Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: Mechanistic and clinical aspects

Abstract

SummaryThe human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic-pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies.

Kallikreins as Biomarkers in Human Malignancies

“…KLK11 is significantly downregulated at both mRNA and protein levels in GC tissues and appears to be an independent marker of superior DFS and OS (Unal et al 2013). Regarding KLK13, is downregulated in GC tissues compared to their normal counterparts and its expression is associated with less GC aggressive features and improved DFS and OS (Kontos et al 2013). Recent results revealed that KLK13 expression is modulated in cultivated GC cell lines, after their exposure to different antineoplastic agents, suggesting that KLK13 may be employed as a treatment-response predictor for GC (Florou et al 2012).…”

“…Colorectal cancer (CRC) remains one of the three most frequently diagnosed malignancies in both genders, despite the recent achievements in resection procedures and chemotherapy (Kontos et al 2013). As a consequence, the identification and establishment of novel biomarkers for GC and CRC is necessary for optimal clinical management of these patients.…”

“…In addition to this, the KLK6 mRNA expression status appears to be a significant prognostic marker of shorter OS. Likewise, KLK12 is overexpressed in GC and is associated with aggressive disease phenotypes and shorter OS periods (Kontos et al 2013).…”

“…Moreover, KLK5-7, KLK11, KLK13, and KLK14 protein content was associated with inferior OS, revealing their potential as markers of unfavorable patients' prognosis. In low rectal cancer, increased KLK11 expression is associated with late-stage disease and shorter OS (Kontos et al 2013). At mRNA level, KLK4 is upregulated in advanced-stage and/or poorly differentiated tumors and correlates with tumor size.…”

“…Their prognostic potential stems from the fact that KLK7 and KLK14 mRNA expression is indicative of shorter DFS, while KLK14 is also associated with limited OS. Additionally, the significant increase in KLK7 and KLK14 transcripts in cancer tissues compared to adenoma specimens can be exploited for the discrimination between these conditions (Kontos et al 2013). …”