Brianna C. Landis (1).
Affiliation
1. Rocky Vista University, College of Osteopathic Medicine, Ivins, Utah, USA.
Contact
255 East Center St. Ivins, UT 84738. Email: brianna.landis@rvu.edu.
Conflict of interest statement
The authors declare no potential conflicts of interest.
Abstract
Despite the mitotically active nature of the ocular lens and near-constant exposure to ultraviolet radiation, there have been no reported cases of primary tumors in the human lens. In contrast, such tumors have been induced and reported in the lens of non-human vertebrates, particularly in cats. This report discusses various theories, including the avascular nature of the lens, the presence of barrier properties within the ocular environment, and the lens capsule composition as a potential chemo-mechanical barrier against tumorigenesis. Despite the significant implications for cancer prevention and treatment, there has been limited research into this phenomenon. Identifying protective mechanisms could contribute to a better understanding of human cancer genetics and potentially lead to preventative treatments.
Significance statement
There are no reported cases of primary tumors within the human lens, a phenomenon that is poorly understood and scarcely investigated. This perspective highlights theories for potential tumor-resistant properties and urges researchers to continue investigating. Further research could have significant implications for understanding cancer biology, tumorigenesis, and future preventative treatments.
Over the past century, the absence of primary tumors of the human lens has been remarked upon in the literature but never rigorously investigated.1–4 If true, this observation is noteworthy and certainly remarkable because all dividing cells, even in invertebrates, can develop genetic mutations and form tumors.5 Immediately posterior to the anterior lens capsule lies a single layer of epithelial cells. Within this layer is the germinative zone. As cells divide, they migrate laterally and then displace centrally, losing organelles as they do so, so that they can laminate and incorporate into the clear crystalline lens that refracts light onto our retina (Figure 1).6 By design, this mitosis occurs throughout life and into old age, thus it is curious that such a mitotically active tissue, with near constant exposure to ultraviolet radiation, is seemingly resistant to tumorigenesis.
Figure 1. The mitotic cycle of epithelial cells within the normal human crystalline lens (6). Image created using BioRender.com.
Limited research has explored this phenomenon, the results of which are equally perplexing. Malignant tumors of the lens can be induced with exposure to carcinogens (7) and oncogenic viruses (8) and can be engineered genetic defects in transgenic animals (9–11). Strikingly, malignant tumors of the lens can occur spontaneously in other nonhuman vertebrate species (cats, rabbits, dogs, and birds) (12–20).
However, no case of malignant or benign tumor of the human lens has been reported or described in the literature. A review of veterinary databases revealed that in non-human species, malignant tumors of the lens occur most commonly in cats, constituting 4.5% of intraocular and adnexal neoplasms in that species (20). It is established that rupture of the lens capsule is a major risk factor for the development of the tumor, coining the nomenclature of feline ocular post-traumatic sarcoma (a benign neoplasm of lens epithelial origin) (14). Retrospective review of previously unreported cases of primary lens tumors in cats from the University of Wisconsin School of Veterinary Medicine's Comparative Ocular Laboratory collection reveals that all cases showed evidence of lens capsule rupture and most had some degree of uveitis, similar to tumors observed in other vertebrate species (birds, rabbit, and dog) (20).
With awareness of the strong correlation of capsular trauma to tumorigenesis, it is even more shocking that such tumors have not been described in humans. Cataract removal is the most commonly performed surgical procedure in humans (21), and by design, the lens epithelium is traumatized and retained during modern extracapsular cataract extraction. Despite frequent surgical injury to the lens epithelium, no benign or malignant lens tumors have been documented (20). Could genetic protective mechanisms exist? And if so, wouldn’t identifying this mechanism hold significant implications to better understanding the genetics of human cancers and ultimately providing preventative treatment?
Several theories have arisen to attempt to explain this phenomenon. The lens is a naturally avascular tissue, sensibly designed to minimize the scattering of light as it passes through to the retina. As such, the lens acquires nutrients from aqueous and vitreous components passing through the semipermeable membrane of the lens capsule (22). It has long been proposed and accepted that adequate vascular supply is essential for tumorigenesis and progression (23). Solid tumors, irrespective of their source, typically begin as a small cluster of cells relying on nutrients diffusing from nearby tissues (23). As the tumor grows, it eventually reaches a size where simple diffusion is inadequate to support further growth and angiogenesis is needed to facilitate further growth. Hence, it is sensible to assume an avascular tissue, such as the lens, could harbor potential tumors to a minimal size dependent on available resources. Interestingly, however, even proangiogenic colonies of neoplastic cells have not been described (24).
