Cathepsin D expression levels in nongynecological solid tumors: Clinical and therapeutic implications

Abstract

Cathepsin D is a lysosomal acid proteinase which is involved in the malignant progression of breast cancer and other gynecological tumors. Clinical investigations have shown that in breast cancer patients cathepsin D overexpression was significantly correlated with a shorter free-time disease and overall survival, whereas in patients with ovarian or endometrial cancer this phenomenon was associated with tumor aggressiveness and a degree of chemoresistance to various antitumor drugs such as anthracyclines, cis-platinum and vinca alkaloids. Therefore, a lot of research has been undertaken to evaluate the role and the prognostic value of cathepsin D also in other solid neoplasms. However, conflicting results have been generated from these studies. The discrepancies in these results may, in part, be explained with the different methodological approaches used in order to determine the levels of expression of the enzyme in tumor tissues and body fluids. Further investigations using well-standardized techniques may better define the clinical significance of cathepsin D expression in solid tumors. Nevertheless, evidence emerging from these studied indicates that this proteinase seems to facilitate early phases of tumor progression such as cell proliferation and local dissemination. These findings support the concept that cathepsin D may be a useful marker for identifying patients with highly malignant tumor phenotypes who may need more aggressive clinical treatment; this enzyme may also be considered as a potential target for a novel therapeutic approach in the treatment of solid neoplasms.

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

“…Cathepsin proteases have been implicated in numerous pathologies, including inflammatory processes, 40 Alzheimer's disease, 41,42 and metastasis of tumor cells. [43][44][45][46] Both cathepsins, cath-D and cath-L, produced by all transfectants studied are reported to be active in human thyroid carcinoma tissues. 46 -48 The significant up-regulation in the production and secretion of cath-L forms in RLN2 transfectants correlated with an enhanced elastinolytic activity and the ability to invade elastin matrices.…”

Depletion of procathepsin D gene expression by RNA interference – A potential therapeutic target for breast cancer

“…[26][27][28] In contrast, pCD (the proform) is overexpressed (2-to 50-fold) in cancerous conditions and its resultant hypersecretion is known to cause enhanced proliferation and neoplastic transformation in various malignancies. [29][30][31] The present study employs the powerful tool of RNAi to determine the effects of long-term knock-down of pCD on cancer progression and thus evaluates the therapeutic efficacy of pCD-shRNA under cancerous conditions. Targeting pCD with antibodies, hammerhead ribozymes and antisense oligonucleotides has been earlier reported.…”

Cathepsin D—Many functions of one aspartic protease

“…Several years later, the first clinical studies found pCD/CD related to metastasis-free survival and disease-free survival in breast cancer patients [168,169]. Since then, numerous clinical studies reported an association between pCD/CD level and tumor size, tumor grade, tumor aggressiveness, incidence of metastasis, prognosis, and a degree of chemoresistance in variety of solid tumors including neuroblastoma, glioma, melanoma, endometrial and ovarian tumors, colorectal carcinoma, head and neck tumors, thyroid tumors, pancreatic tumors, lung carcinoma, liver tumors, bladder carcinoma, prostate tumors and gastric carcinoma [25,170,171]. It should be noted, however, that conflicting results were obtained which may reflect the different methodology used for pCD/CD quantification, patients and diagnosis selection, and the length of follow-up period [25,172,173].…”

“…Since then, numerous clinical studies reported an association between pCD/CD level and tumor size, tumor grade, tumor aggressiveness, incidence of metastasis, prognosis, and a degree of chemoresistance in variety of solid tumors including neuroblastoma, glioma, melanoma, endometrial and ovarian tumors, colorectal carcinoma, head and neck tumors, thyroid tumors, pancreatic tumors, lung carcinoma, liver tumors, bladder carcinoma, prostate tumors and gastric carcinoma [25,170,171]. It should be noted, however, that conflicting results were obtained which may reflect the different methodology used for pCD/CD quantification, patients and diagnosis selection, and the length of follow-up period [25,172,173]. Studies dealing with pCD/CD diagnostic and prognostic value in cancer are complicated by the fact that there are several forms of CD in a cell at the same time -pCD, intermediate enzymatically active CD and mature heavy and light chain CD (Fig 2).…”

“…pCD was found in human, bovine and rat milk [20][21][22], serum [23] and the presence of both pCD and 34 kDa CD was demonstrated in human eccrine sweat and urine [23,24]. pCD is a major secreted protein of numerous types of cancer cells [25]. It has been also shown that secreted pCD can be endocytosed via M6PR or another yet unknown receptor by both cancer cells and fibroblasts.…”