1. ¹Department of Oncology–Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden
2. ²Department of Biochemistry, Nihon University School of Dentistry, Tokyo, Japan
3. ³Department of Medical Biochemistry, Göteborg University, Göteborg, Sweden
4. ⁴Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden
5. ⁵Institute for Genetics and Pathology, Uppsala University, Uppsala, Sweden

Correspondence: Dr Arne Östman, Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, SE-171 76 Stockholm, Sweden. E-mail: Arne.Ostman@ki.se

⁶These authors contributed equally to this work.

Received 27 March 2006; Revised 5 September 2006; Accepted 19 October 2006; Published online 1 February 2007.

Abstract

Basal cell carcinoma (BCC) is characterized by slow growth, virtual absence of metastases, and strong stroma-dependency. Cancer-associated fibroblasts (CAFs) in the tumor stroma influence tumor growth, invasion, and metastasis. To comprehensively characterize CAFs of BCC in their in situ cancer environment, laser capture microdissection, linear gene amplification, microarray analysis, and quantitative real-time PCR (qRT-PCR) were combined. Pair-wise comparison of gene expression of microdissected CAFs and corresponding normal perifollicular fibroblasts identified 65 genes that were significantly upregulated in at least two of three different patients. Among the annotated genes, as many as 13 genes encoded secreted proteins, of which six were previously implicated as CAF-associated proteins in various tumor types. Four of the seven novel CAF genes – matrix Gla-protein, secreted frizzled-related protein 2, angiopoietin-related protein-2, and platelet-derived growth factor receptor-like protein – were selected for further analyses by qRT-PCR and were found to be frequently upregulated in CAFs of three independent BCC tissues. Analyses of CAFs from squamous cell cancer, prostate cancer, and colon cancer did not indicate that these genes were upregulated in these cancers. This study thus validates a novel approach for comprehensive characterization CAFs in their in situ environment of BCC. The results suggest a specific expression profile of CAFs in BCC possibly accounting for disease-specific pathological roles.