Additionally, another avascular ocular tissue, the cornea, can still be invaded by advancing tumors maintaining their angiogenic factors (25). As such, avascularity alone does not entirely explain the lack of primary tumor formation in the lens. However, unlike the lens, the cornea lacks a capsular barrier. Although, it is hypothesized that the Bowman’s layer of the cornea serves as a form of corneal barrier, as tumors in the stroma layer beneath are largely undiscovered despite a notable prevalence of chromosomal abnormalities (26). Hence, it is conceivable that either the ocular environment or the existence of barrier properties could contribute to the absence of tumor development in the lens.
Other theories emphasize this possibility by suggesting the lens capsule is a chemo-mechanical barrier. Among other molecules, the lens capsule is largely composed of collagen types I-IV (27, 28). Fragments of collagens make up endostatins, which are known to act as inhibitors of angiogenesis.29 It is postulated that these endostatin molecules exist near or within the lens capsule to serve a protective mechanism against angiogenesis, both for the purpose of preserving lens transparency but also inhibiting the angiogenesis of tumors (29). Notably, there is evidence indicating that fragments of type IV collagen, the primary constituent of the lens capsule, may impede tumor cell growth (30) and hinder the activation of matrix metalloproteinases (31) in tumor cells believed to contribute to invasiveness. This evidence lends support to the idea that a growth inhibitor associated with the lens capsule could prevent neoplastic transformation in subcapsular epithelial cells.
Interestingly, even highly invasive melanomas and retinoblastomas, sometimes occupying the entirety of the posterior chamber, demonstrate well-defined borders at the lens capsule interface (24). These types of tumors are widely recognized for their infrequent invasion or direct contact with the lens capsule. Instead, the tumor-lens interface becomes filled with debris and fluid (24). Is it possible that these tumors are repelled by an unknown chemo-mechanical property of the lens capsule?
Undeniably, these observations are quite remarkable and impress exciting potential for research to advance cancer prevention and treatment. So then why is there such limited research into this phenomenon? According to NIH.gov, in 2020, the National Institute of Health (NIH), a major research funding agency in the United States, estimated a cost of nearly 6.5 billion dollars to support cancer research efforts. However, a search into the NIH RePORTER database revealed that the NIH has never funded any projects attempting to investigate the seemingly tumor-resistant properties of the human lens capsule epithelium (32). Such research seems to be a prime candidate for identifying a cancer-inhibiting gene or genes in humans. With current genetic techniques, it should be possible to identify the genes involved in lens tumor formation in other species and to use these as candidate genes in identifying the genes responsible for preventing cancer in the human lens. A genetic protective mechanism is hypothesized to exist, and identifying this mechanism may be of significant value in enhancing the understanding of human cancer genetics.
Given the striking absence of primary tumors in the human lens, several experimental approaches could be employed to elucidate the underlying protective mechanisms, such as comparative genomic transcriptomic analysis, CRISPR-based functional genomics, lens capsule extracellular matrix components, in vivo animal models, epigenetic and regulatory network studies, and organoid and 3D cell culture models (Table 1).
Table 1. Potential experimental methodologies and genetic approaches for investigating protective mechanisms of the human lens and their associated research benefits.
By employing these methodologies, researchers could move beyond theoretical explanations and begin identifying actionable molecular targets for preventing tumorigenesis in other tissues. Understanding how the lens naturally resists tumor formation could lead to the development of novel cancer therapies, including biomimetic extracellular matrices, anti-angiogenic compounds, and gene therapies designed to enhance tumor suppression in high-risk tissues.
