Acid, basic, and neutral peptidases present different profiles in chromophobe renal cell carcinoma and in oncocytoma

Abstract

Renal cell carcinomas (RCCs) are neoplasias with high prevalence and mortality. We previously reported that several peptidases may be involved in the pathophysiology of clear cell renal cell carcinoma (CCRCC). Now, to gain insight into the reasons that lead the various RCC types to behave very differently with regard to aggressiveness and response to anticancer treatments, we analyzed subsets of chromophobe renal cell carcinoma (ChRCC), and renal oncocytoma (RO), a benign tumor; as well as different grades and stages of CCRCCs. Particulate APN, APB, and APA activities were decreased in both ChRCC and RO (tumor vs. nontumor tissues). Interestingly, activities were downregulated in a tumor-type specific way and the intensities of the decreases were stronger in the benign tumor than in the malignant type. Moreover, when two key histopathological parameters for tumor prognosis (high vs. low stage and grade) were analyzed, increases of activity were also observed in several of these cell surface peptidases (APN, APB). Some soluble activities (APB, Asp-AP) were also downregulated in the RCCs. With respect to genetic expression, PSA and APN were in a positive correlation related to their activities in both ChRCC and RO; but not APB, Asp-AP, APA, and PGI. These results may suggest an involvement of several peptidases in the pathophysiology of renal cancer, since they presented different patterns of activity and expression in tumors with different behaviors. peptide signaling; renal tumor behavior; chromophobe carcinoma; renal oncocytoma RENAL CELL CARCINOMAS (RCCs) are neoplasias with high prevalence and mortality rates. One of the more difficult challenges in treating RCCs involves identifying and distinguishing aggressive tumors from those likely to remain indolent with little detriment to the patient. The clear cell type of carcinoma (CCRCC) is by far the most frequent histological subtype of RCC, accounting for 70% of cases (27), a prevalence rate that explains its intrinsic clinical interest. However, not all kidney tumors are the same and the different histological subtypes of RCC behave quite differently, both with regard to aggressiveness in the patient and response to treatment (3,22). For example, when CCRCC is localized, prognosis after surgery is good, but patients with spread CCRCC have a decidedly worse prognosis (3). The chromophobe subtype of RCC (ChRCC) is much less frequent (5% of cases) than CCRCC. On the other hand, the renal oncocytoma (RO) is also a relatively uncommon entity, accounting for only 5% of cases of renal tumors (1). With respect to its clinical interest, ChRCC differs from CCRCC in its lower rate of metastasis. As a result, surgical removal of localized or even locally advanced disease is usually associated with a better prognosis (1, 3). Moreover, although ChRCC and RO are thought to share a common lineage (1), ChRCC is malignant and RO is benign. As a consequence, a deeper understanding of the molecular mechanisms underlying these different renal tumors could be helpful in gaining in...

The impact of peptidase activity on clear cell renal cell carcinoma survival

“…We observed that the activity of some peptidases like APN, CAP, and DPPIV was increased in high-grade and advanced stage CCRCC (4,27,29,59). In this work, we show that 5-yr survival of patients with CCRCC was shorter if the activity of these three peptidases was high.…”

“…Our previous studies (4, 5, 27-29, 58, 59) have demonstrated that the activity, protein expression, and mRNA levels of these three and other peptidases are selectively altered in several subtypes of renal cell neoplasms (CCRCC, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and renal oncocytoma). What is more, we have found that several peptidase activities are significantly increased in high-stage and high-grade CCRCC, suggesting the involvement of these enzymes in the biological aggressiveness of these neoplasms (4,27,29,59).…”

“…APB is a ubiquitous enzyme which has been typically described in the soluble fraction, although some authors have also reported a membrane-bound fraction in several neoplastic and nonneoplastic tissues (4,8,33,40,58). Some evidence suggests that APB may regulate immunity and cell proliferation since it is targeted or regulated by several immunomodulators and chemotherapeutic agents (8,49,62).…”

Altered Activity and Expression of Cytosolic Peptidases in Colorectal Cancer

“…In addition, it has been reported that the activity of different cytosolic peptidases such as puromycin-sensitive aminopeptidase (PSA or EC 3.4.11.14), aminopeptidase B (APB or EC 3.4.11.6) and pyroglutamyl-peptidase I (PGI or EC 3.4.19.3) was altered in breast 19,20, kidney 21,22 and thyroid tumors 23.…”

The normal and pathologic renal medulla: A comprehensive overview

“…ACE and ACE2 are expressed in renal tubules and play an essential role in the regulation of the renin-angiotensin system at the local level [15]. Impairment of this system has been studied in various noncancerous kidney diseases [12,[16][17][18], and several types of renal cell carcinomas and oncocytomas [19][20][21].…”