Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

Palma, Luis Mario Aguirre; Gehrke, Iris; Kreuzer, Karl‐Anton

doi:10.1016/j.critrevonc.2014.10.007

Cited by 17 publications

(6 citation statements)

References 116 publications

(182 reference statements)

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“…CLL cells form areas of larger proliferating cells, known as pseudofollicles, establishing intimate contact with the accessory cells that favor CLL survival and proliferation, promote clonal evolution and protect cells from the effect of chemotherapeutics. In addition, CLL cells shape the physiologic network of microvessels in infiltrated-BM and LN compartments, by destabilizing the mature and quiescent status of blood vessels and promoting endothelial cells (EC) proliferation, migration and branching to form a dense weaving of functionally impaired microvessels [ 2 ]. In this context, CLL cells are not innocent bystanders, but actively dominate and model the surrounding microenvironment to aberrantly orchestrate the function of supporting elements and EC [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

et al. 2017

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The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase δ inhibitor idelalisib and to fludarabine. Here, we demonstrate that CLL cells express not only ETA receptor but also ETB receptor. ET-1 acts as a homing factor supporting CLL cells migration and adhesion to microenvironmental cells. In addition, ET-1 stimulates a pro-angiogenic profile of CLL cells increasing VEGF expression through hypoxia-inducible factor-1 (HIF-1α) accumulation in CLL cells. Macitentan, a specific dual inhibitor of ETA and ETB receptors, targets CLL cells affecting leukemic cells migration and adhesion and overcoming the pro-survival and proliferation signals mediated by microenvironment. Furthermore, macitentan cooperates with ibrutinib inhibiting the BCR pathway and with ABT-199 disrupting BCL2 pathway. Our data describe the biological effects of a new drug, macitentan, able to counteract essential processes in CLL pathobiology as survival, migration, trafficking and drug resistance. These findings envision the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients.

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Section: Introductionmentioning

confidence: 99%

Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

et al. 2017

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“…Of particular note is the identification of multiple ontology terms relate to B-cell physiology and morphology, as well as abnormalities of immune system physiology, such as immunodeficiency and agammaglobulinemia (Additional file 2 : Table S10 and Additional file 3 Figure S1), which are characteristic clinical findings in CLL [ 56 ]. Finally, pathway analysis revealed changes in lipid and lipoprotein metabolism, Fc gamma and epsilon receptor signaling, as well as NGF , VEGF , WNT , NOTCH and B-cell signaling and DNA damage response pathways (Additional file 2 : Tables S9 and S10), all of which are known to be perturbed CLL [ 57 – 62 ].…”

Section: Discussionmentioning

confidence: 99%

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis

et al. 2017

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BackgroundB-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.ResultsWe employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0–15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.ConclusionsOur findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4117-4) contains supplementary material. Note to Editor: If Journal regulations permit, the Supplementary material should be available to all without any additional authorisation.

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“…More recently, a study on colon cancer showed that EVs containing miR-92a-3p can facilitate the endothelial-mesenchymal transition and the angiogenesis process affecting the TME [226]. As mentioned in Section 2, the same molecule is involved in a mechanism of activation of the VEGF-based autocrine pathway in CLL B-cells which leads to disease progression and is associated with poor prognosis in CLL [50,51,227]. These observations indicated that an anti-VEFG approach may be therapeutically valid.…”

Section: Role Of Non-coding Rnas In Targeted and Immunotherapeutic Stmentioning

confidence: 97%

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

Pepe

Balatti

2020

JCM

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In the past decade, novel targeted therapy approaches, such as BTK inhibitors and Bcl2 blockers, and innovative treatments that regulate the immune response against cancer cells, such as monoclonal antibodies, CAR-T cell therapy, and immunomodulatory molecules, have been established to provide support for the treatment of patients. However, drug resistance development and relapse are still major challenges in CLL treatment. Several studies revealed that non-coding RNAs have a main role in the development and progression of CLL. Specifically, microRNAs (miRs) and tRNA-derived small-RNAs (tsRNAs) were shown to be outstanding biomarkers that can be used to diagnose and monitor the disease and to possibly anticipate drug resistance and relapse, thus supporting physicians in the selection of treatment regimens tailored to the patient needs. In this review, we will summarize the most recent discoveries in the field of targeted therapy and immunotherapy for CLL and discuss the role of ncRNAs in the development of novel drugs and combination regimens for CLL patients.

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Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

Cited by 17 publications

References 116 publications

Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

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