Sai-Li Duan1,2
Wei-Jie Fu2Ying-Ke Jiang1
Lu-Shan Peng3
Diabate Ousmane2,3Zhe-Jia Zhang1,2*
Jun-Pu Wang2,3,4,5*- 1Department of General Surgery, Xiangya Hospital Central South University, Changsha, China
- 2Xiangya School of Medicine, Central South University, Changsha, China
- 3Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, China
- 4Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, China
- 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
The tumor microenvironment (TME) is an intricate ecosystem that is actively involved in various stages of cancer occurrence and development. Some characteristics of tumor biological behavior, such as proliferation, migration, invasion, inhibition of apoptosis, immune escape, angiogenesis, and metabolic reprogramming, are affected by TME. Studies have shown that non-coding RNAs, especially long-chain non-coding RNAs and microRNAs in cancer-derived exosomes, facilitate intercellular communication as a mechanism for regulating angiogenesis. They stimulate tumor growth, as well as angiogenesis, metastasis, and reprogramming of the TME. Exploring the relationship between exogenous non-coding RNAs and tumor-associated endothelial cells, as well as their role in angiogenesis, clinicians will gain new insights into treatment as a result.
1 Introduction
The tumor microenvironment (TME), an intricate ecosystem, actively participates in every stage of cancer development (Hanahan and Weinberg, 2011; Yang et al., 2020). As a dynamic ecosystem containing a variety of cell types and non-cellular components, TME plays a major role in tumor growth, metastasis, and drug resistance. Cancers exhibit some biological behaviors, such as proliferation, migration, invasion, immune escape, angiogenesis, and metabolic reprogramming, all of which are affected by TME. Biological functions, including autocrine and paracrine functions, are regulated by the complex communication network within TMEs. Exocrine-mediated communication is an important emerging pathway of paracrine signal transduction (Giraldo et al., 2019). Exosomes can carry molecules such as DNA, RNA, and proteins to adjacent cells, where they act as effective signaling molecules between cancer cells and surrounding cells constituting TME. Nontumor cells in TME, such as fibroblasts, endothelial cells (ECs), and immune cells, are affected by tumor-associated active substances and their original cell functions undergo tumor-like changes, constantly adapting to the new environment and promoting tumor growth. The TME is composed of different cell types with various functions, which regulates excessive cell-cell interactions. These interactions orchestrate reprogramming to the environment allowed by each cancer and may have a significant impact on cancer development, progression, and treatment resistance.
ECs are involved in tumor growth, tumor-induced angiogenesis, and vascular secretory functions for self-renewal and differentiation after trauma and thrombosis (Barachini et al., 2023). Angiogenesis plays an important role in all stages of cancer development (Aguilar-Cazares et al., 2019). Angiogenesis is a complex process of growing new capillaries from preexisting blood vessels, typically involving the following steps: stimulation of ECs with vascular endothelial growth factor (VEGF), proliferation, migration, and differentiation of vascular ECs, vessel branches and vessel formation (Ahir et al., 2020; Yang et al., 2022). Tumor vascular growth is a key factor in cancer progression, which is closely related to metastasis and a poor prognosis. Tumor angiogenesis is a recognized target for anticancer therapy by targeting growth factors, their cell surface receptors, and associated signaling pathways. Tissue hypoxia induces an overproduction of VEGF, leading to an imbalance between pro-angiogenic factors and anti-angiogenic factors, causing excessive abnormal angiogenesis that plays a central role in tumor progression (Jászai and Schmidt, 2019). The supply of energy and the removal of waste products are key factors in the development of cancer cells (Anderson and Simon, 2020). Tumor cells can communicate with adjacent tissues through the release of exosomes (Stec et al., 2015; Dominiak et al., 2020). Exosomes contain a variety of substances that promote angiogenesis and thus accelerate cancer invasion and metastasis (Głuszko et al., 2019), and the release of some exosomes also affects immune function (Aslan et al., 2019). Evidence suggests that non-coding RNAs (ncRNAs), especially long-chain non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer-derived exosomes, play an important role in regulating angiogenesis by facilitating intercellular communication, which in turn stimulates tumor growth, as well as angiogenesis, metastasis, and reprogramming of TME (shown in Figure 1) (Zhao et al., 2020).