The apparent resistance of the human lens epithelium to tumorigenesis presents an untapped avenue for oncological research, with potential implications for cancer prevention and treatment. The absence of primary tumors in a tissue that remains mitotically active throughout life, despite continuous exposure to ultraviolet radiation and surgical trauma, suggests the existence of unique protective mechanisms. If genetic or biochemical factors within the lens epithelium or capsule contribute to this resistance, identifying these mechanisms could inform strategies for suppressing tumorigenesis in other tissues. For example, if the lens capsule's extracellular matrix components, such as type IV collagen and endostatins, play a role in inhibiting angiogenesis and tumor invasion, similar mechanisms might be leveraged therapeutically in cancers reliant on angiogenic signaling. Moreover, uncovering genetic factors that prevent neoplastic transformation in the lens could contribute to the identification of novel tumor suppressor genes, expanding our understanding of intrinsic cancer resistance in humans. This phenomenon underscores the necessity of further research, as elucidating these protective mechanisms could inspire innovative approaches to cancer prevention and treatment, shifting the focus from reactive therapies to proactive, biologically informed interventions.
Acknowledgments
The author would like to acknowledge Anthony Pappas, Ph.D. for introducing this fascinating lapse in knowledge, as well as student doctors Parker Webber and Bosten Loveless for their contributions to the poster presentation Paradoxical lack of investigation into the natural tumor-resistant properties of the human lens capsular epithelium. Their efforts were paramount in sparking interest in this subject and highlighting this notable gap in the literature.
References
1. Sachs E, Larsen RL. Cancer and the Lens. Am J Ophthalmol. 1948;31(5):561-564. doi:10.1016/0002-9394(48)90558-3
2. Ullrich K, Casson RJ. Does anybody care that the crystalline lens never gets cancer? Clin Experiment Ophthalmol. 2013;41(8):812-812. doi:10.1111/ceo.12114
3. Mann I. Induction of an Experimental Tumour of the Lens. Br J Ophthalmol. 1947;31(11):676-685. doi:10.1136/bjo.31.11.676
4. M. Seigel G. The enigma of lenticular oncology. Digit J Ophthalmol. 2001;7(4). Accessed December 13, 2023. https://legacy.djo.harvard.edu/site.php%3Furl=%252Fphysicians%252Foa%252F360.html
5. Domazet-Lošo T, Klimovich A, Anokhin B, et al. Naturally occurring tumours in the basal metazoan Hydra. Nat Commun. 2014;5(1):4222. doi:10.1038/ncomms5222
6. Lens and Cataract, Chapter 2: Anatomy. In: 2020–2021 BCSC Basic and Clinical Science Course. American Academy of Ophthalmology. Accessed December 13, 2023. https://www.aao.org/education/bcscsnippetdetail.aspx?id=298fbd36-d41e-4714-80d9-f55e41ec4624
7. Von Sallmann L, E. Halver J, Collins E, Grimes P. Thioacetamide-induced Cataract with Invasive Proliferation of the Lens Epithelium in Rainbow Trout. Cancer Res. 1966;26:1819-1825.
8. Albert DM, Rabson AS, Grimes PA, Von Sallmann L. Neoplastic Transformation in vitro of Hamster Lens Epithelium by Simian Virus 40. Science. 1969;164(3883):1077-1078. doi:10.1126/science.164.3883.1077
9. Chen Q, Hung FC, Fromm L, Overbeek PA. Induction of cell cycle entry and cell death in postmitotic lens fiber cells by overexpression of E2F1 or E2F2. Invest Ophthalmol Vis Sci. 2000;41(13):4223-4231.
10. Zheng H chuan, Nakamura T, Zheng Y, et al. SV40 T antigen disrupted the cell metabolism and the balance between proliferation and apoptosis in lens tumors of transgenic mice. J Cancer Res Clin Oncol. 2009;135(11):1521-1532. doi:10.1007/s00432-009-0599-z
11. Mahon KA, Chepelinsky AB, Khillan JS, Overbeek PA, Piatigorsky J, Westphal H. Oncogenesis of the Lens in Transgenic Mice. Science. 1987;235(4796):1622-1628. doi:10.1126/science.3029873
12. Woog J, Albert DM, Gonder JR, Carpenter JJ. Osteosarcoma in a Phthisical Feline Eye. Vet Pathol. 1983;20(2):209-214. doi:10.1177/030098588302000208
13. Dubielzig RR. Ocular sarcoma following trauma in three cats. J Am Vet Med Assoc. 1984;184(5):578-581.
14. Dubielzig RR, Everitt J, Shadduck JA, Albert DM. Clinical and Morphologic Features of Post-traumatic Ocular Sarcomas in Cats. Vet Pathol. 1990;27(1):62-65. doi:10.1177/030098589002700111
15. Wong CJ, Peiffer RL, Oglesbee S, Osborne C. Feline ocular epithelial response to growth factors in vitro. Am J Vet Res. 1996;57(12):1748-1752.
