Abstract
Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.
Highlights
Angiogenesis is defined as the creation of new blood vasculature from preexisting ones
Our group and others have demonstrated that a bioactive lipid mediator, sphingosine-1-phosphate (S1P), which is produced by sphingosine kinase 1 (SphK1) facilitates angiogenesis in breast cancer [9,10,11], and that SphK1 promotes breast cancer metastasis [12,13]
The angiogenesis pathway score was determined from global tumor gene expression data as the gene set variation analysis (GSVA) score for the Molecular Signatures Database (MSigDb) Hallmark angiogenesis gene set
Summary
Angiogenesis is defined as the creation of new blood vasculature from preexisting ones. Bevacizumab, an anti-VEGF antibody that targets tumor angiogenesis, was granted “accelerated” approval by the FDA in 2008 after results of the E2100 randomized phase 3 trial for the first-line treatment of human epidermal receptor 2 (HER2)-negative metastatic breast cancer This decision was reversed in 2010 due to a lack of efficacy in response and survival [29]. Our group has demonstrated the efficacy of the gene set variation analysis (GSVA) method to summarize the expression of dozens of genes of a specific cellular pathway as a score in order to estimate the degree of the activation of that pathway With this GSVA-based scoring system, we have shown the clinical relevance, such as prognosis and treatment response, for the KRAS [30], G2M checkpoint [31], and E2F [32] pathways in breast cancer. We hypothesize that intra-tumoral angiogenesis as measured with this score correlates with inflammation and metastasis in breast cancer patients
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