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Moses, E.; Rajasegaran, Y.; , .; Mot, Y.; Mohd Yusoff, N. Vascularization and Cancer Biology. Encyclopedia. Available online: https://encyclopedia.pub/entry/22066 (accessed on 24 July 2024).
Moses E, Rajasegaran Y,  , Mot Y, Mohd Yusoff N. Vascularization and Cancer Biology. Encyclopedia. Available at: https://encyclopedia.pub/entry/22066. Accessed July 24, 2024.
Moses, Emmanuel, Yaashini Rajasegaran,  , Yik Mot, Narazah Mohd Yusoff. "Vascularization and Cancer Biology" Encyclopedia, https://encyclopedia.pub/entry/22066 (accessed July 24, 2024).
Moses, E., Rajasegaran, Y., , ., Mot, Y., & Mohd Yusoff, N. (2022, April 21). Vascularization and Cancer Biology. In Encyclopedia. https://encyclopedia.pub/entry/22066
Moses, Emmanuel, et al. "Vascularization and Cancer Biology." Encyclopedia. Web. 21 April, 2022.
Vascularization and Cancer Biology
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9101494

Vascularization is another hallmark of cancer, whereby cancer cells promote the formation of blood vessels to deliver nutrients for fast-growing solid tumors. The most well-known process of vascularization is angiogenesis. In normal cells and tissues, the angiogenesis is a controlled process that is turned on or off depending on the needs of the cells; however, in cancerous cells and tumors, the angiogenesis process is continuous and there is a dysregulation of pro- and antiangiogenesis factors . This continuous activation of angiogenesis allows the cancer cells to form blood vessels to obtain sufficient nutrients for continuous growth and proliferation. There are other ways tumors can achieve vascularization, such as vascular co-option, intussusceptive microvascular growth and vasculogenic mimicry.

microRNA (miRNA) cancer biology angiogenesis

1. Vascularization Mechanisms in Cancer Cells

Vascularization, also known as angiogenesis, is the formation of new blood vessels surrounding a solid tumor into other ducts within the body. Vascularization generally starts when a solid tumor grows to a certain size, as this creates the need for extra nutrients and oxygen to be supplied to the tumor microenvironment for propagation of the primary tumor. This is triggered when there is low oxygen within the tumor microenvironment (Hypoxia). Hypoxia induces HIF1-α (hypoxia-inducible factor-1 alpha) expression, leading to the activation of downstream factors that are crucial for vascularization [1][2][3].
VEGF (vascular endothelial growth factor) is an HIF1-α induction-dependent factor and a potent inducer of tumor vascularization. It was found that anthracycline treatment in prostate cancer-xenografted mice, which blocks the HIF1-α DNA binding potential, attenuates vascular formation via downregulation of the VEGF activity. The results also showed that the reduction of VEGF leads to impaired growth of prostate cancer [4].
In addition, cellular protease was also found to be a contributor in tissue vascularization. An example is matrix metalloproteinase (MMP), a protease that is transcriptionally activated by HIF1-α [5][6]. It was found that fibroblasts surrounding the tumor could also affect angiogenesis; fibroblasts secrete factors crucial for MMP production in neighboring tumor cells [7]. Furthermore, downregulation of MMP attenuates angiogenesis, further supporting the suggestion that vascularization is MMP-dependent [8].
The changes in the genes mentioned earlier affect angiogenesis by modulating the tumor microenvironment, thereby affecting crucial proteins found most predominantly in tight junctions, as well as other cell-to-cell junctions, such as adherens junctions and desmosomes. Additionally, exosomal secretion into the extracellular matrix (ECM) could also affect cell-to-cell junctions, which contribute to angiogenesis [9][10].
The regulation of vascularization via miRNA can be either direct or indirect. Direct regulation can be observed when the miRNA targets both activator and suppressor genes involved in tissue vascularization via 3′-UTR binding on their mRNAs. Similar miRNA–mRNA hybrids occur through indirect regulation; however, these miRNAs target specific factors (transcription cofactors) that influence genes involved directly in vascularization. Control can occur at different levels (exosomal, proteomic, genomic and transcript) of the central dogma of molecular biology, thereby leading to angiogenesis. The microRNA regulation associated with cancer angiogenesis is illustrated in Figure 1.
Figure 1. The microRNA-regulation-targeting genes involved in cancer angiogenesis, which occurs at the proteomic, genomic, exosomic and phenotypic levels. Act/Rep: Activator/repressor, Cof: Cofactor, miRNA: micro-RNA, UTR: untranslated region, TA: transcription activator, P: phosphate group.

