ABSTRACT
CD49d and CD38 are independent negative prognostic markers in chronic lymphocytic leukemia (CLL). Their associated expression marks a disease subset with a highly aggressive clinical course. Here, we demonstrate a constitutive physical association between the CD49d/CD29 integrin complex and CD38 in primary CLL cells and B-cell lines by (i) cocapping, (ii) coimmunoprecipitation and (iii) cell adhesion experiments using CD49d-specific substrates (vascular-cell adhesion molecule-1 or CS-1/H89 fibronectin fragments). The role of CD38 in CD49d-mediated cell adhesion was studied in CD49d(+)CD38(+) and CD49d(+)CD38(-) primary CLL cells, and confirmed using CD38 transfectants of the originally CD49d(+)CD38(-) CLL-derived cell line Mec-1. Results indicate that CD49d(+)CD38(+) cells adhered more efficiently onto CD49d-specific substrates than CD49d(+)CD38(-) cells (P < 0.001). Upon adhesion, CD49d(+)CD38(+) cells underwent distinctive changes in cell shape and morphology, with higher levels of phosphorylated Vav-1 than CD49d(+)CD38(-) cells (P = 0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d(+)CD38(+) cells were more resistant to serum-deprivation-induced (P < 0.001) and spontaneous (P = 0.03) apoptosis than the CD49d(+)CD38(-) counterpart. Altogether, our results point to a direct role for CD38 in enhancing CD49d-mediated adhesion processes in CLL, thus providing an explanation for the negative clinical impact exerted by these molecules when coexpressed in neoplastic cells.
Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Apoptosis , Cell Adhesion/physiology , Integrin alpha4beta1/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Actins/metabolism , Blotting, Western , Cell Proliferation , Culture Media, Serum-Free , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoprecipitation , Integrin alpha4/metabolism , Membrane Microdomains/metabolism , Phosphorylation , Proto-Oncogene Proteins c-vav/metabolism , Tumor Cells, CulturedABSTRACT
Neuroendocrine tumours are rare and often include insulinoma, gastrinoma and other low frequency tumours that secrete gastrointestinal hormones. Their preoperative localization, despite continuous medical advances, is extremely difficult but helpful in guiding the surgeon towards a proper form of treatment. After presenting their cases, the authors conclude that the treatment of choice for these tumours is surgery due to their anatomopathological features (benign, scarcely malign or invasive, slow growth). On the other hand, medical therapy plays an important role in either preparing the surgical intervention or alleviating symptoms when the patient is inoperable.
