Predictions for the future of kallikrein-related peptidases in molecular diagnostics

Abstract

Kallikrein-related peptidases (KLKs) form a cancer-related ensemble of serine proteases. This multigene family hosts the most widely used cancer biomarker that is PSA-KLK3, with millions of tests performed annually worldwide. The present report provides an overview of the biomarker potential of the extended KLK family (KLK1-KLK15) in various disease settings and envisages approaches that could lead to additional KLK-driven applications in future molecular diagnostics. Particular focus is given on the inclusion of KLKs into multifaceted cancer biomarker panels that provide enhanced diagnostic, prognostic and/or predictive accuracy in several human malignancies. Such panels have been described so far for prostate, ovarian, lung and colorectal cancers. The role of KLKs as biomarkers in non-malignant disease settings, such as Alzheimer’s disease and multiple sclerosis, is also commented upon. Predictions are given on the challenges and future directions regarding clinically oriented KLK research.

Keywords::

• biomarker panel
• cancer diagnosis
• cancer prognosis
• kallikrein-related peptidases
• KLK
• molecular tumor marker
• neurodegenerative diseases
• ovarian cancer
• prostate cancer
• PSA

Acknowledgements

We apologize to those investigators whose work, due to space constraints, was not cited.

Financial & competing interests disclosure

This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF) – Research Funding Program: THALES. Investing in knowledge society through the European Social Fund (UoA-BIOPROMO, MIS 377046). The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The Kallikrein-related peptidase (KLK) gene family encodes for 15 secreted serine proteases, many of which have been described as cancer-related molecules.

• KLK3 (also known as prostate-specific antigen [PSA]) represents the most renowned member of the KLK family. The wide application of PSA as a biomarker for prostate cancer screening has provided notable benefits, such as the detection of prostate cancer at early stages and a, much debated, decrease in mortality rates.

• The benefits of PSA testing came with the complications of overdiagnosis and overtreatment. Thus, novel prostate cancer biomarkers should be introduced in order to reduce the amount of unnecessary biopsies.

• Individual KLK members have been described as biomarkers for the majority of human malignancies including prostate, ovarian, breast, lung and colorectal cancers.

• The incorporation of KLKs into multifaceted biomarker panels provides enhanced diagnostic, prognostic and predictive accuracy in several human malignancies. The most successful example is that of the ‘four-kallikrein panel’ for prostate cancer, which has great dynamics for introduction into future clinical practice.

• Multifactorial KLK-driven biomarker panels have also been proposed for ovarian, lung and colorectal cancer decision making.

• KLK-derived information that could be combined in biomarker panels includes data from the KLK expression profiling (mRNA and/or protein levels), KLK-targeting miRNAs, SNPs found within the KLK locus and methylation status of KLK genes.

• KLKs are also regarded as promising biomarkers for nonmalignant diseases such as Alzheimer’s disease and multiple sclerosis.