CCBIO seminar: Arne Östman
Impact of PDGFR-regulated fibroblasts and pericytes on tumor progression, prognosis and drug response
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
PDGF alpha- and beta-receptors are important regulators of cancer-associated fibroblasts (CAFs) and pericytes. Studies in experimental systems have demonstrated a functional impact of PDGFbR-positive fibroblasts on tumor drug uptake and metastasis, and have also indicated tumor type-specific effects of PDGFbR-positive pericytes on tumor growth and metastasis. Clinical relevance of these findings is indicated by associations between high stromal PDGFbR expression and prognosis in breast and prostate cancer.
In ongoing studies these findings have been extended by analyses of ductal carcinoma in situ (DCIS) breast cancer, as well as pancreas and ovarian cancer where high stromal PDGFbR expression was identified as a poor prognosis factor. Analyses of patient samples and experimental studies suggest supportive effects of PDGFbR-stimulated fibroblasts on pancreas cancer stem cell phenotypes. The breast DCIS and pancreas studies uncovered differential expression of stromal PDGFaR and PDGFbR and suggest that these two related receptors define fibroblasts with different functional properties. According to studies in breast DCIS models, TGF-beta signaling appears to be a critical pathway controlling PDGFaR- and PDGFbR-expression in CAFs. Combinations of experimental studies and analyses of human tumor collections suggest that stromal PDGFbR-expressing cells modulate drug- and radiation-sensitivity of cancer cells.
For extended analyses of the tumor stroma of clinical samples an integrated set of procedures has been developed, including digital image analyses of four different double-stainings with fibroblast, pericyte and endothelial cell markers. Ongoing analyses of collections of colorectal, kidney and ovarian cancer, are uncovering tumor-type specific prognostic significance of independently occurring marker-defined pericyte subsets.
Collectively the studies provide mechanistic insight and clinical information regarding functionally distinct marker-defined fibroblast and pericyte subsets. Findings suggest opportunities for development of tumor stroma-derived biomarkers and imply novel therapeutic strategies involving targeting of differentially expressed tumor stroma cell subsets.
Chairperson: Donald Gullberg, CCBIO