The Clinical and Biologic Importance of Neovascularization and Angiogenic Signaling Pathways in Chronic Lymphocytic Leukemia

Shanafelt, Tait D.; Kay, Neil E.

doi:10.1053/j.seminoncol.2006.01.008

Cited by 48 publications

(39 citation statements)

References 125 publications

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“…Independent immunohistochemical studies on lymph node sections revealed a direct association between the number of endothelial cells (CD31 þ ) and the level of CD38 expression by CLL cells, 8 indirectly confirming that CD31/CD38 static interactions occur in vivo. Moreover, the percentage of CD38 þ CLL cells 35,36 and the density of tumor vessels 37,38 correlate with neoplastic proliferation and disease aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

et al. 2010

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Homing of chronic lymphocytic leukemia (CLL) cells to sites favoring growth, a critical step in disease progression, is principally coordinated by the CXCL12/CXCR4 axis. A cohort of 62 CLL patients was divided into migrating and nonmigrating subsets according to chemotaxis toward CXCL12. Migrating patients phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) proteins more than nonmigrating patients (Po0.0002). CD38 expression was the parameter most strongly associated with heightened CXCL12 signaling (Po0.0001), confirmed by independent statistical approaches. Consistent with this observation, CD38À CLL cells in samples with bimodal CD38 expression responded less to CXCL12 than the intact clone (P ¼ 0.003). Furthermore, lentivirus-induced de novo expression of CD38 was paralleled by increased responses to CXCL12, as compared with cells infected with a control virus. CD38 ligation with agonistic monoclonal antibodies (mAbs) enhanced CXCL12 signaling, whereas blocking anti-CD38 mAbs inhibited chemokine effects in vitro. This is attributed to physical proximity on the membrane between CD38 and CXCR4 (the CXCL12 receptor), as shown by (i) coimmunoprecipitation and (ii) confocal microscopy experiments. Blocking anti-CD38 mAbs significantly compromised homing of CLL cells from blood to lymphoid organs in a mouse model. These results indicate that CD38 synergizes with the CXCR4 pathway and support the working hypothesis that migration is a central step in disease progression.

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Section: Discussionmentioning

confidence: 99%

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

et al. 2010

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“…[29][30][31][32] In particular, a strict association between high Ang2 levels and more advanced disease, unfavorable biologic prognostic parameters, and shorter progression-free survival was assessed in small series of CLL patients. [10][11][12] On these premises, we reasoned that Ang2 would have a strong rationale for being tested as an independent prognostic factor in CLL.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia

Maffei

Martinelli

Santachiara

et al. 2010

Blood

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The clinical relevance of angiopoietin-2 (Ang2) in chronic lymphocytic leukemia (CLL) was previously suggested by the association between high Ang2, and shorter progression-free survival reported in small series of patients. Here, we evaluated Ang2 glycoprotein levels in plasma samples collected from a multicentric cohort of CLL patients (n ‫؍‬ 316) using an enzyme-linked immunosorbent assay method, and we investigated its prognostic role in relation to time to first treatment (TTFT) and overall survival. Based on a cutoff equal to 2459 pg/mL, we divided our cohort in 2 subsets (high and low Ang2) composing 100 (31.6%) and 216 (68.4%) patients, respectively. High Ang2 was predictive of reduced TTFT (P < .001) and overall survival (P ‫؍‬ .002). Multivariate analysis confirmed that high Ang2 was an independent prognosticator for TTFT (hazard ratio ‫؍‬ 1.739; 95% confidence interval, 1.059-2.857; P ‫؍‬ .029). Significant associations were found between high Ang2 and advanced Binet stages (P < .001), high ␤ 2 -microglobulin (P < .001), unmutated variable region of immunoglobulin heavy chain gene status (P < .001), high CD38 and -chain-associated protein kinase 70 expression (P < .001 and P ‫؍‬ .003), and intermediate/ high cytogenetic risk (P ‫؍‬ .005). Moreover, Ang2 added prognostic power to other conventional prognosticators and helped to refine prognosis among CLL subsets with both high and low vascular endothelial growth factor plasma levels. Ang2 plasma level may be a useful independent prognosticator for CLL. (Blood. 2010;116(4):584-592)

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“…12 In addition, CLL-infiltrated bone marrow and lymph nodes contain abnormal vascular elements that are related to disease stage and are predictors of poor clinical outcome. 7,[13][14][15] CLL lymphocytes reside in tissues enriched with new microvessels and interact with activated endothelium during recirculation from peripheral blood to the marrow and lymph node compartments. 16 Contradictory results were reported about the role of endothelial cells (EC) in CLL survival.…”

Section: Introductionmentioning

confidence: 99%

Physical contact with endothelial cells through 1- and 2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

Maffei

Fiorcari²,

Bulgarelli³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundChronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia. Design and MethodsWe evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after coculture. ResultsWe found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both b1-and b2-integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFb and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of antiapoptotic molecules such as Bcl2 and Survivin. ConclusionsOur study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.

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The Clinical and Biologic Importance of Neovascularization and Angiogenic Signaling Pathways in Chronic Lymphocytic Leukemia

Cited by 48 publications

References 125 publications

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia

Physical contact with endothelial cells through 1- and 2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

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