Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Abstract

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

Kallikrein-Related Peptidase 6 (KLK6) as a Contributor toward an Aggressive Cancer Cell Phenotype: A Potential Role in Colon Cancer Peritoneal Metastasis

“…Variability could relate also to technical sensitivities (e.g., in silico, qRT-PCR, and ELISA and immunohistochemistry) or to selected tissues (i.e., colon mucosa from healthy donors or paired adjacent mucosa). Indeed, some KLKs are highly expressed at sites of inflammation [ 39 ] and might, therefore, also be elevated both in the immune cells and in the glandular epithelial cells in non-cancer-bearing tissues obtained from individuals with non-diagnostic bowel diseases. In our analysis, we did not detect KLK6 in inflammatory cells and KLK6 staining was restricted to the cancerous mucosa.…”

KLK6 Functions as an Oncogene and Unfavorable Prognostic Factor in Bladder Urothelial Carcinoma

“…Based on TCGA database analysis, KLK6 is significantly upregulated in 16 cancer types. In addition, the elevation of KLK6 expression has been reported in the kinds of literature, such as melanoma [ 33 ], ovarian cancer [ 34 ], gastric cancer [ 35 ], pancreatic ductal adenocarcinoma [ 36 , 37 ], and colon cancer [ 38 ]. In our study, KLK6 is validated as an independent and unfavorable prognostic factor of BLCA.…”

Role of Serine Proteases at the Tumor-Stroma Interface

“…Immunohistochemistry analysis of tissue sections of ovarian and melanoma patients found the overexpression of KLK6 in tumor associated stromal cells and keratinocytes (72,73). In pancreatic ductal adenocarcinoma, immunostaining analysis of epithelial tumor cells and the surrounding stroma and immune cells showed that high KLK6 protein levels in the tumor and immune cells are significantly associated with shorter survival compared to low protein levels (74). mRNA analysis of colorectal cancer (CRC) tissue samples from 136 patients showed upregulated KLK10 expression (75).…”