2. The Role of miRNAs in the Vascularization of Cancer Cells

Cancer tissue vascularization requires specific signalling from various factors for its formation. These factors are regulated by miRNAs. Two high-risk miRNAs, namely miR-148a and miR-30, which regulate HIF1-α via binding directly to its inhibitor FIH1 (factors inhibiting HIF1-α) in the glioblastoma was reported by Wong et al. [11]. Inhibition of these miRNAs results in the downregulation of the HIF1-α protein, which corresponds to the reduction of VEGF expression and attenuation of vascularization. This is an example of the effects of cofactor targeting via miRNA binding, which influences the activity of transcription factors that directly activate gene expression.
Another interesting miRNA control process occurs when the cancer itself secretes miRNA via exosomes, thereby affecting neighbouring cells. In this case, these would be endothelial cells, which allow for high vascular permeability. This was observed in colorectal cancer cells (CC), whereby exosomal secretion from the CCs containing the miR-25-3p significantly affected the vascular integrity [12]. Another study also found that hepatocellular carcinoma cells (HCCs) overexpressed miR-210, which was found in high abundance in HCC secretion (HSS). Further experimentation revealed exosome-rich miRNA, whereby treatment of HSS on HepG2 resulted in the induction of tubal formation by downregulating SMAD4 and STAT6. Furthermore, direct targeting of the miRNA processing via DROSHA downregulation attenuates angiogenesis [13]. Other examples of miRNAs involved in vascularization are shown in Table 1.
Table 1. The miRNA implicated in vascularization.
No miRNA Cancer Target Action Reference
1 miR-124-3p Glioblastoma NRP-1, transcriptional Overexpression leads to the attenuation of angiogenesis [14]
2 miR-526b/miR-655 Breast cancer PTEN tumor suppressor, transcriptional Overexpression improved angiogenesis suggesting roles as oncomiR via PTEN-regulated HIF1-α pathway [15]
3 miR-9 Nasopharyngeal Carcinoma MDK, exosomal secretion Suppression of miR-9 in patient suggest its role as oncomiR. Overexpression attenuated tubal formation HUVECs [16]
4 miR-205 Ovarian Cancer PTEN tumor suppressor, exosomal secretion Treatment of HUVECs with miR-205 exosome leads to an increase in tubal formation [17]
5 miR-6868-5p Colorectal Cancer FOXM1, transcriptional Overexpression leads to the reduction in endothelial tubal formation [18]
6 miR-143-3p Gallbladder Carcinoma ITGA6, transcriptional Suppression was observed in bad overall survival patients. Overexpression leads to increased tubal formation [19]
7 miR-130b Prostate cancer TNF-α, transcriptional Inhibition leads to attenuation of VEGFA, a downstream target of TNF-α suppressing angiogenesis [20]
8 mR-23a Nasopharyngeal Carcinoma TSGA10, exosomal secretion Exosomal overexpression enhanced angiogenesis [21]
9 miR-21 Renal cell carcinoma PCD4, proteomal Inhibition of miR-21 attenuated MMP levels, besides inhibiting angiogenesis [22]
10 miR-574-5p Gastric Cancer Cells PTPN3 proteomal Binds to PTPN3, enhancing ERK/JNK activity and driving angiogenesis [23]
11 miR-27a Pancreatic Cancer BTG2, Exosomal miR-27a was highly expressed in cancer tissue. Exosomal mir-27a stimulates HMVEC tubal formation. [24]
12 miR-155 Gastric Carcinoma C-MYB/, Exosomal Stimulates VEGF expression, leading to enhanced angiogenesis observed on HUVEC [25]
13 miR-183-5p Colorectal Cancer FOXO1, Exosomal CRC-derived- exosome enhanced tubal formation of HMEC-1 cells [26]
14 miR-619-5p Non-Small Cell Lung Cancer RCAN1.4, Exosomal Mimic transfection and leads to the increase in HUVEC tube length and tube abundance [27]
15 miR-3064-5p Hepatocellular carcinoma FOXA1, transcriptional Overexpression improves overall survival of mice and reduces tumor size; angiogenic factor suppression observed [28]
16 miR-141 Pancreatic cancer TM5SF1 transcriptional Angiogenic factors were induced following inhibition of miR-141 [29]
17 miR-195 Squamous cell lung cancer VEGF transcriptional miRNA-195 attenuates tubal formation [30]
18 miR-136 Gall Bladder cancer MAP2K4 transcriptional Mimic treatment resulted in activation of angiopoiesis [31]
19 miR-302 Chronic Myeloid leukemia VEGFA, secretome Low expression was associated with bad OS.
Treatment of K562 media on HUVECS attenuate capillary formation		 [32]
20 miR-148a
miR-30		 Glioblastoma FIH1 Regulates HIF1-α via binding directly to its inhibitor FIH1 and attenuating vascularization [11]
21 miR-29b Breast cancer AKT3 Overexpression resulted in the attenuation of vascularization by downregulating AKT3, which is crucial for VEGF activation [33]
22 miR-140-5p Breast cancer VEGFA Abrogates vascularization by binding and attenuating VEGFA [34]
23 miR-1 Gastric cancer VEGFA Inhibition of miR-1 leads to accumulation of VEGFA [35]
24 miR-30d Prostate cancer MYPT1 Downregulation resulted in the attenuation of angiogenesis, leading to reduction in endothelial capillary tube formation [36]
25 miR-210 Hepatocellular carcinoma SMAD4, STAT6 Promote angiogenesis by inhibiting SMAD4 and STAT6 [13]

