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Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

ABSTRACT: Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

SUBMITTER: Acerbi I

PROVIDER: S-EPMC4593730 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

Acerbi I I Cassereau L L Dean I I Shi Q Q Au A A Park C C Chen Y Y YY Liphardt J J Hwang E S ES Weaver V M VM

Integrative biology : quantitative biosciences from nano to macro 20150511 10

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increa ...[more]

PMID: 25959051

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Project description:BackgroundThis study aims to determine whether NEFM (neurofilament medium) DNA methylation correlates with immune infiltration and prognosis in breast cancer (BRCA) and to explore NEFM-connected immune gene signature.MethodsNEFM transcriptional expression was analyzed in BRCA and normal breast tissues using Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The relationship between NEFM DNA methylation and NEFM transcriptional expression was investigated in TCGA. Potential influence of NEFM DNA methylation/expression on clinical outcome was evaluated using TCGA BRCA, The Human Protein Atlas and Kaplan-Meier plotter databases. Association of NEFM transcriptional expression/DNA methylation with cancer immune infiltration was investigated using TIMER and TISIDB databases.ResultsHigh expression of NEFM correlated with better overall survival (OS) and recurrence-free survival (RFS) in TCGA BRCA and Kaplan-Meier plotter, whereas NEFM DNA methylation with worse OS in TCGA BRCA. NEFM transcriptional expression negatively correlated with DNA methylation. NEFM DNA methylation significantly negatively correlated with infiltrating levels of B, CD8+ T/CD4+ T cells, macrophages, neutrophils and dendritic cells in TIMER and TISIDB. NEFM expression positively correlated with macrophage infiltration in TIMER and TISIDB. After adjusted with tumor purity, NEFM expression weekly negatively correlated with infiltration level of B cells, whereas positively correlated with CD8+ T cell infiltration in TIMER gene modules. NEFM expression/DNA methylation correlated with diverse immune markers in TCGA and TISIDB.ConclusionsNEFM low-expression/DNA methylation correlates with poor prognosis. NEFM expression positively correlates with macrophage infiltration. NEFM DNA methylation strongly negatively correlates with immune infiltration in BRCA. Our study highlights novel potential functions of NEFM expression/DNA methylation in regulation of tumor immune microenvironment.

Project description:BackgroundBreast cancer stem cells (BCSCs) are associated with tumor initiation, invasion, metastasis and drug resistance. It is known that many proteins and signaling pathways are involved in the regulation of BCSCs, however, much more efforts are needed to understand BCSCs comprehensively. Tumor-infiltrating immune cells are important in cancer treatment efficacy and patient prognosis. We tried to identify potential suppressor of BCSCs and analyze its correlation with various immune cells infiltration by bioinformatic and experimental methods.MethodsExpression level and methylation state of OVOL2 were analyzed by tools from bc-GenExMiner v4.8 and UALCAN databases. The Kaplan-Meier plotter was applied to evaluate the prognostic values of OVOL2. Gene expression datasets (GSE7515, GSE15192) were selected to analyze differentially expressed genes (DEGs) related to BCSCs. GO and KEGG pathway analyses of DEGs were conducted. MCODE app plugin of Cytoscape was used to screen modules in PPI network of downregulated DEGs. Correlation of OVOL2 expression with infiltrating immune cells was evaluated by TIMER 2.0. Experiments were conducted to verify whether OVOL2 could inhibit stemness traits of breast cancer cell MDA-MB-231.ResultsThe expression level of OVOL2 in basal/TNBC was significantly lower than that of other subtypes. Survival analyses indicated that high expression of OVOL2 was associated with favorable prognosis. GO and KEGG pathway analyses for upregulated and downregulated DEGs were conducted. The top three clusters of downregulated DEGs showed that tight junction and chemokines may play important roles in BCSCs. OVOL2 is one module of clusters. OVOL2 expression is correlated with various immune cells infiltration. Experiments showed that OVOL2 suppresses CD44+/CD24- ratio and mammospheres formation of MDA-MB-231.ConclusionOVOL2 may play an important role in the regulation of breast cancer stemness and immune cell infiltration, and is likely to be a target for the treatment of breast cancer.

Dataset Information

Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

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Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

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