Abstract
Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for large-scale immunostaining experiments.
Highlights
It is well recognized that the tumor microenvironment, consisting of carcinoma associated fibroblasts (CAFs), endothelial cells, and immune cells, is vital for carcinoma cell proliferation, invasion and metastasis
Since periostin (POSTN) was among the extracellular matrix (ECM) genes that were closely associated with the collagens and PDGFRβ in the the cancer genome atlas (TCGA) analysis, we examined its expression in oral squamous cell carcinoma (OSCC) specimens
From our Nearest Neighbor (NN) analysis within OSCC TCGA data, we considered other potential CAF markers, including PDGFRα, FSP1/S100A4, VIM, and FAP; none of these markers showed as close an association with the average collagen expression as PDGFRβ (S2 Table)
Summary
It is well recognized that the tumor microenvironment, consisting of carcinoma associated fibroblasts (CAFs), endothelial cells, and immune cells, is vital for carcinoma cell proliferation, invasion and metastasis. The activated tumor stroma shares some similarities with generic wound repair, as well as tissue fibrosis. It can be viewed as a biological response to a disrupted or damaged epithelial layer with stromal activation representing a repair process to restore tissue integrity and homeostasis [5]. Alternative local sources may include mesenchymal or adipose-derived stem cells (MSC or ASC), as well as endothelial cells that can give rise to CAFs through endothelial to mesenchymal transition (EnMT). The contribution of bone marrow-derived MSCs and circulating CD34+ fibrocytes was documented in several tumor models [1]
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