 

References

  1. Doktorova, H.; Hrabeta, J.; Khalil, M.A.; Eckschlager, T. Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1. Biomed. Pap. 2015, 159, 166–177.
  2. Lu, Y.; Qin, T.; Li, J.; Wang, L.; Zhang, Q.; Jiang, Z.; Mao, J. MicroRNA-140-5p inhibits invasion and angiogenesis through targeting VEGF-A in breast cancer. Cancer Gene Ther. 2017, 24, 386–392.
  3. Zimna, A.; Kurpisz, M. Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies. BioMed Res. Int. 2015, 2015, 1–13.
  4. Batty, M.; Pugh, R.; Rathinam, I.; Simmonds, J.; Walker, E.; Forbes, A.; Anoopkumar-Dukie, S.; McDermott, C.M.; Spencer, B.; Christie, D.; et al. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers. Int. J. Mol. Sci. 2016, 17, 1339.
  5. Chang, Y.-C.; Chan, Y.-C.; Chang, W.-M.; Lin, Y.-F.; Yang, C.-J.; Su, C.-Y.; Huang, M.-S.; Wu, A.T.; Hsiao, M. Feedback regulation of ALDOA activates the HIF-1α/MMP9 axis to promote lung cancer progression. Cancer Lett. 2017, 403, 28–36.
  6. Li, Y.-Y.; Zheng, Y.-L. Hypoxia promotes invasion of retinoblastoma cells in vitro by upregulating HIF-1α/MMP9 signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 5361–5369.
  7. Oren, R.; Addadi, S.; Haziza, L.N.; Dafni, H.; Rotkopf, R.; Meir, G.; Fishman, A.; Neeman, M. Fibroblast recruitment as a tool for ovarian cancer detection and targeted therapy. Int. J. Cancer 2016, 139, 1788–1798.
  8. Webb, A.H.; Gao, B.T.; Goldsmith, Z.K.; Irvine, A.S.; Saleh, N.; Lee, R.P.; Lendermon, J.B.; Bheemreddy, R.; Zhang, Q.; Brennan, R.C.; et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in In Vitro models of retinoblastoma. BMC Cancer 2017, 17, 434.
  9. Gómez-Escudero, J.; Clemente, C.; García-Weber, D.; Acín-Pérez, R.; Millán, J.; Enríquez, J.A.; Bentley, K.; Carmeliet, P.; Arroyo, A.G. PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production. Sci. Rep. 2019, 9, 1–18.
  10. Roux, Q.; Gavard, J. Endothelial Cell-Cell Junctions in Tumor Angiogenesis. In Tumor Angiogenesis Key Target for Cancer Therapy; Springer: Cham, Switzerland, 2019; pp. 91–119.
  11. Wong, H.-K.A.; El Fatimy, R.; Onodera, C.; Wei, Z.; Yi, M.; Mohan, A.; Gowrisankaran, S.; Karmali, P.; Marcusson, E.; Wakimoto, H.; et al. The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma. Mol. Ther. 2015, 23, 1234–1247.
  12. Zeng, Z.; Li, Y.; Pan, Y.; Lan, X.; Song, F.; Sun, J.; Zhou, K.; Liu, X.; Ren, X.; Wang, F.; et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat. Commun. 2018, 9, 1–14.
  13. Lin, X.-J.; Fang, J.-H.; Yang, X.-J.; Zhang, C.; Yuan, Y.; Zheng, L.; Zhuang, S.-M. Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis In Vitro and In Vivo. Mol. Ther.-Nucleic Acids 2018, 11, 243–252.
