Potential importance of protease activated receptor (PAR)-1 expression in the tumor stroma of non-small-cell lung cancer.
BACKGROUND
Protease activated receptor (PAR)-1 expression is increased in a variety of tumor cells. In preclinical models, tumor cell PAR-1 appeared to be involved in the regulation of lung tumor growth and metastasis; however the role of PAR-1 in the lung tumor microenvironment, which is emerging as a key compartment in driving cancer progression, remained to be explored.


METHODS
In the present study, PAR-1 gene expression was determined in lung tissue from patients with non-small-cell lung cancer (NSCLC) using a combination of publicly available RNA microarray datasets and in house-made tissue microarrays including tumor biopsies of 94 patients with NSCLC (40 cases of adenocarcinoma, 42 cases of squamous cell carcinoma and 12 cases of other type of NSCLC at different stages).


RESULTS
PAR-1 gene expression strongly correlated with tumor stromal markers (i.e. macrophage, endothelial cells and (myo) fibroblast markers) but not with epithelial cell markers. Immunohistochemical analysis confirmed the presence of PAR-1 in the tumor stroma and showed that PAR-1 expression was significantly upregulated in malignant tissue compared with normal lung tissue. The overexpression of PAR-1 in tumor stroma of NSCLC appeared to be independent from tumor type, tumor stage, histopathological differentiation status, disease progression and patient survival.


CONCLUSIONS
Overall, our data provide evidence that PAR-1 in NSCLC is mainly expressed on cells that constitute the pulmonary tumor microenvironment, including vascular endothelial cells, macrophages and stromal fibroblasts.
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands. c.lin@amc.uva.nl.
Cong
C
Lin
Department of Respiratory Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
Christof J
CJ
Majoor
Department of Pathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
Joris J T H
JJ
Roelofs
Department of Respiratory Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.|Department of Pulmonology, Zuyderland Hospital, Henri Dunantstraat 5, 6419 PC, Heerlen, The Netherlands.
Martijn D
MD
de Kruif
Department of Pathology, The Antonie van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands.
Hugo M
HM
Horlings
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.|Inserm UMR1152, Medical School Xavier Bichat, 16 rue Henri Huchard, 75018, Paris, France.|Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
Keren
K
Borensztajn
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
C Arnold
CA
Spek
D000230:Adenocarcinoma / Q000378:metabolism / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000503:physiopathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D044463:Receptor, PAR-1 / Q000235:genetics*; D059016:Tumor Microenvironment; D015854:Up-Regulation
D044463:Receptor, PAR-1
NSCLC and tumor stroma; Protease activated receptor