PMC3781191

[97] Kopparapu PK,Fogelstrand L.MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.FEBS J2015;282:1939-52

[98] Martinelli S,Fiorcari S.The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli.Leuk Res2017;54:17-24

[99] Trimarco V,Facco M.Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival.Oncotarget2015;6:42130-49 PMCID:PMC4747215

[100] Mesaros O,Neaga A.Macrophage polarization in chronic lymphocytic leukemia: nurse-like cells are the caretakers of leukemic cells.Biomedicines2020;8:516 PMCID:PMC7699370

[101] Fiorcari S,Atene CG,Luppi M.Nurse-like cells and chronic lymphocytic leukemia B cells: a mutualistic crosstalk inside tissue microenvironments.Cells2021;10:217 PMCID:PMC7911538

[102] Apte RS.Regulation of angiogenesis by macrophages.Adv Exp Med Biol2010;664:15-9

[103] Riabov V,Wang N,Orekhov A.Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis.Front Physiol2014;5:75 PMCID:PMC3942647

[104] Murray PJ,Biswas SK.Macrophage activation and polarization: nomenclature and experimental guidelines.Immunity2014;41:14-20 PMCID:PMC4123412

[105] Jaiswal S,Majeti R.Macrophages as mediators of tumor immunosurveillance.Trends Immunol2010;31:212-9 PMCID:PMC3646798

[106] Biswas SK.Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat Immunol2010;11:889-96

[107] Noy R.Tumor-associated macrophages: from mechanisms to therapy.Immunity2014;41:49-61 PMCID:PMC4137410

[108] Audrito V,Brusa D.Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia.Blood2015;125:111-23

[109] Jia L,Liu FT.Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia.Blood2014;123:1709-19 PMCID:PMC3954052

[110] Zajac E,Kupriyanova TA.Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9.Blood2013;122:4054-67 PMCID:PMC3862278

[111] Ardi VC,Deryugina EI.Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis.Proc Natl Acad Sci U S A2007;104:20262-7 PMCID:PMC2154419

[112] Deryugina EI,Juncker-Jensen A,Welter L.Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment.Neoplasia2014;16:771-88 PMCID:PMC4212255

[113] Seignez C.The multitasking neutrophils and their involvement in angiogenesis.Curr Opin Hematol2017;24:3-8

[114] Christoffersson G,Vandooren J.VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue.Blood2012;120:4653-62 PMCID:PMC3512240

[115] Massena S,Vågesjö E.Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans.Blood2015;126:2016-26 PMCID:PMC4616235

[116] Manukyan G,Gajdos P.Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects.Oncotarget2017;8:84889-901 PMCID:PMC5689581

[117] Podaza E,Colado A.Chronic lymphocytic leukemia cells increase neutrophils survival and promote their differentiation into CD16^high CD62L^dim immunosuppressive subset.Int J Cancer2019;144:1128-34

[118] Raposo G.Extracellular vesicles: exosomes, microvesicles, and friends.J Cell Biol2013;200:373-83 PMCID:PMC3575529

[119] Liu Y,Chen Y.Exosomes and their role in cancer progression.Front Oncol2021;11:639159 PMCID:PMC8020998

[120] Paggetti J,Seiffert M.Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.Blood2015;126:1106-17 PMCID:PMC4560344

[121] Ghosh AK,Knox TR,Mukhopadhyay D.Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression.Blood2010;115:1755-64 PMCID:PMC2832808

[122] Nisticò N,Iaccino E.Role of chronic lymphocytic leukemia (cll)-derived exosomes in tumor progression and survival.Pharmaceuticals (Basel)2020;13:244 PMCID:PMC7557731

[123] Yeh YY,Lehman AM.Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.Blood2015;125:3297-305 PMCID:PMC4440883

[124] Ferrajoli A,Ivan C.Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.Blood2013;122:1891-9 PMCID:PMC3779381

[125] Farahani M,Liu L,Kalakonda N.CLL exosomes modulate the transcriptome and behaviour of recipient stromal cells and are selectively enriched in miR-202-3p.PLoS One2015;10:e0141429 PMCID:PMC4625016

[126] Prieto D,Seija N.S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression.Blood2017;130:777-88

[127] Geng HY,Zhang JJ.Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGβ1-MAPK/ERK axis.Kaohsiung J Med Sci2021;37:226-35

[128] Crompot E,Pieters K.Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications.Haematologica2017;102:1594-604 PMCID:PMC5685228

[129] Till KJ,Harris RJ,Zuzel M.CLL, but not normal, B cells are dependent on autocrine VEGF and alpha4beta1 integrin for chemokine-induced motility on and through endothelium.Blood2005;105:4813-9

[130] Bonnans C,Werb Z.Remodelling the extracellular matrix in development and disease.Nat Rev Mol Cell Biol2014;15:786-801 PMCID:PMC4316204

[131] García-pardo A.Nonproteolytic functions of matrix metalloproteinases in pathology and insights for the development of novel therapeutic inhibitors.Metalloproteinases Med2015;2:19-28

[132] Bailón E,Gutiérrez-González A.A catalytically inactive gelatinase B/MMP-9 mutant impairs homing of chronic lymphocytic leukemia cells by altering migration regulatory pathways.Biochem Biophys Res Commun2018;495:124-30

[133] Vaisitti T,Pepper C.CD38 signals upregulate expression and functions of matrix metalloproteinase-9 in chronic lymphocytic leukemia cells.Leukemia2013;27:1177-81