  14. Zhang, G.; Chen, L.; Khan, A.A.; Li, B.; Gu, B.; Lin, F.; Su, X.; Yan, J. miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis. Int. J. Cancer 2018, 143, 635–644.
  15. Hunter, S.; Nault, B.; Ugwuagbo, K.; Maiti, S.; Majumder, M. Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer. Cancers 2019, 11, 938.
  16. Lu, J.; Liu, Q.-H.; Wang, F.; Tan, J.-J.; Deng, Y.-Q.; Peng, X.-H.; Liu, X.; Zhang, B.; Xu, X.; Li, X.-P. Exosomal miR-9 inhibits angiogenesis by targeting MDK and regulating PDK/AKT pathway in nasopharyngeal carcinoma. J. Exp. Clin. Cancer Res. 2018, 37, 1–12.
  17. He, L.; Zhu, W.; Chen, Q.; Yuan, Y.; Wang, Y.; Wang, J.; Wu, X. Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis. Theranostics 2019, 9, 8206–8220.
  18. Wang, Y.; Wu, M.; Lei, Z.; Huang, M.; Li, Z.; Wang, L.; Cao, Q.; Han, D.; Chang, Y.; Chen, Y.; et al. Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis. J. Exp. Clin. Cancer Res. 2018, 37, 292.
  19. Jin, Y.-P.; Hu, Y.-P.; Wu, X.-S.; Wu, Y.-S.; Ye, Y.-Y.; Li, H.-F.; Liu, Y.-C.; Jiang, L.; Liu, F.-T.; Zhang, Y.-J.; et al. miR-143-3p targeting of ITGA6 suppresses tumour growth and angiogenesis by downregulating PLGF expression via the PI3K/AKT pathway in gallbladder carcinoma. Cell Death Dis. 2018, 9, 1–15.
  20. Mu, H.Q.; He, Y.H.; Wang, S.B.; Yang, S.; Wang, Y.J.; Nan, C.J.; Bao, Y.F.; Xie, Q.P.; Chen, Y.H. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis. Clin. Transl. Oncol. 2020, 22, 111–121.
  21. Bao, L.; You, B.; Shi, S.; Shan, Y.; Zhang, Q.; Yue, H.; Zhang, J.; Zhang, W.; Shi, Y.; Liu, Y.; et al. Metastasis-associated miR-23a from nasopharyngeal carcinoma-derived exosomes mediates angiogenesis by repressing a novel target gene TSGA10. Oncogene 2018, 37, 2873–2889.
  22. Fan, B.; Jin, Y.; Zhang, H.; Zhao, R.; Sun, M.; Sun, M.; Yuan, X.; Wang, W.; Wang, X.; Chen, Z.; et al. MicroRNA-21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c-Jun (AP-1) signalling pathway. Int. J. Oncol. 2020, 56, 178–192.
  23. Zhang, S.; Zhang, R.; Xu, R.; Shang, J.; He, H.; Yang, Q. MicroRNA-574-5p in gastric cancer cells promotes angiogenesis by targeting protein tyrosine phosphatase non-receptor type 3 (PTPN3). Gene 2020, 733, 144383.
  24. Shang, D.; Xie, C.; Hu, J.; Tan, J.; Yuan, Y.; Liu, Z.; Yang, Z. Pancreatic cancer cell–derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2. J. Cell. Mol. Med. 2020, 24, 588–604.
  25. Deng, T.; Zhang, H.; Yang, H.; Wang, H.; Bai, M.; Sun, W.; Wang, X.; Si, Y.; Ning, T.; Zhang, L.; et al. Exosome miR-155 Derived from Gastric Carcinoma Promotes Angiogenesis by Targeting the c-MYB/VEGF Axis of Endothelial Cells. Mol. Ther.-Nucleic Acids 2020, 19, 1449–1459.
  26. Shang, A.; Wang, X.; Gu, C.; Liu, W.; Sun, J.; Zeng, B.; Chen, C.; Ji, P.; Wu, J.; Quan, W.; et al. Exosomal miR-183-5p promotes angiogenesis in colorectal cancer by regulation of FOXO1. Aging 2020, 12, 8352–8371.