FIGURE 1. The role of exosomes in tumor angiogenesis. Tumor cells can release exosomes, which carry miRNA and lncRNAs that can act on endothelial cells to promote tumor angiogenesis, as well as stimulate tumor growth, invasion, and metastasis.
In hypoxic environments, hypoxia can induce overexpression of ncRNA, which is released by exosomes and participates in tumor angiogenesis by reacting with ECs and other angiogenic cells, thus affecting tumor progression (He et al., 2022; Jia et al., 2022; Yang et al., 2022). In addition to ECs, there are many other remaining cell-derived exosomes in TME that can also promote angiogenesis and thus help tumor cell metastasis. For example, exosomal ncRNAs released by tumor cells regulate ECs and promote or inhibit angiogenesis (Ahmadi and Rezaie, 2020). Tumor-associated macrophage (TAM)-derived exosomal ncRNAs regulate tumor cells and promote angiogenesis (Xu et al., 2022). Stem cells-derived exosomal ncRNAs regulate tumor cells and inhibit tumor angiogenesis (Yang and Teng, 2023). Tumor-derived exosomes (TEXs) of lung cancer cells can transfer miR-21 to ECs in vitro and stimulate ECs angiogenesis to increase VEGF expression and secretion, thus helping to invade and metastasize lung cancer cells (Forder et al., 2021). The overexpression of exosome-derived miR-16 and miR-100 from mesenchymal stem cells downregulates VEGF expression in breast cancer cells, thus inhibiting angiogenesis and tumor growth in vivo and in vitro (Soheilifar et al., 2022). In hepatoma cells, cancer stem cells upregulate VEGF by delivering overexpressed lncRNAH19 to ECs to promote angiogenesis and tumor growth (Yao et al., 2023). TAM-derived exosomes are enriched with miR-501-3p, which enhances the metastatic capacity of pancreatic ductal adenocarcinoma (PDAC) cells (Yin et al., 2019; Cocks et al., 2022). Blood vessel formation is inseparable from the role of ECs, and the relationship between exosomal miRNAs and lncRNAs and endothelial cells in TME is the focus of this review. By summarizing their relationship to explore the role of exogenous ncRNAs in tumor-associated endothelial cells and also their specific role in angiogenesis, clinicians will be able to gain new insights in cancer treatment.
2 Important position of exosomes
Previous studies have shown that a series of growth factors, cell surface receptors, and a large number of signaling molecules drive remodeling of the blood and lymphatic system in cancer (Stacker et al., 2014; Fares et al., 2020; Arcucci et al., 2021a). Recent studies have identified important roles for ncRNAs in the regulation of key aspects of cancer biology, including tumor angiogenesis and lymphangiogenesis. NcRNAs are a class of RNA molecules that do not encode proteins (Zampetaki et al., 2018), of which miRNA is the most studied, which along with lncRNA is the main focus of this review. miRNAs are small RNA molecules that mediate post-transcriptional regulation by targeting mRNAs, thereby resulting in the reduction of gene expression through mRNA degradation and/or translational repression. Nuclear miRNAs have been shown to play a role in transcriptional regulation through the recruitment of transcriptional activators and chromatin remodeling proteins of repressors (Bartel, 2009; Liu et al., 2018). It should be noted that different miRNAs can work together to focus on the expression of the same or multiple genes in related molecular pathways (Uhlmann et al., 2012). LncRNA exhibits a series of different regulatory functions in different cell compartments (Zampetaki et al., 2018). LncRNA plays a role in transcriptional regulation by binding chromatin remodeling proteins and recruiting transcription factors, activators, and inhibitors (Man et al., 2018).