16. Zeiss CJ, Johnson EM, Dubielzig RR. Feline intraocular tumors may arise from transformation of lens epithelium. Vet Pathol. 2003;40(4):355-362. doi:10.1354/vp.40-4-355
17. Carter RT, Giudice C, Dubielzig RR, Colitz CMH. Telomerase Activity with Concurrent Loss of Cell Cycle Regulation in Feline Post-traumatic Ocular Sarcomas. J Comp Pathol. 2005;133(4):235-245. doi:10.1016/j.jcpa.2005.04.009
18. McPherson L, Newman SJ, McLean N, et al. Intraocular Sarcomas in Two Rabbits. J Vet Diagn Invest. 2009;21(4):547-551. doi:10.1177/104063870902100422
19. Dickinson R, Bauer B, Gardhouse S, Grahn B. Intraocular sarcoma associated with a rupture lens in a rabbit ( Oryctolagus cuniculus ). Vet Ophthalmol. 2013;16(s1):168-172. doi:10.1111/vop.12049
20. M. Albert D, O. Phelps P, R. Surapaneni K, et al. The Significance of the Discordant Occurrence of Lens Tumors in Humans versus Other Species. Ophthalmology. 2015;122(9).
21. March 2015 Report to the Congress: Medicare Payment Policy – MedPAC. Accessed December 13, 2023. https://www.medpac.gov/document/http-www-medpac-gov-docs-default-source-reports-mar2015_entirereport_revised-pdf/
22. H. D. The Lens. In: Physiology of the Eye. 5th ed. New York Pergamon Press; :145-149.
23. Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133(2):275-288.
24. Chaturvedi S, Mehrotra AN, Mittal S, Bahadur H. The Conundrum of Lenticular Oncology. A Review. Indian J Ophthalmol. 2003;51(4):297.
25. Langer R, Brem H, Falterman K, Klein M, Folkman J. Isolations of a Cartilage Factor That Inhibits Tumor Neovascularization. Science. 1976;193(4247):70-72. doi:10.1126/science.935859
26. Pettenati MJ, Sweatt AJ, Lantz P, et al. The human cornea has a high incidence of acquired chromosome abnormalities. Hum Genet. 1997;101(1):26-29. doi:10.1007/s004390050580
27. Marshall GE, Konstas AGP, Bechrakis NE, Lee WR. An immunoelectron microscope study of the aged human lens capsule. Exp Eye Res. 1992;54(3):393-401. doi:10.1016/0014-4835(92)90051-S
28. Schmut O. The organization of tissues of the eye by different collagen types. Albrecht Von Graefes Arch Für Klin Exp Ophthalmol. 1978;207(3):189-199. doi:10.1007/BF00411053
29. Sasaki T, Larsson H, Tisi D, Claesson-Welsh L, Hohenester E, Timpl R. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity11Edited by A. Fersht. J Mol Biol. 2000;301(5):1179-1190. doi:10.1006/jmbi.2000.3996
30. Kefalides NA, Monboisse JC, Bellon G, Ohno N, Ziaie Z, Shahan TA. Suppression of tumor cell growth by type IV collagen and a peptide from the NC1 domain of the alpha 3(IV) chain. Medicina (Mex). 1999;59(5 Pt 2):553.
31. Pasco S, Han J, Gillery P, et al. A specific sequence of the noncollagenous domain of the alpha3(IV) chain of type IV collagen inhibits expression and activation of matrix metalloproteinases by tumor cells. Cancer Res. 2000;60(2):467-473.
32.Webber P, Landis B, Loveless B, C Pappas A. Paradoxical lack of investigation into the natural tumor-resistant properties of the human lens capsular epithelium. Invest Ophthalmol Vis Sci. 2023;64(8):4140.