  27. Kim, D.H.; Park, S.; Kim, H.; Choi, Y.J.; Kim, S.Y.; Sung, K.J.; Sung, Y.H.; Choi, C.-M.; Yun, M.; Yi, Y.-S.; et al. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer Lett. 2020, 475, 2–13.
  28. Zhang, P.; Ha, M.; Li, L.; Huang, X.; Liu, C. MicroRNA-3064-5p sponged by MALAT1 suppresses angiogenesis in human hepatocellular carcinoma by targeting the FOXA1/CD24/Src pathway. FASEB J. 2020, 34, 66–81.
  29. Xu, D.; Yang, F.; Wu, K.; Xu, X.; Zeng, K.; An, Y.; Xu, F.; Xun, J.; Lv, X.; Zhang, X.; et al. Lost miR-141 and upregulated TM4SF1 expressions associate with poor prognosis of pancreatic cancer: Regulation of EMT and angiogenesis by miR-141 and TM4SF1 via AKT. Cancer Biol. Ther. 2020, 21, 354–363.
  30. Liu, H.; Chen, Y.; Li, Y.; Li, C.; Qin, T.; Bai, M.; Zhang, Z.; Jia, R.; Su, Y.; Wang, C. miR-195 suppresses metastasis and angiogenesis of squamous cell lung cancer by inhibiting the expression of VEGF. Mol. Med. Rep. 2019, 20, 2625–2632.
  31. Niu, J.; Li, Z.; Li, F. Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4. Am. J. Physiol. Liver Physiol. 2019, 317, G670–G681.
  32. Cao, J.; Li, L.; Han, X.; Cheng, H.; Chen, W.; Qi, K.; Chen, C.; Wu, Q.; Niu, M.; Zeng, L.; et al. miR-302 cluster inhibits angiogenesis and growth of K562 leukemia cells by targeting VEGFA. OncoTargets Ther. 2019, 12, 433–441.
  33. Li, Y.; Cai, B.; Shen, L.; Dong, Y.; Lu, Q.; Sun, S.; Liu, S.; Ma, S.; Ma, P.X.; Chen, J. MiRNA-29b suppresses tumor growth through simultaneously inhibiting angiogenesis and tumorigenesis by targeting Akt3. Cancer Lett. 2017, 397, 111–119.
  34. Lu, Y.; Yu, S.-S.; Zong, M.; Fan, S.-S.; Lu, T.-B.; Gong, R.-H.; Sun, L.-S.; Fan, L.-Y. Glucose-6-Phosphate Isomerase (G6PI) Mediates Hypoxia-Induced Angiogenesis in Rheumatoid Arthritis. Sci. Rep. 2017, 7, 40274.
  35. Xie, M.; Dart, D.A.; Guo, T.; Xing, X.-F.; Cheng, X.-J.; Du, H.; Jiang, W.G.; Wen, X.-Z.; Ji, J.-F. MicroRNA-1 acts as a tumor suppressor microRNA by inhibiting angiogenesis-related growth factors in human gastric cancer. Gastric Cancer 2017, 21, 41–54.
  36. Lin, Z.-Y.; Chen, G.; Zhang, Y.-Q.; He, H.-C.; Liang, Y.-X.; Ye, J.-H.; Liang, Y.-K.; Mo, R.-J.; Lu, J.-M.; Zhuo, Y.-J.; et al. MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer. Mol. Cancer 2017, 16, 1–14.
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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Emmanuel Moses
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Yaashini Rajasegaran
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Yik Mot
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Narazah Mohd Yusoff
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