Nuclear miRNAs can affect transcription by active ting or silencing of transcribed genes (Liu et al., 2018), and miRNAs participate in post-transcriptional processes by regulating mRNA. For example, miR-29-b regulates the expression of VEGFA and Akt3 by negatively inhibiting angiogenesis (Chen et al., 2017; Li et al., 2017). LncRNA Hotair can promote angiogenesis by directly activating the transcription of VEGFA genes (Fu et al., 2016). LncRNA can influence the cell cycle by regulating mRNAs. For example, lncRNA MALAT1 can regulate the variable splicing of the carcinogenic transcription factor B-MYB in endothelial cells (Tripathi et al., 2013), WTAPP1 lncRNA promotes migration by increasing the expression of matrix metalloproteinase MMP1 (Li et al., 2018), and tie-1As lncRNA selectively binds and degrades tie-1 mRNA, leading to specific defects in cell connection and tube formation (Li et al., 2010). Furthermore, lncRNA H19 regulates the biological behaviors of endothelial cells by suppressing miR-29a, thus inhibiting angiogenesis (Jia et al., 2016). LncRNAs facilitate epigenetic control of gene expression by recruiting transcription activators or inhibitors (Lam et al., 2013; Melo et al., 2013) or chromatin remodeling proteins as transcription regulators (Creamer and Lawrence, 2017). After gene transcription, LncRNAs can also be regulated, mainly by regulating mRNA splicing (Gong and Maquat, 2011), or by eliciting proteins that degrade mRNAs (Hutchinson et al., 2007) or acting as bait for proteins involved in mRNA degradation (Lee et al., 2016). LncRNAs can regulate various cancer-associated mRNAs by competitively sponging various miRNAs, and thus participate in relevant signaling pathways (Zhong et al., 2019). It is worth emphasizing that both miRNAs and lncRNAs can regulate the gene expression in complex biological responses: miRNAs regulate gene expression of proteins associated with their related molecular pathways by targeting mRNAs, and in addition, miRNAs can collaborate with other molecules to precisely mediate gene silencing. LncRNAs regulate gene expression by controlling chromatin remodeling, or by targeting miRNAs regulate gene expression by controlling chromatin remodeling or by targeting miRNAs (Guo et al., 2020; Mao et al., 2020).
2.1 The relationship between exosomal miRNAs and endothelial cells
Endothelial cells can form vascular systems to transport nutrients and metabolites, which can help tumor proliferation, invasion, and metastasis. Crosstalk stimulation between tumor cells and endothelial cells can promote the growth of both, improve tumor malignancy, and even develop resistance to treatment (Shweiki et al., 1992; Carmeliet and Jain, 2011). Tumor cells and certain immune cell subsets can promote angiogenesis by expressing and secreting growth factors or inducing hypoxia (Ding et al., 2014; Zhou et al., 2014), resulting in leakage of vascular structures that promote angiogenesis and metastatic spread of tumor cells. MiRNAs are endogenous ncRNAs consisting of 21–25 nucleotides that promote post-transcriptional regulation of target genes mainly by binding to the 3′untranslated region (UTR) of mRNAs. Meanwhile, miRNAs regulate more than 30% of gene expression in the body, and their functions are closely related to cell proliferation, differentiation, apoptosis, embryonic development, tissue and organ formation, as well as the occurrence and development of various diseases (Bartel, 2004). Recent studies have shown that exosome-mediated miRNAs transfer from cancer cells to endothelial cells, contributing to the breakdown of the endothelial cell barrier and allowing cancer cells to spread and metastasize to distant locations, such as cell-derived exosomal miR-27b-3p in colorectal cancer (Zhou et al., 2014; Dou et al., 2021). Furthermore, miRNA-containing exosomes from leukemia cells, such as miR-17-92, play an important role in communication between tumor and endothelial cells, thus regulating the process of tumor angiogenesis (Umezu et al., 2013).
