title: Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia.
abstract: The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.
authors.affiliation: 1 Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Gusella
authors.affiliation: 1 Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bolzonella
authors.affiliation: 2 Department of Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Paolini
authors.affiliation: 2 Department of Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rodella
authors.affiliation: 1 Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bertolaso
authors.affiliation: 3 Department of Transfusion Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Scipioni
authors.affiliation: 3 Department of Transfusion Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bellini
authors.affiliation: 4 Department of Medical Sciences, Section of Hematology, University of Ferrara, Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.affiliation: 1 Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Pasini
authors.affiliation: 2 Department of Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ramazzina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement / Q000502:physiology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D008218:Lymphocytosis / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Chronic lymphocitic leukemia; cell trafficking; matrix metalloproteinases; prognosis