[134] Lee YK,Strege AK,Jelinek DF.VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia.Blood2004;104:788-94

[135] Lee YK,Bone ND,Jelinek DF.VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance.Leukemia2005;19:513-23

[136] Pepper C,Lin TT.Highly purified CD38+ and CD38- sub-clones derived from the same chronic lymphocytic leukemia patient have distinct gene expression signatures despite their monoclonal origin.Leukemia2007;21:687-96

[137] Farahani M,Toh CH.Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells.Leukemia2005;19:524-30

[138] Avraamides CJ,Varner JA.Integrins in angiogenesis and lymphangiogenesis.Nat Rev Cancer2008;8:604-17 PMCID:PMC2577722

[139] König A,Lynen S.Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis.Leukemia1997;11:258-65

[140] Bairey O,Shaklai M.Bcl-2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia.Br J Haematol2001;113:400-6

[141] Romanov VV,Sherrington PD.Basic fibroblast growth factor suppresses p53 activation in the neoplastic cells of a proportion of patients with chronic lymphocytic leukaemia.Oncogene2005;24:6855-60

[142] Martinez-Torres AC,Attout T.CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.PLoS Med2015;12:e1001796 PMCID:PMC4348493

[143] Ringshausen I,Schneller F.Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells.Leukemia2004;18:1964-70

[144] Condoluci A.Richter syndrome.Curr Oncol Rep2021;23:26 PMCID:PMC7880969

[145] Kohlhaas V,Al-Maarri M.Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1.Blood2021;137:646-60

[146] Keating MJ,Albitar M.Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.J Clin Oncol2005;23:4079-88

[147] Molica S,Tucc L.Reversal of bone marrow angiogenesis in chronic lymphocytic leukemia following fludarabine therapy.Haematologica2005;90:698-700

[148] Molica S,Ribatti D.Intense reversal of bone marrow angiogenesis after sequential fludarabine-induction and alemtuzumab-consolidation therapy in advanced chronic lymphocytic leukemia.Haematologica2007;92:1367-74

[149] López-Guerra M,Rosich L.The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.Leukemia2015;29:96-106

[150] Maffei R,Vaisitti T.Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia.Oncotarget2017;8:90013-27 PMCID:PMC5685728

[151] Moreira AL,Zmuidzinas A,Smith KA.Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.J Exp Med1993;177:1675-80 PMCID:PMC2191046

[152] D'Amato RJ,Flynn E.Thalidomide is an inhibitor of angiogenesis.Proc Natl Acad Sci U S A1994;91:4082-5 PMCID:PMC43727

[153] Chanan-Khan A,Takeshita K.Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).Blood2005;106:3348-52

[154] Kotla V,Nischal S.Mechanism of action of lenalidomide in hematological malignancies.J Hematol Oncol2009;2:36 PMCID:PMC2736171

[155] Chanan-Khan A,Musial L.Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study.J Clin Oncol2006;24:5343-9

[156] Ferrajoli A,Schlette EJ.Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia.Blood2008;111:5291-7 PMCID:PMC4082321

[157] Maffei R,Bulgarelli J.Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia.Exp Hematol2014;42:126-36.e1

[158] Aue G,Tian X.Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia.Am J Hematol2011;86:835-40 PMCID:PMC3414537

[159] Egle A,Melchardt T.Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.Ann Hematol2018;97:1825-39 PMCID:PMC6097797

[160] Mauro FR,Molica S.Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial.Leuk Lymphoma2017;58:1640-7

[161] Strati P,Peterson CB.Efficacy and predictors of response of lenalidomide and rituximab in patients with treatment-naive and relapsed CLL.Blood Adv2019;3:1533-9 PMCID:PMC6517659

[162] Ossenkoppele GJ,Maertens J.Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK).Blood2012;120:4706-11

[163] Paesler J,Poll-Wolbeck SJ.Targeting the vascular endothelial growth factor in hematologic malignancies.Eur J Haematol2012;89:373-84

[164] Bogusz J,Mędra A,Robak T.Mechanisms of action of the anti-VEGF monoclonal antibody bevacizumab on chronic lymphocytic leukemia cells.Postepy Hig Med Dosw (Online)2013;67:107-18

[165] Shanafelt T,Byrd J.Phase II trials of single-agent anti-VEGF therapy for patients with chronic lymphocytic leukemia.Leuk Lymphoma2010;51:2222-9 PMCID:PMC3928074

[166] Kay NE,LaPlant BR.A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia.Oncotarget2016;7:78269-80 PMCID:PMC5346637

[167] Paesler J,Gandhirajan RK.The vascular endothelial growth factor receptor tyrosine kinase inhibitors vatalanib and pazopanib potently induce apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo.Clin Cancer Res2010;16:3390-8

[168] Cornwall S,Joske D.Green tea polyphenol "epigallocatechin-3-gallate", differentially induces apoptosis in CLL B-and T-Cells but not in healthy B-and T-Cells in a dose dependant manner.Leuk Res2016;51:56-61

[169] Huber S,Decker T.Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1.Leukemia2011;25:838-47

[170] Messmer D,O'Hayre M,Handel TM.Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib.Blood2011;117:882-9 PMCID:PMC3035080

[171] Dwojak M,Bil J.Sorafenib improves rituximab and ofatumumab efficacy by decreasing the expression of complement regulatory proteins.Blood Cancer J2015;5:e300 PMCID:PMC4450327