Exosomal miRNAs can regulate the migration of tumor endothelial cells and the formation of lymphatic and blood vessels (Table 1; Figure 2). Within tumors, most exosomal miRNAs are thought to be produced by tumor cells (Huang et al., 2022). When internalized by endothelial cells, some of these miRNAs can stimulate angiogenesis or lymphangiogenesis by inhibiting the expression of proteins that inhibit the main pathways driving these processes (Duan et al., 2019; Kim et al., 2020; Masoumi-Dehghi et al., 2020). Exosomal miRNAs have been shown to downregulate several anti-angiogenic transcription factors in endothelial cells or inhibit the expression of VEGFA, a key inducer of angiogenesis, thus turning on the angiogenic switch (Li J. et al., 2020). For example, in gastric cancer, exosomal miR-130a and miR-155 secreted by gastric cancer cells can inhibit the expression of the transcription factor c-MYB, indirectly promoting the expression of VEGFA (Arcucci et al., 2021b), which promotes angiogenesis and further assists in invasion and metastasis of gastric cancer cells.
TABLE 1. Relationship between exosomal miRNAs and angiogenesis in different types of cancer.
FIGURE 2. Exosomal miRNAs acting on endothelial cells affect tumor angiogenesis. Exosomal miRNAs can translocate from tumor cells to endothelial cells, which in turn acts on angiogenesis-related transcription factors, thereby stimulating angiogenesis.
2.1.1 Hepatocellular carcinoma cells
Current studies have shown that in hepatocellular carcinoma (HCC), exosomal miR-210 secreted by HCC cells can be transferred to endothelial cells, thus promoting tumor angiogenesis by targeting SMAD4 and STAT6 (Lin X. J. et al., 2018). miR-1290 targeting SMEK1 promotes angiogenesis of hepatocellular carcinoma, and miR-451a targeting LPIN1 suppresses hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis (Zhao et al., 2019; Wang Q. et al., 2021). HANR is responsible for lymphangiogenesis in HCC cells via the exosomal miR-296 and the EAG1/VEGF axis (Shi et al., 2019). miR-103 was delivered to ECs through exosomes and then attenuated the integrity of the endothelial junction by directly inhibiting the expression of VE-Cadherin (VE-Cad) (Fang et al., 2018). miR-638 can promote vascular permeability by downregulating endothelial expression of VE-Cad and ZO-1 (Yokota et al., 2021). Exosomal miR-200b-3p from hepatocytes inhibited endothelial ERG expression, while reduction of miR-200b-3p in cancer cells promoted angiogenesis in HCC tissues by improving endothelial ERG expression (Moh-Moh-Aung et al., 2020).
2.1.2 Colorectal cancer cells
The exosome miR-21-5p can be delivered from colon cancer cells to endothelial cells, targeting KRIT1 and thus inducing angiogenesis and vascular permeability, as can the exosome miR-25-3p, which also transfers to ECs and promotes CRC metastasis by targeting KLF2 and KLF4 to regulate growth factors in endothelial cells. Furthermore, there is miR-1229 that promotes angiogenesis by targeting HIPK2 (Zeng et al., 2018; Hu et al., 2019; He Q. et al., 2021). miR-27b-3p is transferred by EMT-CRC cells into the exosomes of human umbilical vein endothelial cells (HUVEC), weakening the vascular barrier (Dou et al., 2021).
2.1.3 Lung cancer cells
miR-23a directly inhibits its targets, prolyl hydroxylases 1 and 2 (PHD1 and 2), in exosomes from lung cancer cells, resulting in the accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) in endothelial cells. Finally, hypoxic lung cancer cells enhanced angiogenesis through hypoxic cancer-derived exosomes under normoxic and hypoxic conditions (Hsu et al., 2017). For lung adenocarcinoma (LUAD), miRNAs affect cancer cells and ECs bidirectionally; for example, miR-629-5p in lung adenocarcinoma transfers to endothelial cells, and by inhibiting CELSR1, which is lower in endothelial cells in invasive LUAD (a miR-30a-5p, a non-canonical cadherin, increases endothelial monolayer permeability, while overexpression of miR-30a-5p in endothelial cells inhibited tumor development (Li et al., 2020b; Tao et al., 2021). The exosome miR-141 is transported into HUVEC cells and targets KLF12 to promote angiogenesis in small cell lung cancer (SCLC), and miR-375-3p destroys vascular endothelial cells by directly binding to the 3′UTR of the tight junction protein CLDN1 and negatively regulating its expression tight junctions (Mao et al., 2020; Mao et al., 2021). miR-486-5p in non-small cell lung cancer (NSCLC) targets the CADM1/tight junction axis in vascular endothelial cells to promote metastasis of non-small cell lung cancer cells (Sun et al., 2021).
