Abstract
Angiogenesis, a process highly regulated by pro-angiogenic and anti-angiogenic factors, is disrupted and dysregulated in cancer. Despite the increased clinical use of angiogenesis inhibitors in cancer therapy, most molecularly targeted drugs have been less effective than expected. Therefore, an in-depth exploration of the angiogenesis pathway is warranted. In this study, the expression of angiogenesis-related genes in various cancers was explored using The Cancer Genome Atlas datasets, whereupon it was found that most of them were protective genes in the patients with kidney renal clear cell carcinoma (KIRC). We divided the samples from the KIRC dataset into three clusters according to the mRNA expression levels of these genes, with the enrichment scores being in the order of Cluster 2 (upregulated expression) > Cluster 3 (normal expression) > Cluster 1 (downregulated expression). The survival curves plotted for the three clusters revealed that the patients in Cluster 2 had the highest overall survival rates. Via a sensitivity analysis of the drugs listed on the Genomics of Drug Sensitivity in Cancer database, we generated IC50 estimates for 12 commonly used molecularly targeted drugs for KIRC in the three clusters, which can provide a more personalized treatment plan for the patients according to angiogenesis-related gene expression. Subsequently, we investigated the correlation between the angiogenesis pathway and classical cancer-related genes as well as that between the angiogenesis score and immune cell infiltration. Finally, we used the least absolute shrinkage and selection operator (LASSO)–Cox regression analysis to construct a risk score model for predicting the survival of patients with KIRC. According to the areas under the receiver operating characteristic (ROC) curves, this new survival model based on the angiogenesis-related genes had high prognostic prediction value. Our results should provide new avenues for the clinical diagnosis and treatment of patients with KIRC.
Highlights
Renal cell carcinoma (RCC) ranks as the eighth most diagnosed malignant disease in humans in the United States [1]
Tumor-driven hypoxia increases the expression of proangiogenic factors, leading to the formation of new blood vessels that are required for the growth of solid tumors [47]
We observed that most angiogenesisrelated genes existed as protective genes in the patients with kidney renal clear cell carcinoma (KIRC), which was inconsistent with the previous findings that overexpression of the angiogenesis pathway can lead to cancer development
Summary
Renal cell carcinoma (RCC) ranks as the eighth most diagnosed malignant disease in humans in the United States [1]. Kidney renal clear cell carcinoma (KIRC), a highly vascularized tumor that derives from proximal tubular epithelial cells of the nephrons, is to date the most common pathological type of RCC [2, 3]. As ∼70% of the kidney cancers are localized or locally advanced when first diagnosed, they can be treated via surgical resection; radical nephrectomy is the most common treatment [5]. Approximately one-third of the patients who have undergone renal tumor resection still develop distant metastasis eventually [6]. Many patients develop drug resistance and eventually experience cancer progression. Such setbacks force us to rethink the current treatments for RCC
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