|
 |
| ORIGINAL ARTICLE |
|
| Year : 2003 | Volume
: 51
| Issue : 4 | Page : 297-301 |
|
RETRACTED ARTICLE: The conundrum of lenticular oncology. A review
S Chaturvedi, Amar Nath Mehrotra, S Mittal, H Bahadur
Department of Ophthalmology, Himalayan Institute of Medical Sciences, Dehradun, Uttaranchal, India
Correspondence Address:
S Chaturvedi
Department of Ophthalmology, Himalayan Institute of Medical Sciences, Dehradun, Uttaranchal
India
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 14750616 
It is a long - accepted dogma in ophthalmology that the lens is a tumour-free tissue. Yet, in the lens, there is lifelong mitotic activity in the subcapsular epithelium. Therefore, these subcapsular epithelial cells must have the potential for cellular transformation. How then can we explain the fact that no scientist has ever seen a naturally occurring primary tumour of the lens in vivo ? This review discusses the early work of Mann, von Hallermann, Courtois and others who addressed the issue of tumour resistance of the lens. Keywords: Crystalline lens, avascularity, lens capsule, anti-angiogenic factors
How to cite this article:
Chaturvedi S, Mehrotra AN, Mittal S, Bahadur H. RETRACTED ARTICLE: The conundrum of lenticular oncology. A review. Indian J Ophthalmol 2003;51:297-301 |
In the 1940s Ida Mann studied tumour-immunity in the lens. When rabbit lens in situ was micro injected with highly carcinogenic 0.4% methylcholanthrene in liquid paraffin, the small puncture of the capsule sealed completely, and no change of the lens could be seen after 10 months.[1] However, when mouse lenses were transferred to a vascularised site on the flank of inbred mice and treated with methylcholanthrene, a few lens - derived tumours were seen. In 38 experiments, only three carcinomas of the subcapsular epithelium were reported; the remainder were described as host-derived sarcomas or epitheliomas of the skin. In all cases of lens-derived tumour formation, the lens capsule was ruptured. Without modern antibody markers, we cannot exclude the possibility that the observed "carcinomas" and "sarcomas" may have represented epithelial hyperplasia, or a granular tissue response. In these early experiments, the putative lens - derived tumours did not occur in vivo , unless transplanted to a vascularised site, treated with a strong carcinogen, and the lens capsule ruptured.[1]
The combination of these tumour-favourable conditions resulted in a small (8%) incidence of observed lens-derived tumour formation. Questions arise as to the explanation(s) for the low incidence of tumour formation. It is possible that lens tumours did not form because of the low mitotic index of the cells treated with methylcholanthrine in this model.
Another possibility is that the lens or even the surrounding environment lacked the growth promoters necessary to induce transformed cells to divide. Since the work of Ida Mann in 1948, the question of lens tumour resistance continues to be considered, taking into account the unique properties of the lens and lens capsule.
One unique property of the lens is the terminal differentiation of lens fibre cells accompanied by denucleation, a DNA fragmentation process akin to classical apoptosis.[2],[3] This process appears to involve a caspase 3-like cysteine proteast,[4] suggesting involvement of the apoptotic cycle in lens fibre differentiation. The location and extent of apoptosis in the lens may contribute to the lack of tumour formation. One hypothesis is that this could occur through regulation of apoptotic pathway genes, such as P53 and GADD45. Transgenic mouse models are used to explore the role of apoptosis in lens cell cycle progression.[5]
These studies may further address the potential role of apoptosis in the lifelong control of lens cell division. The apoptotic process associated with lens fibre cells denucleation still does not completely explain the lack of naturally-occurring neoplastic transformation of the subcapsular epithelium.
Lens subcapsular epithelial cells do not spontaneously transform in vivo
Spontaneous transformation of lens subcapsular epithelial cells in vivo has never been reported. Is this lack of neoplastic transformation a special property of the in vivo environment? In the late 1970s Courtois and colleagues studied the spontaneous transformation of bovine lens epithelial cells in vitro .[6] Under in vitro conditions, long-term lens epithelial cell cultures were shown to acquire unlimited growth characteristics. When transplanted into nude mice, these long-term cultured lens cells actively proliferated and formed tumours, which later regressed. When freshly dissociated lens epithelial cells were injected into nude mice at the same concentrations, tumours were not seen. In a later study by Messiaen and colleagues, cultures of mouse lens explants also acquired tumour-forming abilities approximately after 17 passages, but were not metastatic.[7] These in vitro studies demonstrated the possibility that long-term culture conditions can alter the growth characteristics through perturbation of the lens capsule and/or oncoviral infection. One question to consider is whether these lens cells were truly oncogenically transformed, or merely acquired a limited lifespan extension. Tumour regression could be explained by the fact that these cells grew to the end of their limited lifespan extension and then reached a point of senescence.
Other investigators have established lens epithelial cells lines, using SV40 virus in vitro .[8] Importantly, these results show that lens epithelial cells, per se , are not resistant to oncogenic transformation under the appropriate circumstances. In addition transgenic mice were developed expressing MSV-SV 40 large T-construct[9] or murine alpha A-crystalline/SV 40 T antigen construct.[10],[11] In these transgenic mice, lens tumours of varying pathologies were observed. In the case of MSV-SV 40 large T-construct, one case of malignant transformation of the lens epithelium was found.[9] In the murine alpha A-crystalline/SV40 T antigen construct, the alpha T1 line developed fast growing, poorly differentiated lens tumours, whereas the alpha T2 line produced slow growing and well differentiated lens tumours.[10] However, these transgenic mice represent deviations from the natural lenticular environment. Perhaps there is something unique about the in vivo environment that provides protection against naturally-occurring neoplastic transformation of lens subcapsular epithelial cells.