2.2 The relationship between exosomal lncRNAs and endothelial cells
LncRNAs are a diverse class of transcribed RNA molecules that are more than 200 nucleotides llong and have limited protein coding potential (Nagano and Fraser, 2011; Spizzo et al., 2012). Current estimates from the GENCODE database (www.gencodegenes.org) suggest that the human genome contains approximately 16,000 lncRNA genes encoding over 28,000 distinct lncRNAs. Many lncRNAs have emerged as key players in the regulation of numerous biological processes in cancer, such as differentiation, cell cycle regulation, and immune responses (Guttman et al., 2009; Qiu et al., 2015; Bach and Lee, 2018). They can act directly as tumor suppressors or oncogenes, or be regulated by well-known tumor suppressors or oncogenes at the transcriptional or post-transcriptional level (Barsyte-Lovejoy et al., 2006; Huarte et al., 2010). ECs that line the inner surface of the blood vessels are an important part of the matrix in the TME (Junttila and de Sauvage, 2013; Kohlhapp et al., 2015). They are believed to be critical for angiogenesis and tumor metastasis, and lncRNAs may affect tumor progression by regulating endothelial cell biological behavior (Table 2; Figure 3). For example, lncRNA H19 has been reported to be significantly upregulated in glioma-associated endothelial cells cultured in glioma-conditioned medium. Knockdown of lncRNA H19 inhibited glioma-induced endothelial cell proliferation, migration, and tube formation in vitro. Mechanistic evidence suggests that lncRNA H19 regulates the biological behavior of glioma-associated endothelial cells by inhibiting miR-29a (Jia et al., 2016). Furthermore, lncRNA-APC1 plays an important tumor suppressor role in the pathogenesis of colorectal cancer. The following mechanistic studies show that lncRNA-APC1 reduces exosome production in colorectal cancer cells by reducing Rab5b mRNA stability, and this effect inhibits tumor angiogenesis by inhibiting the over-activation of the MAPK pathway in endothelial cells (Wang F. W. et al., 2021). Dysregulated lncRNAs affect endothelial cell biological behavior through multiple mechanisms, so regulation of specific lncRNA expression in tumor cells or/and endothelial cells may have a significant impact on cancer progression.
TABLE 2. Ways of exosomal lncRNAs to promote angiogenesis in different types of cancer.
FIGURE 3. Exosomal LncRNAs act on endothelial cells to regulate tumor angiogenesis through a variety of mechanisms. Dysregulated lncRNAs can act directly as tumor factors or act on miRNAs at the transcriptional level, which in turn regulate tumor angiogenesis.
2.2.1 Gastric cancer cells
PVT1 is an oncogenic lncRNA that is significantly expressed in gastric cancer, especially in patients with low differentiation and progressive stages. PVT1 can bind to different proteins to exert oncogenic effects, and in gastric cancer, PVT1 can bind to the signal transduction activator STAT3 to ensure that it is not degraded, thus activating the STAT3 signaling pathway and thus increasing VEGFA in gastric cancer, thus activating the STAT3 signaling pathway and increasing the expression of VEGFA to promote gastric cancer angiogenesis. At the same time, activated STAT3 can also occupy the promoter of PVT1 and promote PVT1 expression, forming a positive feedback regulation (Zhao et al., 2018). Similarly, in NSCLC, the lncRNA TNK2-AS1 can also bind to STAT3 to inhibit its degradation, thus activating the STAT3 signaling pathway and promoting tumor progression and angiogenesis. In addition, STAT3 can also bind to the lncRNA TNK2-AS1 promoter to promote its transcription in positive feedback (Wang et al., 2018a). LINC01410 is also one of the molecules that promote angiogenesis in gastric cancer. LINC01410 can inhibit miR-532-5p expression, while silencing miR-532-5p reduces inhibition of NCF2, thus upregulating NCF2 expression and activating the NF-κB signaling pathway, exacerbating malignant progression and angiogenesis of gastric cancer. Interestingly, NCF2 can bind to the LINC01410 promoter, thereby promoting its transcription, forming a positive feedback loop that exacerbates the development of gastric carcinogenesis (Zhang et al., 2018).
