Cancer Stem Cells and Therapeutic Angiogenesis

  • Sambhavi Bhagavatheeswaran
  • Anandan Balakrishnan


Angiogenesis is a highly regulated process of formation of new blood vessel from preexisting blood vessel during fetal development, ovulation, and wound healing. Tumor growth and maintenance are critically controlled by tumor angiogenesis by facilitating the ingress of tumor cells into the circulatory system and in turn metastatic spread of the tumor. Apart from self-renewal and proliferating capabilities, cancer stem cells (CSCs) are also involved in tumor angiogenesis. CSCs establish a vascular niche by expressing vascular-related mediators to induce neovascularity around tumors. Developing antiangiogenic agents that also targets CSCs and evaluating its effect on a three-dimensional (3D) angiogenesis spheroid model are significant cancer therapeutic measures as the interactions between niche and CSCs and the heterogeneity can be understood better by using 3D spheroid. Furthermore exploiting the antiangiogenic effect of phytochemicals is beneficial over other available conventional drugs as they have relative pharmacological safety and target multiple molecular pathways to exert its anticancer effect.


Cancer stem cells Vascular niche Phytochemicals Spheroid Antiangiogenesis 



ATP-binding cassette subfamily G member 2


Activin A receptor-like type 1


Basement membrane


Bone morphogenic proteins


Bone morphogenetic protein receptor




Cancer stem cell


Endothelial cell


Extracellular matrix


Epigallocatechin gallate


Endothelial progenitor cell


Fibroblast growth factor


Leucine-rich repeat-containing G-protein coupled receptor 5


Microvessel density


Platelet-derived endothelial cell growth factor 1


Platelet-derived growth factor


Prostaglandin E2


Stromal cell-derived factor 1


Transforming growth factor


Tumor necrosis factor-α


Vascular endothelial growth factor


Vascular endothelial growth factor receptor 2



This work was supported in part by DST-SERB-ECR Grant (DST No: ECR/2015/000265).


