Prostate kallikrein markers in diagnosis, risk stratification and prognosis

Abstract

Summary The kallikrein, prostate-specific antigen (PSA), is one of the world’s most frequently used disease biomarkers. After almost two decades of research and clinical experience, we are now starting to comprehend its diagnostic and monitoring limitations. Most physicians are aware of PSA’s low cancer-specificity among older men with benign prostatic conditions, but fewer are aware of recent data showing that a prior negative biopsy or a prior PSA below cut-off may have even stronger negative impact. Furthermore, a subtle PSA rise at early middle age strongly correlates to prostate cancer of unquestionable significance. We thoroughly review current and past reports on prostate kallikreins in relation to pathology and epidemiology.

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…Apart from their physiological roles, PARs can intervene in cancer-associated molecular cascades affecting cell proliferation and migration (Hollenberg et al , 2008 ;Oikonomopoulou et al , 2010b ). Given that IGFBPs and PARs are well-documented substrates of KLKs, an abnormal Kwiatkowski et al , 1998 ;Magklara et al , 1999 ;Nam et al , 2000 ;Steuber et al , 2007 PSA/KLK3 Screening; diagnosis; treatment monitoring; unfavorable prognosis Stephan et al , 2007 ;Lilja et al , 2008 ;Ulmert et al , 2009 ;Avgeris et al , 2010 KLK4 Unfavorable prognosis Avgeris et al , 2011b KLK5 Favorable prognosis Yousef et al , 2002b ;Korbakis et al , 2009 KLK11 Diagnosis; favorable prognosis Diamandis et al , 2002 ;Nakamura et al , 2003a,b ;Bi et al , 2010 KLK14 Unfavorable prognosis Yousef et al , 2003e ;Rabien et al , 2008 KLK15 Unfavorable prognosis Mavridis et al , 2010a ;Rabien et al , 2010 Breast cancer PSA/KLK3 Diagnosis; treatment response; favorable prognosis Yu et al , 1998 ;Foekens et al , 1999 ;Black et al , 2000 ;Sauter et al , 2004a Kim et al , 2001 ;Diamandis et al , 2003a ;Dong et al , 2003 ;Yousef et al , 2003b ;Oikonomopoulou et al , 2008b ;Dorn et al , 2011a,b KLK6 Diagnosis; unfavorable prognosis Diamandis et al , 2000Diamandis et al , , 2003bHoffman et al , 2002 ;Shih Ie et al , 2007 ;Kountourakis et a...…”

Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies

“…The combination of KLK2 with tPSA and fPSA measurements in serum increases the ability of discrimination of PCa from benign prostate hyperplasia, particularly in the PSA 'gray zone' (Raaijmakers et al, 2007). Additionally, increased KLK2 serum levels in parallel with low f/tPSA rate are associated with rapid PCa progression (Ulmert et al, 2009). Moreover, an unfavorable prognostic significance for PCa patients has also been revealed for KLK4 expression.…”

“…Therefore, the current clinical aim is focused on the early diagnosis and the determination of PCa patients' outcome. Preoperative PSA serum measurements are also an independent unfavorable prognostic biomarker, positively correlated with advanced disease stage and poor clinical outcome (Ullah and Aatif, 2009;Ulmert et al, 2009). In parallel to tPSA, recent clinical trials demonstrate the ability of %fPSA to predict the aggressiveness of prostate tumors and the outcome of PCa patients.…”

“…Increasing KLK2 serum levels have been associated with residual tumors and biochemical recurrence after the local treatment of patients, designating in this way the presence of a clinical relapse (Ulmert et al, 2009). Additionally, recent promising studies reported severe overexpression of KLK5 gene transcription levels, after treatment of the androgen-independent prostate cancer cell lines PC3 and DU145 with various and broadly used, in clinical practice, chemotherapeutic agents (Thomadaki et al, 2009;Mavridis et al, 2010b).…”

“…However, PSA serum concentration measurement today remains the cornerstone of monitoring tools used for the early detection of PCa recurrence. In particular, elevation of serum PSA levels after surgical or radiation treatment, known as biochemical recurrence or PSA failure, is a strong indicator of any residual tumors and putative disease recurrences (Ullah and Aatif, 2009;Ulmert et al, 2009). This biochemical recurrence, which emerges significantly prior to clinical recurrence, provides an opportunity for a better active surveillance of therapy course for these patients, as well for the earlier initiation of an adjuvant treatment, resulting in improved survival probabilities.…”