High Expression of Cathepsin D in Non-Hodgkin’s Lymphomas Negatively Impacts on Clinical Outcome

Giuseppina Nicotra,Roberta Castino,Claudia Peracchio,Federica Manfroi,Simonetta Kerim,Carlo Follo,Ciro Isidoro,Guido Valente,Nicola Fusco

doi:10.1155/2010/465040

Abstract

The lysosomal protease Cathepsin D (CD) has been implicated in the homeostasis of lymphatic tissues. We investigated whether the level of CD expression influences the progression and the clinical outcome in Non-Hodgkin’s Lymphomas (NHLs). The expression of CD was assessed by immunohistochemistry and immunofluorescence in biopsies of Diffuse Large B Cell Lymphomas (DLBCL, 35 cases), Follicular Lymphomas (FL, 9 cases of grade I-II plus 14 cases of grade IIIB), Chronic Lymphocytic Leukaemias (CLL, 17 cases) and Peripheral T-cell Lymphomas (PTCL, 5 cases). CD staining showed a cytoplasmic punctate pattern compatible with its lysosomal localization. Based on the level of CD expression and the proportion of positive cells, lymphomas were classified as ‘low expressing’ (< 20% of tumor cells) or ‘highly expressing’ (≥ 20% of tumor cells). Lymphomas highly expressing CD were associated with a worse stage (III-IV) at diagnosis (31/34 cases;p= 0.002) and with a poor clinical outcome (i.e., partial remission and death; 28/34 cases;p= 0.03). In the subgroup of aggressive/high grade of malignancy lymphomas (i.e., DLBCL, FL IIIB and PTCL), the Kaplan-Meier curve revealed a very low cumulative overall survival probability (~20% at 5 year) for patients bearing a NHL with > 40% CD-positive cells compared to that of patients bearing a NHL with < 20% CD-positive cells (~70% at 5 year). This correlation was statistically significant (log-rank test,p= 0.01). In Cox multivariate analysis CD failed to be a prognosticator independent of pathologic stage, though the hazard ratio confirmed the association of low expression with a better survival probability. These data indicate that the presence of a high percentage of CD-positive tumor cells negatively reflects on the progression of NHLs.

Highlights

Non-Hodgkin’s Lymphomas (NHLs) encompass malignant lymphoproliferative disorders that originateG
We have studied the expression of Cathepsin D (CD) in a series of different NHL histologic types and searched for any correlation between the extent of CD-positive tumor cells and the clinico-pathological parameters and patient’s clinical outcome after therapy
Western blotting analysis revealed that the mature double-chain form, which is resident within lysosomes, is the main CD molecular form expressed in NHLs, regardless of the histotype and of clinical features

Summary

Introduction

Non-Hodgkin’s Lymphomas (NHLs) encompass malignant lymphoproliferative disorders that originateG. On the basis of the clinical presentation and the patient’s life expectancy, oncologists categorize NHLs in ‘aggressive’ or ‘indolent’ lymphomas, which correspond to the intermediate/high grade of malignancy and low grade of malignancy subgroups, respectively (reviewed in 1,2). CD was shown of vital importance for cell survival and tissue homeostasis, as deduced from the phenotype of mice homozygously knocked-out for CD [10]. These mice are not vital beyond the third-fourth week after birth and show atrophy of primary lymphoid organs,intestine and heart [10]. CD expression was analyzed by immunohistochemistry (IHC) and immunofluorescence (IF) in a wide series of NHLs, which included 54 cases classified as ‘aggressive’ or high grade of malignancy and 26 cases classified as ‘indolent’ or low grade of malignancy.

Methods

Results

Conclusion