Expression of Cathepsin D in Colorectal Adenocarcinomas: Correlation with Clinicopathologic Features

Abstract

F Yilmaz, AK Uzunlar, N Kilinc, HG Yilmaz, Expression of Cathepsin D in Colorectal Adenocarcinomas: Correlation with Clinicopathologic Features. 2003; 23(3-4): 208-211 Colorectal carcinoma is the second most frequent carcinoma, after carcinoma of the lung, in Western countries. 1 The prognosis for patients with colorectal carcinoma seems to be related mainly to the control of both progression and metastasis of the malignant tumor. In metastasis, proteolytic enzymes play an important role in mediating passage of the malignant cell through the cell membrane.2 Proteases are thought to be important factors for tumor invasion and metastasis because they can degrade extracellular matrices and basement membranes, 3,4 which play a defensive role for tumor invasion and metastasis.5 Cathepsin D (CD) is known to be a lysosomal acid protease that is mainly included in intracellular protein catabolism and is inducible by estrogens.6 Therefore, many investigators have studied intensively the role of CD in breast carcinomas. These studies have suggested that the expression of CD is correlated with the invasion and metastasis of breast carcinomas, 7-9 but the role of CD expression in predicting prognosis or invasive potential in colorectal carcinoma is unknown. 1In this study, we evaluated the expression of CD in a series of colorectal carcinomas and its correlation with conventional clinicopathologic features such as age, gender, tumor size, tumor grade and Dukes' stage. Patients and MethodsTissue samples were obtained from the surgical specimens of 100 primary colorectal adenocarcinomas. All specimens were collected at the Department of Pathology, Dicle University Hospital, Diyarbakir, Turkey between 1995 and 2000. The clinical data were obtained from pathological reports. The specimens were fixed in formalin and embedded in paraffin. Consecutive 4-mm-thick sections were stained with hematoxylin and eosin for histological diagnosis.Histologically, all colorectal carcinomas were adenocarcinomas. The grade of differentiation was high in 17, moderate in 58, and low in 25 cases. Staging of cases was pathological only (Dukes' stage A, B and C). There were 10 cases of stage A, 31 cases of stage B and 59 cases of stage C. The mean age of the patients was 53.7 years (range,24 to 80 years), and the male/female ratio was 1.3 (56/44). Most adenocarcinomas were located in the rectosigmoid (n=65).One or two blocks from each tumor were stained for immunohistochemical analysis using the Avidin-Biotin and immunoperoxidase methods. Additional 4-mm-thick sections were cut from paraffin blocks. After blockage of endogenous peroxidase with H 2 O 2 in methanol for 30 minutes, sections were immersed in citrate buffer (pH=6.0) in a microwave-resistant container. Subsequently, the sections were incubated with a protein-blocking solution for five minutes and then incubated with a mouse anti-human cathepsin D monoclonal antibody (Dako, Carpinteria, USA). Immunoperoxidase detection was employed, using the diaminobenzidine substrate (DAB). Counter s...

Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release

“…CatD expression in carcinoma cells was present in 68% of the cases, and CatD positivity was higher when the grade of differentiation was higher. 17 Yet another study showed that the majority of CRC (93/106) stained positive for CatD, whereas normal colon was almost completely negative. 35 It is therefore apparent that some, but not all, CRC cells overexpress CatD in comparison to normal colon mucosa.…”

“…CatD protein levels in CRC clinical cases show divergent expression patterns, suggesting a complex regulation and function of this protease. 17, 28, 35, 36, 37, 38, 39, 40, 41 One study showed that the average CatD protein content was not different in 59 CRC when compared with normal mucosa, but individual tumors demonstrated marked changes in CatD expression levels. 16 Measurement of protein content of tumor versus normal pairs on western blots revealed loss of CatD in >50% of CRC.…”

“…15 CatD has emerged as a central player in the apoptotic response, although its role is cell-type and context-dependent. Expression patterns of CatD protein are divergent in CRC, suggesting a complex regulation and function of this protease, 16, 17 though its precise role remains poorly understood.…”

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“…However, various heterogeneous factors, mainly genetic and environmental, have been implicated. These include chromosomal abnormalities (chromosomes 3 and 10), alcohol consumption, toxoplasmosis, rubella, cytomegalovirus and herpes simplex (TORCH) infections, maternal diabetes, maternal exposure to teratogenic drugs (lithium, aspirin, retinoic acid, amidopyrine, corticosteroids, anti-convulsant) and ionic radiation [11,14,15]. In our case, none of these factors were identified, although we cannot completely rule them out since the use of over-the-counter drugs and street medications are common in our setting [16,17].…”