Abstract
BackgroundThere are several indications that the composition of the tumor stroma can contribute to the malignancy of a tumor. Here we utilized expression data sets to identify metagenes that may serve as surrogate marker for the extent of matrix production and vascularization of a tumor and to characterize prognostic molecular components of the stroma.MethodsTCGA data sets from six cancer forms, two breast cancer microarray sets and one mRNA data set of xenografted tumors were downloaded. Using the mean correlation as distance measure compact clusters with genes representing extracellular matrix production (ECM metagene) and vascularization (endothelial metagene) were defined. Explorative Cox modeling was used to identify prognostic stromal gene sets.ResultsClustering of stromal genes in six cancer data sets resulted in metagenes, each containing three genes, representing matrix production and vascularization. The ECM metagene was associated with poor prognosis in renal clear cell carcinoma and in lung adenocarcinoma but not in other cancers investigated. Explorative Cox modeling using gene pairs identified gene sets that in multivariate models were prognostic in breast cancer. This was validated in two microarray sets. Two notable genes are TCF4 and P4HA3 which were included in the sets associated with positive and negative prognosis, respectively. Data from laser-microdissected tumors, a xenografted tumor data set and from correlation analyses demonstrate the stroma specificity of the genes.ConclusionsIt is possible to construct ECM and endothelial metagenes common for several cancer forms. The molecular composition of matrix-producing cells, rather than the extent of matrix production seem to be important for breast cancer prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2864-2) contains supplementary material, which is available to authorized users.
Highlights
There are several indications that the composition of the tumor stroma can contribute to the malignancy of a tumor
extracellular matrix (ECM) and endothelial gene sets were expanded by selecting genes from the The Cancer Genome Atlas (TCGA) breast cancer data set that had a correlation coefficient above 0.84 with at least one gene in the seeding sets defined as genes in our previously defined signatures 1 and 2 (ECM) and in signature 4 and 5 [17]
We used the genes in the two ECM-related signatures to expand the gene list by identifying all genes that in the TCGA breast cancer RNA-seq data had a correlation coefficient above 0.84 with at least one gene in the original sets (Additional file 3: Table S3)
Summary
There are several indications that the composition of the tumor stroma can contribute to the malignancy of a tumor. Tumors contain a complex microenvironment which consists of an extracellular matrix (ECM) and a large variety of non-cancerous stromal cells. The microenvironment is in constant interaction with the cancer cells and becomes modified during tumor progression, exemplified by vascularization, remodeled ECM and augmented tissue stiffness [1,2,3]. Stromal cells can promote tumorigenesis by inducing an angiogenic switch which may contribute to a more aggressive phenotype of the tumor. This includes increased endothelial cell proliferation and microvessel density [10]
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