Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer

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.

Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC)

“…In order to quantify the activity of the DNA repair pathway, we defined the DNA repair pathway score based on the gene set variation analysis (GSVA) score of the Molecular Signatures Database Hallmark DNA repair gene set ( Table S1 ), using the methodology we previously reported [ 4 , 5 , 9 , 10 , 11 ]. The DNA repair score correlated with expression of BRCA1 and BRCA2, arguably the most clinically significant DNA repair genes associated with cancer prognosis and treatment sensitivity ( Figure S1 ; Spearman’s rank correlation coefficient (r) = 0.576 ( p < 0.01) and 0.471 ( p < 0.01), respectively).…”

“…The E2F target pathway score also demonstrated potential as a predictive biomarker for neoadjuvant therapy in breast cancer [ 10 ]. The angiogenesis pathway score revealed the association of intratumoral angiogenesis with inflammation, immune reaction, and metastatic recurrence in breast cancer [ 11 ]. These findings support the idea that pathway scores may be a useful tool in understanding the role of the DNA repair pathway in cancer.…”

“…The DNA repair score was measured as the gene set variation analysis (GSVA) score for the “Hallmark DNA repair” gene set of the Molecular Signatures Database (MSigDB) Hallmark gene set collections [ 23 ] using the GSVA algorithm [ 51 ] in the Bioconductor package (version 3.10), as we previously reported [ 4 , 5 , 9 , 10 , 11 ].…”

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

“…These tumors only grow to smaller lesions, which is correlated with the formation of fewer metastatic lesions [ 5 ]. Additionally, data show that tumors with a high angiogenesis score were associated with recurrent metastasis, especially to the brain and bone [ 178 ]. Additionally, DLL4 expression is increased in distant metastases compared to primary HNSCC tumors and associated with poor outcome [ 56 ].…”

Links between Inflammation and Postoperative Cancer Recurrence

“…Analyses comparing molecular characteristics and the location of primary and recurrent tumors will elucidate the extent to which inflammation contributes to the regrowth of the primary tumor, disease recurrence, development of micrometastases, or the emergence of entirely new malignancies. Oshi et al demonstrated that intratumoral angiogenesis is associated with inflammation, immune reactions, and metastatic recurrence in breast cancer [ 53 ]. Although the direct correlation between inflammation in the primary tumor and cancer recurrence was not revealed, a relationship via angiogenesis may exist and have an important role in tumor recurrence.…”