Abstract
BackgroundThe tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR.MethodsThe expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I – III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -β, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope.ResultsThe transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1+/CD45+ cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors.ConclusionsThe increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification.
Highlights
The tumor microenvironment has a critical role in regulating cancer cell behavior
Considering that the different Cancer-associated fibroblast (CAF) markers tested stained different cells, this suggests that a single fibroblast marker cannot recapitulate the heterogeneous composition of CAFs in the tumor stroma
Gene expression data showed an increased expression of CAF markers in stroma-high compared to stroma-low tumors
Summary
The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The tumor-stroma ratio (TSR) is a prognostic tool that stratifies tumors into stroma-low and stroma-high based on the quantity of stroma scored in hematoxylin & eosin (H&E) stained sections [2, 3]. CAFs are a heterogeneous cell population in terms of origin and biological function and derive mainly from mesenchymal cells that are resident or recruited by the tumor [12]. They are situated close to cancer cells and other components of the stroma like immune cells, blood vessels and components of the extracellular matrix (ECM). The identification and nomenclature of fibroblasts present in the tumor remain challenging due to the lack of specific markers for known and still undefined subtypes
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