Review

. 2020 Sep 30;39(1):204.

doi: 10.1186/s13046-020-01709-5.

The role of microenvironment in tumor angiogenesis

Xianjie Jiang^{1

2}, Jie Wang², Xiangying Deng², Fang Xiong³, Shanshan Zhang³, Zhaojian Gong⁴, Xiayu Li⁵, Ke Cao⁵, Hao Deng⁵, Yi He¹, Qianjin Liao¹, Bo Xiang^{1

2}, Ming Zhou^{1

2}, Can Guo², Zhaoyang Zeng^{1

2}, Guiyuan Li^{1

2}, Xiaoling Li^{6

7}, Wei Xiong^{8

9}

Affiliations

¹ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
² The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China.
³ Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China.
⁶ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. lixiaoling@csu.edu.cn.
⁷ The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China. lixiaoling@csu.edu.cn.
⁸ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. xiongwei@csu.edu.cn.
⁹ The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China. xiongwei@csu.edu.cn.

PMID: 32993787
PMCID: PMC7526376
DOI: 10.1186/s13046-020-01709-5

Review

The role of microenvironment in tumor angiogenesis

Xianjie Jiang et al. J Exp Clin Cancer Res. 2020.

. 2020 Sep 30;39(1):204.

doi: 10.1186/s13046-020-01709-5.

Authors

Affiliations

¹ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
² The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China.
³ Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China.
⁶ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. lixiaoling@csu.edu.cn.
⁷ The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China. lixiaoling@csu.edu.cn.
⁸ NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. xiongwei@csu.edu.cn.
⁹ The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China. xiongwei@csu.edu.cn.

PMID: 32993787
PMCID: PMC7526376
DOI: 10.1186/s13046-020-01709-5

Abstract

Tumor angiogenesis is necessary for the continued survival and development of tumor cells, and plays an important role in their growth, invasion, and metastasis. The tumor microenvironment-composed of tumor cells, surrounding cells, and secreted cytokines-provides a conducive environment for the growth and survival of tumors. Different components of the tumor microenvironment can regulate tumor development. In this review, we have discussed the regulatory role of the microenvironment in tumor angiogenesis. High expression of angiogenic factors and inflammatory cytokines in the tumor microenvironment, as well as hypoxia, are presumed to be the reasons for poor therapeutic efficacy of current anti-angiogenic drugs. A combination of anti-angiogenic drugs and antitumor inflammatory drugs or hypoxia inhibitors might improve the therapeutic outcome.

Keywords: Angiogenic factor; Hypoxia inhibitor; Inflammatory factor; Tumor angiogenesis; Tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
The role of hypoxia in tumor angiogenesis. a Under normoxic conditions, HIF-1α and HIF-2α are hydroxylated by PHDs and FIH-1. Subsequently, pVHL can recognize and ubiquitinate hydroxylated HIF-1α/HIF-2α and degrade them via proteasome-mediated degradation. b Under hypoxic conditions, the inactivation of FIH-1 and PHDs cannot hydroxylate HIF-1/HIF-2α, decreases HIFα-VHL binding, and promotes the formation of HIFα-HIFβ dimers that enter the nucleus to activate downstream targets. HIF-1α/HIF-2α can activate EphA1, ANGPT, VEGFA, VEGFR1, and other angiogenesis related genes to promote tumor angiogenesis. Alternatively, HIF-1α/HIF-2α can activate Claudin-4, Vimentin, LOXL2, Twist1, VE-cadherin to promote vasculogenic mimicry

**Fig. 2**
Cytokines and cell growth factors secreted in the tumor microenvironment

**Fig. 3**
Schematic representation of key VEGF/VEGFR signal transduction pathways. **Proliferation:** VEGFR can interact with Grab/Src/Gab1/Shb/PKCγ to activate RAF/MEK/MAPK and PI3K/AKT signaling pathways, and promote the proliferation of endothelial cells. **Migration and invasion:** VEGFR can activate PI3K/AKT by binding to cdc42, Rho, and RacGTPases, and promotes the migration and invasion of endothelial cells. **Permeability**: VEGFR can enhance blood vessel permeability by activating NFAT/β-catenin/VE-cadherin, and eNOS. **Vasculogenic mimicry:** VEGFR can promote EMT-induced vasculogenic mimicry by upregulating the expression of EMT-related genes

**Fig. 4**
The regulatory network of tumor angiogenesis in the tumor microenvironment

**Fig. 5**
Role of non-coding RNA in regulating tumor angiogenesis

See this image and copyright information in PMC

References

1. Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM. Tumor Angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med. 2019;9(1):81. doi: 10.3390/jcm9010084. - DOI - PMC - PubMed
1. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8. doi: 10.1056/NEJM199101033240101. - DOI - PubMed
1. Cao Y. Tumor angiogenesis and molecular targets for therapy. Front Biosci (Landmark Ed) 2009;14:3962–73. doi: 10.2741/3504. - DOI - PubMed
1. Herbert SP, Stainier DY. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol. 2011;12(9):551–64. doi: 10.1038/nrm3176. - DOI - PMC - PubMed
1. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. doi: 10.1038/nature10144. - DOI - PMC - PubMed

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The role of microenvironment in tumor angiogenesis

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The role of microenvironment in tumor angiogenesis

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Conflict of interest statement

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