ABSTRACT
BACKGROUND: Chronic lymphocytic leukemia (CLL) microenvironment plays a critical role in disease pathogenesis. Matrix metalloproteinases (MMPs) are involved in CLL-B cell migration and survival. CD147 is associated with MMPs production by tumor and stromal cells. AIM: To analyze CD147, MMP2 and MMP9 expression in CLL-B cells and its modulation by fibroblasts (Fb)-CLL-B cell interaction. METHODS: CLL-B cells were co-cultured with Fb, as a simulation of CLL microenvironment. CD147 was evaluated in healthy donor (HD)-B cells and CLL-B cells by flow cytometry. MMP2 and MMP9 activity in CLL-plasma samples and conditioned media (CMs) was studied by zymography. RESULTS: MMP9/MMP2 plasma levels were significantly higher in CLL patients than in HD. CD147 expression (median fluorescence intensity) in CLL patients characterized 3 groups: low- (19.1 ± 3.2; n=3), middle- (42.7 ± 12.8; n=18) and high- (76.5 ± 9.6; n=5) related to CD147 expression in HD-B cells. CD147 expression significantly increased in CLL-B cells after Fb-CLL-B cell co-culture. A significant increase in proMMP2 activity was observed in CMs obtained from Fb-CLL-B cell co-cultures in comparison with isolated CLL-B cells. CONCLUSIONS: CD147 expression in CLL-B cells and MMPs secretion was induced by Fb-CLL-B cell contact, suggesting CD147 participation in the CLL pathophysiology.
Subject(s)
B-Lymphocytes/metabolism , Basigin/biosynthesis , Cell Communication , Gene Expression Regulation, Leukemic , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Neoplasm Proteins/biosynthesis , Adult , B-Lymphocytes/pathology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Stromal Cells/metabolism , Stromal Cells/pathologyABSTRACT
BACKGROUND: Metalloproteinases (MMPs) are relevant modulators of inflammation, tumor microenvironment, cancer invasion and metastasis. They can be regulated by the Low density lipoprotein Receptor-related Protein 1 (LRP-1), a receptor reported to mediate the clearance of lipoproteins, extracellular matrix (ECM) macromolecules and proteinases. The aim of this study was to evaluate the expression of LRP-1, MMP-2 and MMP-9 across various grades of prostatic diseases as benign prostatic hyperplasia (BPH), BPH plus prostatitis (BPH+P), high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer (PCa). METHODS: LRP-1 was analyzed using immunohistochemistry and MMPs proteolytic activity by zymography in prostate tissues with different prostatic diseases. RESULTS: LRP-1 was detected in epithelial cells in BPH (16/18), BPH+P (21/21) and HGPIN (6/6), with a staining intensity of 1+, 1+/2+ and 3+, respectively. In PCa, LRP-1 was absent in 19/27 samples while a low expression was observed in 8/27 biopsies. MMP-9 activity was higher and statistically significant in PCa than in BPH (p≤0.01). CONCLUSION: Considering that LRP-1, by mediating the clearance of MMPs, is involved in the regulation of ECM remodeling and cell migration, we conclude that a decreased expression of LRP-1 could be involved with the increasing activity of MMPs shown in cancers.
Subject(s)
Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Matrix Metalloproteinase 9/metabolism , Prostate/metabolism , Prostatic Hyperplasia/metabolism , Prostatic Intraepithelial Neoplasia/metabolism , Prostatic Neoplasms/metabolism , Prostatitis/metabolism , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Prostate/pathology , Prostatic Hyperplasia/pathology , Prostatic Intraepithelial Neoplasia/pathology , Prostatic Neoplasms/pathology , Prostatitis/pathologyABSTRACT
The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1 (ICAM-1, 70.1 +/- 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 +/- 5.2%) positive cells, while a weak expression of MHC class II (IA, 2.2 +/- 0.2% and IE, 17.4 +/- 3.7%) and B7 (12.1 +/- 2.2%) antigens was detected. In our tumor experimental model, after implantation of tumor cells, visible tumor masses were present at days 5-7 with a relatively fast tumor growth until day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity may lead to a tumor invasive phenotype.
