Abstract PS17-51: Angiogenesis in a bulk tumor is associated with cancer immunity and metastasis
Authors: Oshi Masanori , Stephanie Newman , Tokumaru Yoshihisa , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki 
Published: February 2021

Angiogenesis is included in one of the hallmarks of cancer because it not only provides conduit to supply oxygen and nutrients to the cancer cells, but also deliver molecules that confer immune resistance, cell adhesion proteins, and other various growth factors. We hypothesized that angiogenetic score that accumulate 200-related genes will accurately grasp angiogenesis in bulk tumor that enable as to assess clinical relevance of angiogenesis in breast cancer. Angiogenesis pathway score was defined using the molecular Signatures Database Hallmark angiogenesis gene set. Median was used to divide into high and low score groups within each cohort. High angiogenesis score is associated with high expression of Vascular endothelial growth factor (VEGF)- (VEGFA/B, VEGFR1/2/3; p = 0.094, &lt; 0.001, &lt; 0.001, &lt; 0.001, &lt; 0.001, respectively), Endothelial cell surface marker- (CD31 and VWF; all p &lt; 0.001), Vascular stability- (TIE1/2, ANGPT1/2, VE-Cadherin, Claudin 5 and JAM2; all p &lt; 0.001), Hypoxia- (HIF1A/1B; p &lt; 0.001 and 0.004), and Shlingosine-1-phosphate (S1P)- (SphK1/2, S1PR1, SPNS2; all p &lt; 0.001) related genes in TCGA cohort. These results were validated by METABRIC cohort. Even though none of the angiogenesis-related genes analyzed were included in the angiogenesis pathway score except for VEGFA. Although angiogenesis score was not associated with aggressive clinical features nor response to neoadjuvant chemotherapy, high angiogenesis score tumors were associated with both favorable and unfavorable immune cell infiltrations including CD4 memory (p &lt; 0.001 and 0.03), T helper 1 (Th1) (p &lt; 0.001 in both cohorts), B cell (p &lt; 0.001 in both cohorts), T helper 2 (p &lt; 0.001 in both cohorts) and regulatory T cell (p &lt; 0.001 and 0.037) in both cohorts. On the other hand, Dendritic cell and M2 macrophage were highly infiltrated in high angiogenesis score tumors in both cohorts (p &lt; 0.001 in both cohorts). TIL regional fraction was higher in the low angiogenesis score group (p &lt; 0.001), while Leukocyte fraction and lymphocyte infiltration signature showed higher values in the high angiogenesis score tumors (both p &lt; 0.001). High angiogenesis pathway score significantly enriched immune response-related Hallmark gene sets; interferon (IFN)-γ response, IL2-STAT5 signaling, and IFN-α response. Furthermore, high angiogenesis score significantly enriched unfavorable inflammation-related Hallmark gene sets; inflammatory response, IL6-JAK-STAT3 signaling, TNF-α signaling via NFkB, and TGF-β signaling and hypoxia. Furthermore, we found that metastasis-related genes sets; including epithelial mesenchymal transition (EMT), HEDGEHOG signaling, NOTCH signaling and WNT-β catenin signaling were also enriched in high angiogenesis score group in both cohorts (all FDR &lt; 0.25). In particular, EMT pathway score was strongly correlated with angiogenesis pathway score in both cohorts (spearman r = 0.894 [p &lt; 0.01] and 0.868 [p &lt; 0.868] respectively). High angiogenesis pathway scores were significantly associated with site-specific metastasis-free survival especially brain and bone metastasis (p = 0.029 and 0.043 respectively). In conclusion, the angiogenesis score covers many of the angiogenesis-related genes, and it show the correlation between the amount of angiogenesis with inflammation and metastasis in breast cancer.

Citation Format: Masanori Oshi, Newman Stephanie, Yoshihisa Tokumaru, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Angiogenesis in a bulk tumor is associated with cancer immunity and metastasis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-51.