A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10−21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.
Author summary Angiogenesis is the formation of new blood vessels from pre-existing ones and it is the process for revascularization that predominates in adult life. Although angiogenesis is essential in physiological processes, such as wound healing, it also participates in pathological conditions, collectively known as angiogenesis-dependent diseases. Cancer and retinopathies are examples of such diseases. In cancer, angiogenesis is considered one of its hallmarks as tumors depend on a constant supply of oxygen and nutrients to grow. The more angiogenic the tumor, the more aggressive it is for the patient. In the present work, we used a well-suited animal model of retinopathy, an angiogenesis-dependent disease, to study the molecular signature for angiogenesis. We analyzed differences in gene expression from retinas developing under physiological and in retinopathic conditions to identify a molecular gene signature for angiogenesis. Because of the association between these two diseases, we tested our gene signature using data from human cancer. We showed that our gene signature has a robust prognostic value to predict breast cancer patient survival. Our results may lead to a better understanding of molecular mechanisms of pathological angiogenesis and its contribution to breast cancer.