Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma

Abstract

Taken together, these results indicate that elevated levels of KLK6 in GBM are likely to promote the resistance of tumor cells to cytotoxic agents and are an indicator of reduced patient postsurgical survival times.

10 Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

“…Consistent with most reports, we found high KLK6 expression in primary tumor samples of 42.6 % HNSCC patients. However, while induced KLK6 expression alone or in combination with other KLK family members was associated with poor progression-free and overall survival in colorectal cancer [31,32], gastric cancer [33,34], pancreatic ductal adenocarcinoma [35], ovarian cancer [36,37], lung cancer [38], and intracranial tumors [39,40], a high KLK6 expression pattern served as favorable prognostic biomarker in our OPSCC and LSCC patient cohorts. These data suggest a contextspecific role of KLK6 in regulating the malignant progression and response to therapy, with both tumor promoting and tumor protective functions depending on the cellular origin of the tumor tissue.…”

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

“…Because of the aggressive and destructive growth pattern of this tumor entity, more efficient systemic therapies, and prognostic markers are urgently needed. Aberrant expression of KLK6 has been detected in a variety of malignant tumors like pancreas, breast [31], ovarian, skin cancer [32], HNSCC [22] and glioma [20]. An increase in KLK6 expression is a common feature of most human malignancies, but the correlation between KLK6 upregulation and the clinical outcome is poorly understood and even led to controversial findings concerning tumor-regulating properties of KLK6 in tumor [21,31,32].…”

“…Most tumors were characterized by a strong increase of KLK6 transcript and protein levels as compared to normal tissues [14,19]. In several publications, KLK6 has also been described as a promising biomarker for early diagnosis and clinical outcome [20]. However, recent studies questioned the general oncogenic role of KLK6 and stressed the importance to consider its context-dependent, tumor-protective function, as exemplified in breast and renal cancer as well as squamous cell carcinoma of the head and neck (HNSCC) [21,22].…”

Kallikrein-related peptidase 6 orchestrates astrocyte form and function through proteinase activated receptor-dependent mechanisms

“…First, Klk6 is the most abundant serine proteinase in the adult CNS and its levels are dynamically altered in the context of CNS injury and disease (Scarisbrick 2012). In the human CNS, KLK6 levels are increased in active MS lesions (Scarisbrick et al 2002), after traumatic spinal cord injury SCI (Scarisbrick et al 2006; Radulovic et al 2013; Radulovic et al 2015) and in high grade astrocytoma (Drucker et al 2013; Drucker et al 2015), but decreased in Alzheimers (Little et al 1997; Diamandis et al 2000; Ogawa et al 2000; Zarghooni et al 2002; Ashby et al 2010) and Parkinsons disease (Iwata et al 2003; Spencer et al 2013; Spencer et al 2015; Pampalakis et al 2017). Indeed, astrocytes express very low levels of Klk6 in the intact CNS (Scarisbrick et al 1997; Scarisbrick et al 2000), however astrocyte Klk6 is up regulated in response to a variety of insults.…”

“…Prior studies demonstrate astrocytes treated with Klk6 undergo a rapid transition from an epithelioid to a stellate morphology, increase IL-6 expression and secretion (Scarisbrick et al, 2012), and show activation of the mitogen-activated protein kinases (MAPK) (Vandell et al, 2008) and signal transducer and activator of transcription 3 (STAT3) (Radulovic et al 2015; Radulovic et al 2016) signaling pathways. KLK6 also promotes survival and resistance of astrocytoma cell lines to irradiation and temozolomide with higher tumor KLK6 levels associated with reduced patient survival (Drucker et al 2013; Drucker et al 2015). …”