title: TIMP-1 expression in anaplastic large cell lymphoma is usually restricted to macrophages and only seldom observed in tumour cells.
abstract: Anaplastic large cell lymphomas (ALCLs) can be subdivided into two subgroups on the basis of their expression of the ALK protein. ALK protein expression leads to activation of signal transducer and activator of transcription (STAT) 3, which is more commonly expressed in ALK-positive than in ALK-negative tumours. Activated STAT3 leads to the induction of several genes such as Mcl-1, Bcl-2 and Bcl-X(L), and tissue inhibitor of metalloproteinase (TIMP)-1. In this study, we analysed TIMP-1 expression in five ALCL cell lines and 11 tumours by quantitative RT-PCR and immunohistochemistry. We identified high-level TIMP-1 expression by RT-PCR in three ALK-positive ALCL-derived cell lines and in all ALK-positive ALCLs, whereas ALK-negative ALCLs generally demonstrated a lower level of TIMP-1 expression. Concordant with these results, we observed TIMP-1 immunostaining in all ALK-positive ALCLs and in only two of six ALK-negative ALCLs. No relationship was observed between the levels of ALK and TIMP-1 expression in the ALK-positive tumours. STAT3 expression levels were similar in all ALCL samples. Double staining with either CD30 or CD68 demonstrated that TIMP-1 expression was restricted to macrophages in the majority of TIMP-1-positive tumours. Expression of the TIMP-1 substrate MMP-2 was more prominent in ALK-negative tumours, while MMP-9 levels were low in all cases. Expression levels of IL-6 and TGF-beta1, which are cytokines known to induce TIMP-1, were higher in ALK-negative ALCLs and moderate in ALK-positive tumours. No clear relationship was observed between IL-10 expression and ALK positivity. Overall, no correlation was seen in ALCLs between the expression of TIMP-1 and that of cytokines that induce TIMP-1. Lack of TIMP-1 expression in the tumour cells of ALK-positive ALCLs argues against a direct role for ALK-induced activation of STAT3 in the regulation of TIMP-1 expression in ALCL.
authors.affiliation: Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Rust
authors.forename: Tjasso
authors.initials: T
authors.lastname: Blokzijl
authors.forename: Geert
authors.initials: G
authors.lastname: Harms
authors.forename: Megan
authors.initials: M
authors.lastname: Lim
authors.forename: Lydia
authors.initials: L
authors.lastname: Visser
authors.forename: Willem A
authors.initials: WA
authors.lastname: Kamps
authors.forename: Sibrand
authors.initials: S
authors.lastname: Poppema
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D015703:Antigens, CD / Q000032:analysis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000737:chemistry*; D020782:Matrix Metalloproteinases / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050796:STAT3 Transcription Factor; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis*; D015534:Trans-Activators / Q000032:analysis
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases