Increased serum levels of soluble CD44 standard, but not of variant isoforms v5 and v6, in B cell chronic lymphocytic leukemia

Rossi, Giulio De; Marroni, Paola; Paganuzzi, Michela; Mauro, F. R.; Tenca, Claudya; Zarcone, Daniela; Velardi, Andrea; Molica, S.; Grossi, CE

doi:10.1038/sj.leu.2400525

Cited by 40 publications

(30 citation statements)

References 7 publications

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“…In CLL, elevated CD44 serum levels and high panCD44 as well as CD44v surface levels have been suggested as prognostic markers. While apparent consensus exists on the association of high CD44 serum levels with poor clinical outcome (17,18,28), the prognostic relevance of panCD44 and CD44v surface levels on circulating CLL cells remains arguable. Our data do not support a prognostic value of high CD44 levels on peripheral blood CLL cells.…”

Section: Discussionmentioning

confidence: 99%

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CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility

et al. 2013

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Microenvironmental interactions are crucial for the survival and proliferation of chronic lymphocytic leukemia (CLL) cells. CD4þ T cells that express CD40 ligand (CD40L), along with other accessory immune and stromal cells within CLL lymph nodes, provide signals needed for activation and outgrowth of the tumor clone. Furthermore, correct positioning of CLL cells within lymphoid subcompartments is essential for the transmission of these supportive signals. Thereby, interstitial cell migration and adhesion events, influenced by activational stimuli, determine CLL cell localization. CD44 has been implicated in cell activation, migration, and tissue retention via binding to its extracellular matrix ligand hyaluronan (HA). In this study, we investigated the role of CD44-HA interactions for CLL positioning and interaction with supportive microenvironments in peripheral lymph nodes, focusing on its regulation via CD40L-dependent, T-cellmediated activation of CLL cells. We found that hyaluronan triggered a robust CCL21-induced motility of resting CLL cells. However, CD40L stimulation promoted the firm, CD44-mediated adhesion of CLL cells to hyaluronan, antagonizing their motile behavior. N-linked glycosylations of CD44, particularly associated with the variant isoform CD44v6 after CD40L activation, seemed to facilitate hyaluronan recognition by CD44. We propose that the CD40L-CD40 signaling axis provides a stop signal to motile CLL cells within lymph node compartments by inducing high avidity CD44-HA adhesion. This might retain CLL cells close to T-cell stimuli and facilitate essential interactions with hyaluronan-bearing stromal cells, collectively promoting CLL cell proliferation and survival. Cancer Res; 73(2); 561-70. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

“…Correlative studies have suggested CD44 as a negative prognostic marker in CLL (17)(18)(19), but the underlying molecular mechanisms are not fully understood. Here, we aimed to examine the role of CD44-HA interactions for CLL cell positioning within lymph node compartments.…”

Section: Introductionmentioning

confidence: 99%

CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility

et al. 2013

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“…Published results 16,43 and our in silico meta-analysis (supplemental Figure 1A and Table 2) support both of these findings. Available reports on surface vs soluble and on CD44s vs CD44v isoforms in CLL 37,[43][44][45][46][47][48][49][50] show in their entirety no clear-cut prognostic associations. However, they implicate a higher CD44 turnover in CLL over normal lymphocytes, especially in more aggressive disease subsets.…”

Section: Discussionmentioning

confidence: 99%

CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia

Fedorchenko

Stiefelhagen

Zada

et al. 2013

Blood

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Key Points• CD44 expression in CLL is micromilieu instructed and promotes leukemic cell survival, which can be antagonized by CD44 antibodies.• As a surface coreceptor, CD44 supports leukemogenesis by modulating stimuli of MCL1 expression (eg, B-cell receptor signals).The cell-surface glycoprotein CD44 is expressed in chronic lymphocytic leukemia (CLL), but its functional role in this disease is poorly characterized. We therefore investigated the contribution of CD44 to CLL in a murine disease model, the Em-TCL1 transgenic mouse, and in CLL patients. Surface CD44 increased during murine CLL development. CD44 expression in human CLL was induced by stimulation with interleukin 4/soluble CD40 ligand and by stroma cell contact. Engagement of CD44 by its natural ligands, hyaluronic acid or chondroitin sulfate, protected CLL cells from apoptosis, while anti-CD44 small interfering RNAs impaired tumor cell viability. Deletion of CD44 during TCL1-driven murine leukemogenesis reduced the tumor burden in peripheral blood and spleen and led to a prolonged overall survival. The leukemic cells from these CD44 knockout animals revealed lower levels of antiapoptotic MCL1, a higher propensity to apoptosis, and a diminished B-cell receptor kinase response. The inhibitory anti-CD44 antibodies IM7 and A3D8 impaired the viability of CLL cells in suspension cultures, in stroma contact models, and in vivo via MCL1 reduction and by effector caspase activation. Taken together, CD44 expression in CLL is mediated by the tumor microenvironment. As a coreceptor, CD44 promotes leukemogenesis by regulating stimuli of MCL1 expression. Moreover, CD44 can be addressed therapeutically in CLL by specific antibodies. (Blood. 2013;121(20):4126-4136)

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“…There is no clear difference between the colorectal carcinoma Astler-Coller's stage B patients group and the colorectal carcinoma Astler-Coller's stage C patients group, although the heterogeneity and the intensity of the bands were greater in the Astler-Coller's stage C patients group. CD44 as a marker of disease progression (Guo et al, 1994;De Rossi et al, 1997;Ristamäki et al, 1998). For instance in ovarian cancer, the concentration of sCD44std was found to be higher and sCD44v5 to be lower than in healthy controls (Zeimer et al, 1997).…”

Section: Purification Of Scd44mentioning

confidence: 99%

Soluble CD44: quantification and molecular repartition in plasma of patients with colorectal cancer

et al. 1999

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Summary Based on the important role of CD44 in tumour progression and metastasis, we evaluated, in a prospective study, plasma-soluble CD44 (sCD44) as a serum marker in colorectal cancer. Blood plasma specimens from 89 patients with colorectal neoplasm, 22 patients with a gastrointestinal disease and 23 healthy donors were analysed for quantitation (ELISA assay) and purification of sCD44. The concentration of sCD44, indicating the concentration of all isoforms, was significantly higher in patients with colorectal cancer and intestinal disease than in normal individuals, but no significant differences were found between the two groups. We found no association between plasma levels and staging of the colorectal cancer patients according to Astler and Coller. A two-step batch purification combining ion exchange and immunoaffinity chromatography, followed by Western blot analysis, revealed a complex pattern with a major band corresponding to the standard form of CD44 and minor bands that may correspond to larger variant forms. No particular sCD44 isoform was clearly associated with anatomopathological or biological information.

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Increased serum levels of soluble CD44 standard, but not of variant isoforms v5 and v6, in B cell chronic lymphocytic leukemia

Cited by 40 publications

References 7 publications

CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility

CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility

CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia

Soluble CD44: quantification and molecular repartition in plasma of patients with colorectal cancer

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