2.2.2 Pancreatic cancer cells
An important feature of the tumor microenvironment is hypoxia caused by inadequate oxygen flow and abnormal tumor vasculature, and exposure of cancer cells to conditions of oxygen deficiency increases the release of exosomes, which in turn promotes angiogenesis and tumor metastasis. In hypoxic PC cells, the expression of lncRNA UCA1 increases and can be transferred to human microvascular endothelial cells HUVECs, promoting angiogenesis and tumor growth via the miR-96-5p/AMOTL2/ERK1/2 axis (Guo et al., 2020). In addition to this, PC cell-derived exosomal CRNDE enhanced angiogenesis by binding to miR-451a to increase CDKN2D expression (Zhu et al., 2021).
2.2.3 Glioma cells
One of the keys to glioma development is abnormal generation of tumor blood vessels, and high-grade gliomas clearly have a higher density of tumor blood vessels that contribute more to tumor development than low-grade gliomas. It has been shown that glioma cells can regulate the tumor microenvironment by secreting exosomes, for example, glioma exosomes can promote angiogenesis by transferring LINC-POU3F3 to human brain microvascular endothelial cells (HBMEC) (Lang et al., 2017a). Additionally, LINC-CCAT2 was found to be highly expressed in glioma cells U87-MG and could be transferred to HUVECs to activate the production of the angiogenic factors VEGFA and TGFβ, while inhibiting the expression of the apoptotic molecules Bax and caspase-3, thus promoting angiogenesis and inhibiting apoptosis in glioma cells (Lang et al., 2017b). LncRNA HULC is one of the most common oncogenes with the potential to promote invasion and angiogenesis. In glioma, Zhu Yu et al. showed that HULC can activate the PI3K/AKT/mTOR signaling pathway, which in turn regulates downstream angiogenic factors VEGF and ESM-1. Furthermore, in a hypoxic environment, HULC can upregulate HIF-1α, which is also one of the key molecules that promote the secretion of angiogenic factors (Zhu et al., 2016).
2.2.4 Hepatocellular carcinoma cells
As tumor growth requires more and more nutrients, this requires the secretion of angiogenic substances to promote tumor angiogenesis. LncRNA has been shown to regulate ECs function and promote the expression of angiogenic factors to regulate angiogenesis. Lin et al. demonstrated that the lncRNA UBE2CP3 can activate the ERK/HIF-1α/p70S6K signaling pathway, increase VEGFA expression and regulate ECs function, thus promoting angiogenesis in hepatocellular carcinoma (Lin J. et al., 2018). Cancer stem-like cells, also known as CD90+ hepatocellular carcinoma cells, are enriched in lncRNA H19, which can be released by encapsulating in exosomes and then transported to endothelial cells, promoting the expression of the angiogenic factor VEGF in endothelial cells and thus regulating hepatocellular carcinoma angiogenesis (Conigliaro et al., 2015). Direct exosomal transfer of MALAT1 to hepatocytes leads to increased invasion and migration of hepatocytes through activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling (Li et al., 2020c). Exosomal SNHG16 increases GALNT1 expression by sponging miR-4500 to promote angiogenesis. The SNHG16/miR-4500/GALNT1 axis plays an important role in exosome-mediated angiogenesis and tumor growth in vitro and in vivo (Li et al., 2021). Furthermore, elevated expression of lncRNA-OR3A4 in hepatocellular carcinoma is associated with angiogenesis and promotes the tube formation capacity of HUVEC, mainly through activation of the AGGF1/AKT/mTOR pathway (Li et al., 2019). CRNDE is upregulated in many tumors, promotes cell growth and migration, and is a recognized oncogene, also in hepatoblastoma. CRNDE knockdown inhibits tumor angiogenesis and reduces cell viability in hepatoblastoma, primarily through regulation of mTOR signaling (Dong et al., 2017).
