title: CD99 is a novel prognostic stromal marker in non-small cell lung cancer.
abstract: The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindskog
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Hanna
authors.initials: H
authors.lastname: Göransson-Kultima
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Maria
authors.initials: M
authors.lastname: Planck
authors.forename: Leif
authors.initials: L
authors.lastname: Johansson
authors.forename: Mats
authors.initials: M
authors.lastname: Lambe
authors.forename: Lars
authors.initials: L
authors.lastname: Holmberg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyberg
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.forename: Per
authors.initials: P
authors.lastname: Landelius
authors.forename: Kristina
authors.initials: K
authors.lastname: Lamberg
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
mesh_terms: D000071443:12E7 Antigen; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D021381:Protein Transport; D020543:Proteome; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C061828:CD99 protein, human; D015815:Cell Adhesion Molecules; D020543:Proteome