Ocular Cancer Stem Cells: Advances in Therapeutic Interventions

  • Upasna Reddy
  • Raaghav Sen
  • Swathi Kaliki
  • Jaganmohan R. Jangamreddy


Cancers affecting the eye are rare and can be either initiated in the eye, primary intraocular cancers, or invaded into the eye as a malignant tumor started elsewhere, secondary intraocular cancers. Melanoma and non-Hodgkin lymphoma in adults and retinoblastoma and medulloepithelioma in children are the most common intraocular cancers. Similar to other cancers, cancer stem cells are reported among retinoblastoma, lymphoma, and melanomas that can be malignant even though are very rare in occurrence. Here, we explore the cancers of the eye and cancer stem cells with the perspective of advanced therapeutic applications for vision and globe salvage.


Cancer stem cells Ocular tumors Eye cancer metastasis Retinoblastoma Ocular melanoma 


  1. 1.
    Dhamodaran K et al (2014) Ocular stem cells: a status update! Stem Cell Res Ther 5(2):56PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66(4):1883–1890. discussion 1895-6PubMedCrossRefGoogle Scholar
  3. 3.
    Ajani JA et al (2015) Cancer stem cells: the promise and the potential. Semin Oncol 42:S3–S17PubMedCrossRefGoogle Scholar
  4. 4.
    Hall PA, Watt FM (1989) Stem cells: the generation and maintenance of cellular diversity. Development 106(4):619–633. PMID: 2562658.PubMedGoogle Scholar
  5. 5.
    Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110(4):1001–1020. PMID: 2100251.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Morrison SJ, Weissman IL (1994) The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1(8):661–673. PMID: 7541305.PubMedCrossRefGoogle Scholar
  7. 7.
    Boulton M, Albon J (2004) Stem cells in the eye. Int J Biochem Cell Biol 36(4):643–657PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Hongxiang Hui YT, Hu M, Zhao X (2011) In: Gholamrezanezhad A (ed) Stem cells: general features and characteristics, stem cells in clinic and research. IntechOpen, LondonGoogle Scholar
  9. 9.
    Morrison SJ, Shah NM, Anderson DJ (1997) Regulatory mechanisms in stem cell biology. Cell 88(3):287–298PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Reya T et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111PubMedCrossRefGoogle Scholar
  11. 11.
    Li F et al (2007) Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 17(1):3–14PubMedCrossRefGoogle Scholar
  12. 12.
    Osei-Bempong C, Figueiredo FC, Lako M (2013) The limbal epithelium of the eye—a review of limbal stem cell biology, disease and treatment. Bioessays 35(3):211–219PubMedCrossRefGoogle Scholar
  13. 13.
    Chen Z et al (2004) Characterization of putative stem cell phenotype in human limbal epithelia. Stem Cells 22(3):355–366PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Khoshzaban A, Jafari E, Soleimani M, Tabatabaei SA, Nekoozadeh S et al (2018) Introduction of stem cells in ophthalmology. J Stem Cells Clin Pract 1(1):104Google Scholar
  15. 15.
    Du Y et al (2005) Multipotent stem cells in human corneal stroma. Stem Cells 23(9):1266–1275PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Rosellini A et al (2007) Human conjunctival epithelial precursor cells and their progeny in 3D organotypic culture. Int J Dev Biol 51(8):739–743PubMedCrossRefGoogle Scholar
  17. 17.
    Arnhold S et al (2004) Iris pigment epithelial cells: a possible cell source for the future treatment of neurodegenerative diseases. Exp Neurol 187(2):410–417PubMedCrossRefGoogle Scholar
  18. 18.
    Xu H et al (2007) Characteristics of progenitor cells derived from adult ciliary body in mouse, rat, and human eyes. Invest Ophthalmol Vis Sci 48(4):1674–1682PubMedCrossRefGoogle Scholar
  19. 19.
    Tay CY et al (2012) Identification and characterization of mesenchymal stem cells derived from the trabecular meshwork of the human eye. Stem Cells Dev 21(9):1381–1390PubMedCrossRefGoogle Scholar
  20. 20.
    Du Y et al (2012) Multipotent stem cells from trabecular meshwork become phagocytic TM cells. Invest Ophthalmol Vis Sci 53(3):1566–1575PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Banin E et al (2006) Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 24(2):246–257PubMedCrossRefGoogle Scholar
  22. 22.
    Tsai CL et al (2011) Identification of multipotent stem/progenitor cells in murine sclera. Invest Ophthalmol Vis Sci 52(8):5481–5487PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chien MH et al (2012) Systemic human orbital fat-derived stem/stromal cell transplantation ameliorates acute inflammation in lipopolysaccharide-induced acute lung injury. Crit Care Med 40(4):1245–1253PubMedCrossRefGoogle Scholar