2.2.5 Other cancer cells
Some other cancer exosomal lncRNAs are still associated with endothelial cells (Table 2). Osteosarcoma originates from bone and is the most common of primary malignancies. Zhang et al. showed that lncRNA MALAT1 is associated with osteosarcoma angiogenesis and hypoxic response and that MALAT1 activates the mTOR/HIF-1α pathway, thereby promoting the production of angiogenic factors (Zhang Z. C. et al., 2017). In lung adenocarcinoma, the lncRNA LOC100132354 can affect the downstream target gene VEGFA to promote tumor angiogenesis (Wang et al., 2018b). Some non-angiogenic lncRNAs have the ability to inhibit angiogenesis. For example, GAS5 can inhibit the activation of the Wnt/β-catenin pathway to suppress angiogenesis in CRC (Song et al., 2019). Regarding MEG3, a recognized tumor suppressor, it inhibits tumor progression in breast cancer mainly by suppressing AKT signaling and also inhibits capillary angiogenesis in endothelial cells by reducing the expression of tumor angiogenic factors (Lu et al., 2020). The lncRNA MALAT1 can be transported through exosomes to endothelial cells in epithelial ovarian cancer (EOC) and then regulates the vasculature of endothelial cells by generating related genes that stimulate pro-angiogenic behavior. In addition, serum exosomal MALAT1 levels were strongly associated with advanced and metastatic outcomes, which were independent predictors of overall survival in EOC (Qiu et al., 2018). Interestingly, lncRNAs can affect exosome production in addition to being transported by exosomes. In colorectal cancer, activation of the Adenomatous Polyp in Colon (APC) gene of lncRNA (lncRNA APC1) can directly affect the stability of Rab5b mRNA, thereby inhibiting exosome production by CRC cells and ultimately tumor angiogenesis (Wang F. W. et al., 2021). Moreover, exosomal lncRNA PDAT1 regulates the activity of the miR-329-3p/Netrin-1-CD146 complex to promote tumor metastasis (Fang et al., 2022). In lung cancer, the exosomal lncRNA LINC01356 and the exosomal lnc-MMP2-2 derived from NSCLC cells play a key role in the remodeling of the blood-brain barrier, thereby participating in brain metastasis (Geng et al., 2022). Exosomal lnc-MMP2-2 promotes brain metastasis via the miRNA-1207-5p/EPB41L5 axis (Wu et al., 2021). In thyroid cancer, exosome FGD5-AS1 targets the miR-6838-5p/VAV2 axis to promote angiogenesis and metastasis (Liu et al., 2022).
3 Conclusion and prospect on endothelial cells and exosomes
Exosomes are important carriers of cell-to-cell communication signals and genetic material in the tumor microenvironment. In this review, we divide them into different types of cancer and summarize the relationship between miRNAs and lncRNAs with endothelial cells, promoting tumor angiogenesis and tumor angiogenesis. Mechanisms of lymphangiogenesis, demonstrating the complexity of their mediated angiogenesis in cancer development. Although ncRNAs do not encode proteins, they do play critical roles in regulating the levels of many cellular and extracellular proteins, particularly in the early stages of certain tumors, by mediating gene silencing at the transcriptional level to regulate the expression of cancer-related proteins, which in turn affects aspects of angiogenesis, apoptosis, and tumor metastasis. NcRNAs can be used as a new class of markers for early clinical diagnosis and prognosis, and exosomes can be used as carriers to deliver them to various parts of the body, helping them participate more actively in intercellular communication and function. Cancer-derived exosomal ncRNAs can promote tumor angiogenesis and lymphangiogenesis by altering gene expression in a vatiety of cell types, including endothelial cells. Therefore, the regulatory functions of ncRNAs in tumor angiogenesis and lymphangiogenesis can be considered multidimensional.
