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Multi-Omics Analysis of Tumor Angiogenesis Characteristics And Zheng et al. Cell Commun Signal (2021) 19:39 https://doi.org/10.1186/s12964-021-00728-9 RESEARCH Open Access Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma Wenzhong Zheng1†, Shiqiang Zhang2† , Huan Guo3, Xiaobao Chen1, Zhangcheng Huang1, Shaoqin Jiang1 and Mengqiang Li1* Abstract Background: Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. Method: Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identifed using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and diferential methylation analysis (DMA). The master transcription factors (MTF) that cause the diference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. Results: The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was signifcantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correla- tion coefcient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signa- ture identifed two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed difer- ent angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identifed 59,654 diferential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identifed as top three MTF in regulating angiogenesis signature in KIRC patients. *Correspondence: [email protected] †Wenzhong Zheng and Shiqiang Zhang contributed equally to this study 1 Department of Urology, Fujian Province, Fujian Medical University Union Hospital, Gulou District, 29 Xinquan Road, Fuzhou 200001, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zheng et al. Cell Commun Signal (2021) 19:39 Page 2 of 16 Conclusion: Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients. Keywords: Tumor angiogenesis, Kidney renal clear cell carcinoma (KIRC), Microenvironment score, Diferential methylation sites, Master transcription factors Background functions, resulting in tumor metastasis [13, 14]. In addi- Malignant renal cell carcinoma (RCC) account for 2% tion, the TAMs in hypoxia microenvironment achieve of the global cancer burden, and ~ 350,000 new cases a pro-angiogenic performance either by upregulating will occur worldwide in 2018 [1]. Tere are several his- angiogenic molecules (such as VEGF, type I receptor for topathological subtypes of RCC, each characterized by VEGF, angiopoietin, FGF2, CXCL8, and IL-8) or through a specifc molecular pattern. Kidney renal clear cell car- upregulation of angiogenic modulators (such as COX2, cinoma (KIRC) is the most prevalent heterogeneous MMP7, and iNOS) [15]. Terefore, hypoxia, abnormal subtype, accounting for 75% of all renal cell carcinomas immune status, and angiogenesis form a positive feed- (RCC) and most of them arises from the proximal tubule back regulation cycle to promote cancer cells metastasis. cells of the renal nephron [2]. Te prognosis of meta- In this study, we systematically analyzed the relation- static KIRC patients remains poorly, and less than 10% ship between angiogenesis signals, immune signals, and of these cases were alive over 5 years after diagnosis [3, hypoxia signals in TCGA KIRC patients. 4]. Te development and metastasis of malignant tumor With the breakthrough of targeted therapy, anti-angi- cells depends on the establishment of a sufcient blood ogenic targeted therapy has attracted more and more supply, that is, tumor angiogenesis. In most normal tis- attention in advanced or metastatic renal cell cancer sues, factors that anti-angiogenic is predominate, how- research [8, 16]. Clearly, vascular endothelial growth ever in frequency dividing organs and tissues, the balance factor (VEGF) which served as pro-angiogenic growth of angiogenesis factor shift to pro-angiogenic growth factor is an efective drug target in metastatic kidney efect [5]. During the process of angiogenesis, tumor cells cancer patients and many agents to inhibit this path- express high level of pro-angiogenic growth factor and way have shown clinical beneft [17, 18]. On the other overwhelming the efects of anti-angiogenic factor to the hand, multi-targeted tyrosine kinase inhibitors (TKI) development of new blood vessels [6]. that inhibit vascular endothelial growth factor recep- Te initial of tumor angiogenesis program involves a tors (VEGFRs) have been approved by the America food series of change in local equilibrium cells between anti- and drug administration (FDA) as standard treatment angiogenic and pro-angiogenic regulators that are pro- for advanced or metastatic KIRC patients [19]. Immune duced by surrounding cancer stem cell, stromal cells, checkpoint blocker, such as anti-PD-1 antibody, heralded infltrating leukocytes, and cancer cells [5, 7]. Terefore, a new era in the therapy of metastatic renal cell carci- aberrant angiogenesis in tumorigenesis and metastasis noma (mRCC) [20]. Anti-angiogenic targeted therapy is closely related to abnormal tumor microenvironment. may also enhance the efect immune checkpoint blocker Hypoxia and the expression of the hypoxia inducible by up-regulating major histocompatibility complex class factor (HIF) proteins in cancer microenvironment were I (MHC-I) expression and promoting T cell infltration contributed to tumor angiogenesis and linked to poor [20]. Terefore, combining an anti-angiogenic targeted prognosis in kidney cancer patients [8–10]. Tis is easy therapy with an immune checkpoint blocker is a closely to state, as tumor cell grows require an adequate sup- tailored treatment to test in the clinic. In 2020 National ply of oxygen and nutrients based on vascular supply Comprehensive Cancer Network (NCCN) clinical prac- and uncontrolled cancer cell exceed a size that outgrows tice guidelines in renal cancer, anti-angiogenic targeted their host vascular system supply and result in local therapy and immunotherapy combination therapies have hypoxia. Consequently, hypoxia and related HIF fam- been added to frst-line treatment options [21]. On the ily proteins such as HIF-α proteins (1α, 2α, and 3α) and other hand, neoadjuvant targeted therapy in both local- HIF-β (1β, 2β, and 3β) proteins stimulate of neoangio- ized and locally advanced RCC has emerged as a strategy genesis and/or vasculogenesis for cancer cells growth to render primary kidney cancer amenable to planned [11, 12]. On the other hand, hypoxia induced release surgical resection in settings where radical nephrectomy of chemoattractants (such as HIF-1α and HIF-2α) and (RN) or nephron-sparing surgery (NSS) was not thought tumor derived cytokines (such as IL-10, IL-4, and TGF- to be feasible or safe [22]. Pre-surgical tumor reduc- β) are able to hijack tumor-associated macrophages tion (TR) has been demonstrated in a number of rand- (TAMs) and tumor-associated dendritic cells (TADCs) omized double-blind placebo-controlled studies, and an Zheng et al. Cell Commun Signal (2021) 19:39 Page 3 of 16 expanding body of literature suggests clinical beneft in from EMBL-EBI
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