  24. 24.
    Kim N et al (2015) Cancer stem cell markers in eyelid sebaceous gland carcinoma: high expression of ALDH1, CD133, and ABCG2 correlates with poor prognosis. Invest Ophthalmol Vis Sci 56(3):1813–1819PubMedCrossRefGoogle Scholar
  25. 25.
    Deprez M, Uffer S (2009) Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature. Am J Dermatopathol 31(3):256–262PubMedGoogle Scholar
  26. 26.
    Pe’er J (2016) Pathology of eyelid tumors. Indian J Ophthalmol 64(3):177–190PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Yu SS et al (2018) A retrospective study of 2228 cases with eyelid tumors. Int J Ophthalmol 11(11):1835–1841PubMedPubMedCentralGoogle Scholar
  28. 28.
    Karan S et al (2016) Clinicopathological study of eye lid tumours in Hyderabad—a review of 57 cases. J Med Allied Sci 6:1CrossRefGoogle Scholar
  29. 29.
    Kersten RC et al (1997) Accuracy of clinical diagnosis of cutaneous eyelid lesions. Ophthalmology 104(3):479–484PubMedCrossRefGoogle Scholar
  30. 30.
    Weinstein GW, Goldman JN (1963) Metastatic adenocarcinoma of the breast masquerading as Chalazion*. Am J Ophthalmol 56(6):960–963PubMedCrossRefGoogle Scholar
  31. 31.
    Riley FC (1970) Metastatic tumors of the eyelids. Am J Ophthalmol 69(2):259–264PubMedCrossRefGoogle Scholar
  32. 32.
    Hogan MJ, Zimmerman LE, American Academy of Ophthalmology and Otolaryngology (1962) Otolaryngology, ophthalmic pathology, an atlas and textbook. Saunders, PhiladelphiaGoogle Scholar
  33. 33.
    Benson JR, Rovere GQ d, Nasiri N (2001) Eyelid metastasis. Lancet 358(9290):1370–1371PubMedCrossRefGoogle Scholar
  34. 34.
    Hood CI, Font RL, Zimmerman LE (1973) Metastatic mammary carcinoma in the eyelid with histiocytoid appearance. Cancer 31(4):793–800PubMedCrossRefGoogle Scholar
  35. 35.
    Kanitakis J, Faure M, Claudy A (2001) Clinical picture: eyelid metastasis. Lancet 358(9275):33PubMedCrossRefGoogle Scholar
  36. 36.
    Mehta KS et al (2012) Metastatic basal cell carcinoma: a biological continuum of basal cell carcinoma? Case Rep Dermatol Med 2012:4Google Scholar
  37. 37.
    Faustina M et al (2004) Patterns of regional and distant metastasis in patients with eyelid and periocular squamous cell carcinoma. Ophthalmology 111(10):1930–1932PubMedCrossRefGoogle Scholar
  38. 38.
    Shields CL et al (2004) Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology 111(9):1747–1754PubMedCrossRefGoogle Scholar
  39. 39.
    Emmanuel B et al (2012) Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-AARP Diet and Health Study. Ecancermedicalscience 6:254–254PubMedPubMedCentralGoogle Scholar
  40. 40.
    Shields CL et al (2017) Conjunctival tumors: review of clinical features, risks, biomarkers, and outcomes—the 2017 J. Donald M. Gass Lecture. Asia Pac J Ophthalmol (Phila) 6(2):109–120Google Scholar
  41. 41.
    Maggs DJ (2008) Chapter 10—cornea and sclera. In: Maggs DJ, Miller PE, Ofri R (eds) Slatter’s fundamentals of veterinary ophthalmology, 4th edn. W.B. Saunders, Saint Louis, pp 175–202CrossRefGoogle Scholar
  42. 42.
    Ofri R (2008) Chapter 2—Development and Congenital Abnormalities**The author wishes to acknowledge the contribution of Dr. Robert Barishak, and to thank him for his input throughout the years and to this chapter. In: Maggs DJ, Miller PE, Ofri R (eds) Slatter’s fundamentals of veterinary ophthalmology, 4th edn. W.B. Saunders, Saint Louis, pp 20–32CrossRefGoogle Scholar
  43. 43.
    Shields CL, Shields JA (2004) Tumors of the conjunctiva and cornea. Surv Ophthalmol 49(1):3–24PubMedCrossRefGoogle Scholar
  44. 44.
    Othman IS (2009) Ocular surface tumors. Oman J Ophthalmol 2(1):3–14PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Freeman RG, Knox JM (1964) Ultraviolet-induced corneal tumors in different species and strains of animals. J Invest Dermatol 43:431–436PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Sabourin CLK et al (1993) Expression of fibroblast growth factors in ultraviolet radiation—induced corneal tumors and corneal tumor cell lines from Monodelphis domestica. Mol Carcinog 7(3):197–205PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Kiratli H et al (1996) Metastatic tumours to the conjunctiva: report of 10 cases. Br J Ophthalmol 80(1):5–8PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Shields CL et al (2011) Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology 118(2):389–395.e2PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Shields CL et al (2000) Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol 118(11):1497–1507PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Iliff WJ, Marback R, Green WR (1975) Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 93(2):119–122PubMedCrossRefGoogle Scholar