  1. 1.
    Sinha M, Ghatak S, Roy S, Sen CK (2015) microRNA-200b as a switch for inducible adult angiogenesis. Antioxid Redox Signal 22(14):1257–1272PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267(16):10931–10934PubMedGoogle Scholar
  3. 3.
    Oklu R, Walker TG, Wicky S, Hesketh R (2010) Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol 21:1791–1805PubMedCrossRefGoogle Scholar
  4. 4.
    Papetti M, Herman IM (2002) Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282:C947–C970PubMedCrossRefGoogle Scholar
  5. 5.
    Presta M, Dell'Era P, Mitola S et al (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178PubMedCrossRefGoogle Scholar
  6. 6.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMedCrossRefGoogle Scholar
  8. 8.
    Fessler E, Dijkgraaf FE, De Sousa E, Melo F, Medema JP (2013) Cancer stem cell dynamics in tumor progression and metastasis: is the microenvironment to blame? Cancer Lett 341(1):97–104PubMedCrossRefGoogle Scholar
  9. 9.
    Lugano R, Ramachandran M, Dimberg A (2019) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77(9):1745–1770PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Nussenbaum F, Herman IM (2010) Tumor angiogenesis: insights and innovations. J Oncol 2010:132641PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL (2000) Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 97(26):14608–14613PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Investig 103(2):159–165PubMedCrossRefGoogle Scholar
  13. 13.
    Carmeliet P, Mackman N, Moons L et al (1996) Role of tissue factor in embryonic blood vessel development. Nature 383(6595):73–75PubMedCrossRefGoogle Scholar
  14. 14.
    Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55(18):3964–3968PubMedGoogle Scholar
  15. 15.
    Zagzag D, Hooper A, Friedlander DR et al (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159(2):391–400PubMedCrossRefGoogle Scholar
  16. 16.
    Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422):1994–1998PubMedCrossRefGoogle Scholar
  17. 17.
    Tuxhorn JA, McAlhany SJ, Yang F, Dang TD, Rowley DR (2002) Inhibition of transforming growth factor-β activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res 62(21):6021–6025PubMedGoogle Scholar
  18. 18.
    Waite KA, Eng C (2003) From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family. Nat Rev Genet 4(10):763–773PubMedCrossRefGoogle Scholar
  19. 19.
    Ota T, Fujii M, Sugizaki T et al (2002) Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-β in human umbilical vein endothelial cells. J Cell Physiol 193(3):299–318PubMedCrossRefGoogle Scholar
  20. 20.
    Zhao Y, Bao Q, Renner A, Camaj P, Eichhorn M, Ischenko I, Angele M, Kleespies A, Jauch KW, Bruns C (2011) Cancer stem cells and angiogenesis. Int J Dev Biol 55(4–5):477–482PubMedCrossRefGoogle Scholar
  21. 21.
    Saunders NA, Simpson F, Thompson EW, Hill MM, Endo-Munoz L, Leggatt G, Minchin RF, Guminski A (2012) Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol Med 4:675–684PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kise K, Kinugasa-Katayama Y, Takakura N (2016) Tumor microenvironment for cancer stem cells. Adv Drug Del Rev 99:197–205CrossRefGoogle Scholar
  23. 23.
    Nguyen LV, Vanner R, Dirks P, Eaves CJ (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer 12:133–143PubMedCrossRefGoogle Scholar
  24. 24.
    Plaks V, Kong N, Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16:225–238PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bao S, Wu Q, Sathornsumetee S et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848PubMedCrossRefGoogle Scholar
  26. 26.
    Achilles EG, Fernandez A, Allred EN, Kisker O, Udagawa T, Beecken WD, Flynn E, Folkman J (2001) Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for “no take” of human tumors in mice. J Natl Cancer Inst 93(14):1075–1081PubMedCrossRefGoogle Scholar
  27. 27.
    Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71(15):5346–5356PubMedCrossRefGoogle Scholar
  28. 28.
    Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, Ng IO, Man K, To KF, Lai PB, Lo CM (2012) CD133+ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 55(3):807–820PubMedCrossRefGoogle Scholar
  29. 29.
    Shao ES, Lin L, Yao YA, Bostrom KI (2009) Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood 114:2197–2206PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco FA, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765PubMedCrossRefGoogle Scholar
  31. 31.
    Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa RA, Mckay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826PubMedCrossRefGoogle Scholar
  32. 32.
    Gridley T (2007) Notch signaling in vascular development and physiology. Development 134:2709–2718PubMedCrossRefGoogle Scholar
  33. 33.
    Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, Sofia Correia A, Soulet D, Major T, Menon J et al (2010) Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28:1019–1029PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M et al (2007) A perivascular niche f. or brain tumor stem cells. Cancer Cell 11:69–82PubMedCrossRefGoogle Scholar
  35. 35.
    Bautch VL (2011) Stem cells and the vasculature. Nat Med 17(11):1437–1443PubMedCrossRefGoogle Scholar
  36. 36.
    Tonini T, Rossi F, Claudio PP (2003) Molecular basis of angiogenesis and cancer. Oncogene 22:6549–6556PubMedCrossRefGoogle Scholar
  37. 37.
    ALHulais RA, Ralph SJ (2019) Cancer stem cells, stemness markers and selected drug targeting: metastatic colorectal cancer and cyclooxygenase-2/prostaglandin E2 connection to WNT as a model system. J Cancer Metastasis Treat 5:3–71Google Scholar
  38. 38.
    Oh J, Hlatky L, Jeong YS, Kim D (2016) Therapeutic effectiveness of anticancer phytochemicals on cancer stem cells. Toxins 8(7):199PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM et al (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559–1561PubMedCrossRefGoogle Scholar
  40. 40.
    Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A et al (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67:2187–2196PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66:6063–6071PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA et al (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci 104:4048–4053PubMedCrossRefGoogle Scholar
  43. 43.
    Lee SH, Nam HJ, Kang HJ, Kwon HW, Lim YC (2013) Epigallocatechin-3-gallate attenuates head and neck cancer stem cell traits through suppression of Notch pathway. Eur J Cancer 49:3210–3218PubMedCrossRefGoogle Scholar
  44. 44.
    Lin CH, Shen YA, Hung PH, Yu YB, Chen YJ (2012) Epigallocatechin gallate, polyphenol present in green tea, inhibits stem-like characteristics and epithelial-mesenchymal transition in nasopharyngeal cancer cell lines. BMC Complement Altern Med 12:201PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Mineva ND, Paulson KE, Naber SP, Yee AS, Sonenshein GE (2013) Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells. PLoS One 8:e73464PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Clarke N, Germain P, Altucci L, Gronemeyer H (2004) Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med 6:1–23PubMedCrossRefGoogle Scholar
  47. 47.
    Ying M, Wang S, Sang Y, Sun P, Lal B, Goodwin CR, Guerrero-Cazares H, Quinones-Hinojosa A, Laterra J, Xia S (2011) Regulation of glioblastoma stem cells by retinoic acid: role for notch pathway inhibition. Oncogene 30:3454–3467PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122(3):777–785PubMedCrossRefGoogle Scholar
  49. 49.
    Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486–498PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Correa de Sampaio P, Auslaender D, Krubasik D, Failla AV, Skepper JN, Murphy G, English WR (2012) A Heterogeneous in vitro three dimensional model of tumour-stroma interactions regulating sprouting angiogenesis. PLoS One 7(2):e30753PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Pfisterer L, Korff T (2016) Spheroid-based in vitro angiogenesis model. In: Martin S, Hewett P (eds) Angiogenesis protocols. Methods in molecular biology, vol 1430. Humana, New York, NY, pp 167–177CrossRefGoogle Scholar
  52. 52.
    Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, Meyer-Schaller N, Cornille K, Hopfer U, Bentires-Alj M, Christofori G (2014) VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res 74(5):1566–1575PubMedCrossRefGoogle Scholar
  53. 53.
    Mohammadinejad R, Biagioni A, Arunkumar G et al (2020) EMT signaling: potential contribution of CRISPR/Cas gene editing. Cell Mol Life Sci.

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Sambhavi Bhagavatheeswaran
    • 1
  • Anandan Balakrishnan
    • 1
  1. 1.Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia

Personalised recommendations