Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines

Abstract

Objectives: Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression.Methods: Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation.Results: Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines.Conclusion: Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.

Progression inference for somatic mutations in cancer

“…The upregulation of EGFR and KIT in ovarian cancer has been widely reported in literature [131], [132], [133], [134]. Our results also identified two smaller trees, one rooted by amplification in GRIN2B, which appears to precede upregulation in TP53 [135], [136], and an even smaller tree rooted by amplification of PLCH1. Our MIBN results, shown in Figure 11, identified TP53 as the single precursor event of all alterations in ovarian cancer.…”

Heterogeneous Responses of Ovarian Cancer Cells to Silver Nanoparticles as a Single Agent and in Combination with Cisplatin

“…All three cell lines we tested are generally used as models for high-grade serous carcinoma, though there is some debate on whether these may be further stratified into different molecular subtypes based on mRNA expression profiles [ 37 ]. Both OVCAR3 and SKOV3 cells possess loss-of-function mutations in TP53 [ 38 ], but A2780 cells are TP53 wild-type [ 39 ]. Furthermore, loss of p53 activity is associated with CDDP resistance and decreased survival in ovarian cancer patients [ 40 ].…”

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

“…This observation was supported by a report that mutant p53-harboring ovarian cancer cells exhibit high EFNB2 expression compared with those harboring wild-type p53. 35 Hubs are generally associated with greater importance in regulating key cellular pathways, and perturbations of genes encoding hubs are more likely to confer lethality than those of non-hubs. 36 Hence, identification of mutant p53-bound hub genes and subsequent perturbation of their expression might be crucial in understanding the mechanism(s) of chemoresistance, and greatly facilitate therapeutic intervention in a large proportion of tumors.…”