The mechanistic summary in this paper can help develop effective and precise cancer therapies and, based on current research related to the regulation of tumor angiogenesis by ncRNAs, can be used to develop new cancer biomarkers and therapies depending on the type of cancer. Identifying the different mechanisms involved in identifying therapeutic approaches has seminal implications for new cancer treatments, and more research is needed to achieve this. In addition, certain specific ncRNAs can be used as a new class of markers for early clinical diagnosis and prognosis, also providing a new idea for tumor treatment. LncRNAs and miRNAs may be a feasible strategy to monitor the efficacy of anti-angiogenic therapy and predict prognosis. In addition, regulation of angiogenesis-related signaling pathways may also serve as a new therapeutic direction, and the molecular mechanisms of miRNAs and lncRNAs in tumor development and development need to be investigated in more depth, thus contributing to the improvement of tumor diagnosis and treatment.
Author contributions
S-LD and W-JF contributed to the direction and guidance of this review; S-LD and Y-KJ collected formal resources, wrote the original draft and prepared the figures; L-SP, DO, Z-JZ and J-PW provided critical revisions and contributed to the editing of the paper. All authors contributed to the article and approved the submitted version.
Funding
This work was partially supported by the National Natural Science Foundation of China (project NO. 81602167), the Hunan Provincial Natural Science Foundation of China (project NO. 2017JJ3494 and 2021JJ31100), and the Science and Technology Program Foundation of Changsha City (project NO. kq2004085).
Acknowledgments
We thank all authors to collect data and make improvement of this manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
TME, Tumor microenvironment; ECs, endothelial cells; VEGF, vascular endothelial growth factor; ncRNAs, non-coding RNAs; lncRNAs, long-chain non-coding RNAs; miRNAs, microRNAs; TAM, Tumor-associated macrophage; TEXs, Tumor-derived exosomes; PDAC, pancreatic ductal adenocarcinoma; UTR, untranslated region; VASH2, Vasohibin 2; HCC, hepatocellular carcinoma; VE-Cad, VE-Cadherin; CRC, colorectal cancer; HUVEC, human umbilical vein endothelial cells; PHD1 and 2, prolyl hydroxylases 1 and 2; HIF-1α, hypoxia-inducible factor 1 alpha; LUAD, lung adenocarcinoma; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; HBMEC, human brain microvascular endothelial cells; ERK1/2, extracellular signal-regulated kinase 1/2; EOC, epithelial ovarian cancer; APC, Adenomatous Polyp in Colon; EOC, epithelial ovarian cancer.
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Keywords: exosomes, endothelial cells, exosomes-derived non-coding RNAs, tumorassociated angiogenesis, tumor microenvironment, lncRNA, miRNA, cancer
Citation: Duan S-L, Fu W-J, Jiang Y-K, Peng L-S, Ousmane D, Zhang Z-J and Wang J-P (2023) Emerging role of exosome-derived non-coding RNAs in tumor-associated angiogenesis of tumor microenvironment. Front. Mol. Biosci. 10:1220193. doi: 10.3389/fmolb.2023.1220193
Received: 10 May 2023; Accepted: 27 July 2023;
Published: 04 August 2023.
Edited by:
Arun Malhotra, University of Miami, United StatesReviewed by:
Nahid Arghiani, Stockholm University, SwedenYu-Ping Yang, University of Miami, United States
Copyright © 2023 Duan, Fu, Jiang, Peng, Ousmane, Zhang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhe-Jia Zhang, zhangzhejia@csu.edu.cn; Jun-Pu Wang, wang-jp2013@csu.edu.cn