title: High density of tryptase-positive mast cells in human colorectal cancer: a poor prognostic factor related to protease-activated receptor 2 expression.
abstract: Tryptase(+) mast cells (MCs), abundant in the invasive front of tumours, contribute to tissue remodelling. Indeed, protease-activated receptor-2 (PAR-2) activation by MC-tryptase is considered an oncogenic event in colorectal cancer (CRC). Recently, we have suggested NHERF1 as a potential new marker in CRC. In this study, we aimed to determine the distribution of tryptase(+) MCs and PAR-2 and to examine the relationship between PAR-2 and NHERF1, investigating their reputed usefulness as tumour markers. We studied a cohort of 115 CRC specimens including primary cancer (C) and adjacent normal mucosa (NM) by immunohistochemical double staining, analyzing the protein expression of MC-tryptase, PAR-2 and cytoplasmic NHERF1. MC density was higher in NM than in C. Tumours with high TNM stage and poor grade showed the highest MC density. A higher PAR-2 immunoreactivity characterized tumours most infiltrated by MCs compared with samples with low MC density. Furthermore, PAR-2 overexpression was associated with advanced TNM stage, poor grade and lymphovascular invasion (LVI). A positive correlation existed between tryptase(+) MC density and PAR-2 expression. Cytoplasmic NHERF1 was higher in C than in NM and overexpressing tumours resulted associated with nodal and distant metastases, poor grade and LVI. PAR-2 correlated with cytoplasmic NHERF1 and the PAR-2(+)/cytoplasmic NHERF1(+) expression immunophenotype identified tumours associated with unfavourable prognosis and aggressive clinical parameters. Our data indicate that the high density of tryptase(+) MCs at invasive margins of tumours was associated with advanced stages of CRC and was strongly correlated with PAR-2 expression.
authors.affiliation: Functional Biomorphology Laboratory, National Cancer Research Centre, Giovanni Paolo II, Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Malfettone
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
authors.forename: Concetta
authors.initials: C
authors.lastname: Saponaro
authors.forename: Girolamo
authors.initials: G
authors.lastname: Ranieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Stefano
authors.initials: S
authors.lastname: Caruso
authors.forename: Ondina
authors.initials: O
authors.lastname: Popescu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simone
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002452:Cell Count; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000473:pathology*; D008875:Middle Aged; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism; D011379:Prognosis; D044464:Receptor, PAR-2 / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D053802:Tryptases / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D044464:Receptor, PAR-2; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D053802:Tryptases
keywords: Colorectal cancer; NHERF1; PAR-2; aggressiveness; invasiveness; mast cell; prognostic factor; tryptase