  51. 51.
    Goldberg RA, Rootman J (1990) Clinical characteristics of metastatic orbital tumors. Ophthalmology 97(5):620–624PubMedCrossRefGoogle Scholar
  52. 52.
    Shields JA, Shields CL, Scartozzi R (2004) Survey of 1264 patients with orbital tumors and simulating lesions: the 2002 Montgomery Lecture, part 1. Ophthalmology 111(5):997–1008CrossRefGoogle Scholar
  53. 53.
    Selva D et al (2004) Primary bone tumors of the orbit. Surv Ophthalmol 49(3):328–342PubMedCrossRefGoogle Scholar
  54. 54.
    Blandford A, Perry J (2019) Classification of orbital tumors. In: Clinical ophthalmic oncology, pp 9–15CrossRefGoogle Scholar
  55. 55.
    Nabavi, C.B., J.D. Perry, and J.A. Foster. Orbital tumors: differential diagnosis in adults. 2019Google Scholar
  56. 56.
    Goldberg RA, Rootman J, Cline RA (1990) Tumors metastatic to the orbit: a changing picture. Surv Ophthalmol 35(1):1–24PubMedCrossRefGoogle Scholar
  57. 57.
    Albert DM, Rubenstein RA, Scheie HG (1967) Tumor metastasis to the eye: part I. incidence in 213 adult patients with generalized malignancy. Am J Ophthalmol 63(4):723–726PubMedCrossRefGoogle Scholar
  58. 58.
    Albert DM, Rubenstein RA, Scheie HG (1967) Tumor metastasis to the eye: part II. Clinical study in infants and children. Am J Ophthalmol 63(4):727–732PubMedCrossRefGoogle Scholar
  59. 59.
    Kiratli H (2016) Intraocular metastases. S. Karger AG, BaselCrossRefGoogle Scholar
  60. 60.
    Konstantinidis L, Damato B (2017) Intraocular metastases—a review. Asia Pac J Ophthalmol 6(2):208–214Google Scholar
  61. 61.
    Gunalp I, Gunduz K (1995) Metastatic orbital tumors. Jpn J Ophthalmol 39(1):65–70PubMedGoogle Scholar
  62. 62.
    Shields CL et al (2001) Factors associated with elevated intraocular pressure in eyes with iris melanoma. Br J Ophthalmol 85(6):666–669PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Gragoudas E et al (2002) Evidence-based estimates of outcome in patients irradiated for intraocular melanoma. Arch Ophthalmol 120(12):1665–1671PubMedCrossRefGoogle Scholar
  64. 64.
    Aerts I et al (2006) Retinoblastoma. Orphanet J Rare Dis 1:31PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Dimaras H et al (2015) Retinoblastoma. Nat Rev Dis Primers 1:15021PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Damato B (2006) Vasoproliferative retinal tumour. Br J Ophthalmol 90(4):399–400PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Dollfus H et al (2002) Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 43(9):3067–3074PubMedGoogle Scholar
  68. 68.
    Tucker MA et al (1985) Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 313(13):789–792PubMedCrossRefGoogle Scholar
  69. 69.
    Arepalli S, Kaliki S, Shields CL (2015) Choroidal metastases: origin, features, and therapy. Indian J Ophthalmol 63(2):122–127PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Shields CL et al (1997) Survey of 520 eyes with uveal metastases. Ophthalmology 104(8):1265–1276PubMedCrossRefGoogle Scholar
  71. 71.
    Nichols EE, Richmond A, Daniels AB (2016) Tumor characteristics, genetics, management, and the risk of metastasis in uveal melanoma. Semin Ophthalmol 31(4):304–309PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Shields CL et al (1994) Optic nerve invasion of retinoblastoma. Metastatic potential and clinical risk factors. Cancer 73(3):692–698PubMedCrossRefGoogle Scholar
  73. 73.
    Shields CL (2019) Retinoblastoma. In: Rojanaporn D (ed) Ocular oncology. Retina atlas. Springer, SingaporeGoogle Scholar
  74. 74.
    Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411(6835):349–354PubMedCrossRefGoogle Scholar
  75. 75.
    Zhang CL et al (2017) Stem cells in cancer therapy: opportunities and challenges. Oncotarget 8(43):75756–75766PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Upasna Reddy
    • 1
    • 2
  • Raaghav Sen
    • 1
    • 2
  • Swathi Kaliki
    • 2
  • Jaganmohan R. Jangamreddy
    • 1
    • 2
    • 3
  1. 1.Prof. Brien Holden Eye Research CenterKallam Anji Reddy Campus, LV Prasad Eye InstituteBanjara HillsIndia
  2. 2.Operation Eyesight Universal Institute for Eye CancerKallam Anji Reddy Campus, LV Prasad Eye InstituteBanjara HillsIndia
  3. 3.The Cornea InstituteKallam Anji Reddy Campus, LV Prasad Eye InstituteBanjara HillsIndia

Personalised recommendations