title: Characterization of cathepsin X in colorectal cancer development and progression.
abstract: The lysosomal cysteine carboxypeptidase cathepsin X (CTSX), localized predominantly in immune cells, has been associated with the development and progression of cancer. To determine its specific role in colorectal carcinoma (CRC), we analyzed CTSX expression in non-malignant mucosa and carcinoma of 177 patients as well as in 111 adenomas and related it with clinicopathological parameters. Further, the role of CTSX in the adhesion and invasion of the colon carcinoma cell lines HT-29 and HCT116 was investigated in an in vitro culture cell system with fibroblasts and monocytes, reflecting the situation at the tumor invasion front. Epithelial CTSX expression significantly increased from normal mucosa to adenoma and carcinoma, with highest expression levels in high grade intraepithelial neoplasia and in early tumor stages. Loss of CTSX occurred with tumor progression, and correlated with advanced local invasion, lymph node and distal metastasis, lymphatic vessel and vein invasion, tumor cell budding and poorer overall survival of patients with CRC. The subcellular distribution of CTSX changed from vesicular paranuclear expression in the tumor center to submembranous expression in cells of the invasion front. Peritumoral macrophages showed highest expression of CTSX. In vitro assays identified CTSX as relevant factor for cell-cell adhesion and tumor cell anchorage to fibroblasts and basal membrane components, whereas inhibition of CTSX caused increased invasiveness of colon carcinoma cells in mono- and co-culture. In conclusion, CTSX is involved in early tumorigenesis and in the stabilization of tumor cell formation in CRC. The results suggest that loss of CTSX may be needed for tumor cell detachment, local invasion and tumor progression. In addition, CTSX in tumor-associated macrophages indicates a role for CTSX in the anti-tumor immune response.
authors.affiliation: Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Electronic address: doerthe.jechorek@med.ovgu.de.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Jechorek
authors.affiliation: Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Votapek
authors.affiliation: Department of General, Visceral and Vascular Surgery, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Meyer
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Kandulski
authors.affiliation: Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.affiliation: Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Franke
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism*; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology / Q000473:pathology; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D002403:Cathepsins; D056657:Cathepsin K
keywords: Cathepsin X; Coculture; Colorectal cancer