Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients' survival

Abstract

The histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

Figure 1

(A) Representative histological features showing the lepidic (left), acinar, papillary, micropapillary and solid (right) patterns. (B) Six gene sets, including SINGH KRAS Dependency Signature, CAMP UP.V1 UP, MYC UP.V1 UP, RB P107 DN.V1 DN, E2F1 UP.V1 UP and CSR LATE UP.V1 UP, associated with lung adenocarcinoma. (C) Venn diagram showing the distribution of gene sets according to the five histological types.

Figure 2

Survival analyses of the five types. (A) Disease-specific survival: lepidic, acinar, papillary, micropapillary and solid types (p = 0.939, 0.005, 0.555, 0.205 and 0.02, respectively). (B) Disease-free survival: lepidic, acinar, papillary, micropapillary and solid types (p = 0.902, 0.006, 0.651, 0.979 and 0.05, respectively).

Figure 3

Bar plots of the solid type. (A) Proliferation, non-silent mutation rate and cancer-testis antigen score (p = 0.001, < 0.001 and 0.005, respectively). (B) Cytolytic activity score, memory B cells and CD8 T cells (p = 0.022, 0.015 and < 0.001, respectively). (C) Activated memory CD4 T cells, regulatory T cells and CD274 (PD-L1) (p < 0.001, 0.021 and < 0.001, respectively).

Figure 4

(A) Grouping of networks based on functionally enriched Gene Ontology (GO) terms and pathways in the solid type. The functionally grouped networks are linked to their biological function, where only the most significant term in the group is labeled. (B) Bar plots of EGFR, ERBB2, ERBB4 and VEGF-A (p = 0.13, 0.281 < 0.001 and 0.005, respectively).

Figure 5

(A) Representative histological features: coagulative necrosis (left) and tumor-infiltrating lymphocytes (TILs) (right). (B) Bar plots of VEGF-A according to necrosis (coagulative necrosis)/immune response↑ (elevated TILs) (p = 0.035) (left) and disease-specific survival/disease-free survival according to necrosis/immune response↑ (p = 0.041 and 0.831, respectively). (C) Pearson’s correlations and boxplots showing the natural log half-maximal inhibitory concentration (LN IC50) of axitinib [r =  − 0.768, p = 0.044 (Pearson’s correlation) and 0.035 (Student’s t-test)] (left) and sorafenib [r =  − 0.96, p = 0.04 (Pearson’s correlation) and 0.008 (Student’s t-test)] (right).