Avascularity of the lens
The lens is an avascular tissue, acquiring its nutrients from aqueous and vitreous components (proteins, ions, growth factors) that pass through its semipermeable membrane, the lens capusle.[12] An adequate vascular supply is essential for tumour progression. As early as the 1970's. Folkman[13] proposed that most solid tumours, regardless of origin, begin as a small population of cells dependent on nutrients that diffuse from surrounding tissues. Eventually small tumour colonies grow to a size where simple diffusion is insufficient to sustain growth. At this point, angiogenesis, fueled by tumour-derived factors, is necessary for further tumour growth. This would be the logical point where an avascular tissue, such as the lens, could confine potential tumours to a small size. However, even such preangiongenic colonies of neoplastic cells have not been described in the lens.
Therefore, it is possible that avascularity alone does not entirely explain the lack of primary tumour formation in the lens. In another avascular ocular tissue, the cornea, Folkman and colleagues showed that inhibition of vascularisation in an experimental tumour model could prevent tumour progression.[14] Yet, the cornea, despite its normally healthy state of avascularity, can still be invaded by advancing tumour tissue carrying its own angiogenic factors.[14]
However, one important difference between the cornea and lens is that the cornea lacks a capsular barrier. Bowman's layer may serve as a type of corneal barrier. Primary tumours of the corneal stroma are virtually unknown, despite the fact that there is a high incidence of chromosomal abnormalities.[15] Therefore, it is likely that there is something about the ocular environment, and/or the presence of barriers that accounts for the lack of tumour formation in the lens.
The lens capsule as a chemo-mechanical barrier
The lens capsule is composed of collagen types I-IV,[16],[17] laminin, entactin, heparan, sulfate proteoglycan and gibronectin.[18] Interestingly, fragments of collagens (type XVIII and XV) make up endostatins,[19] the potent inhibitors of angiogenesis. One interesting speculation is that a collagen-derived endostatin-like molecule exists near and/or within the lens capsule as a protection mechanism against unwanted neovascularisation. The presence of an endostatin-like molecule associated with the lens capsule would not only preserve the transparency of the lens but also inhibit the angiogenesis of tumours in close proximity. Another possibility is the presence of a lens capsule-associated cell growth inhibitor that prevents subcapsular epithelial cells from undergoing neoplastic transformation or uncontrolled growth in vivo . There is evidence in the literature that fragments of collagen type IV, the main component of the lens capsule, have the ability to suppress tumour cell growth,[20] as well as inhibit activation of matrix metalloproteinases of tumour cells,[21] believed to play a role in tumour invasiveness.
Some evidence in favor of the lens capsule as a chemo-mechanical barrier can be seen in [Figure - 1]. Even highly invasive melanomas [Figure - 1]a and b and retinoblastomas [Figure - 1]c that fill nearly the entire vitreous, demonstrate well-defined borders at the lens capsule interface. As generally seen in these tumours, there is no evidence of invasion, or direct contact with the lens capsule. Rather, the interface is filled with debris and fluid. It is tempting to speculate that the tumour is repelled by some type of chemo-mechanical property of the lens capsule.
In vitro experiments have demonstrated that tumour cells[22],[23] and leukocytes[24] do secrete proteolytic enzymes with the ability to digest lens capsule components. Yet, with the exception of the work by von Hallerman[25] in 1954, and another brief mention by Grossniklaus,[26] invasion of the lens capsule by invading tumour cells appears to be an extremely rare event. Von Hallerman described lenticular invasion by melanosarcoma of the ciliary body and choroid.[25] A few presumptive tumour cells were described within a tear of the lens substance. These tumour cells demonstrated no signs of mitotic activity. In another area, a few subcapsular tumour cells were shown with mitoses.
Is this an unusual phenomenon a fixation artifact, or an invasion of a non-intact lens capsule? The extreme rarity of lens tumour invasion leads to the possibility that the lens capsule itself or the surrounding ocular milieu inhibits digestion of the lens capsule by invasive tumour cells.
Based on our knowledge of the lens, there are several possible ways that tumour formation can be inhibited. [Figure - 2] schematically illustrates several hypotheses, including the presence of anti-angiogenic factors, growth inhibitors, as well as anti-lens capsule digestion factors. These factors may or may not be lens-derived, but rather in close proximity to the lens. One or more of these factors could play a role in tumour-resistance of the lens. Future experiments to test the capacity of the lens capsule as a chemo-mechanical barrier could be designed quite readily. The lens capsule could be placed in a chamber filled with vitreous like fluid. Tumour cells, such as retinoblastoma or melanoma cells, could be placed into the chamber on one side of the lens capsule. Then, the behavior of these tumour cells with respect to the lens capsule could be studied. Important questions could be addressed by adding anti-angiogenic factors, angiogenic factors, growth inhibitors, as well as anti-lens capsule digestion factors. The thickness of the lens capsule could also be tested as part of the barrier phenomenon.
Another potential study would be an analysis of the effects of endostatins, angiogenesis factors, and pro/anti-apoptotic factors on the behavior of immortalised lens cells transplanted back into lens capsule ghosts, or alternatively, on the behavior of lentoid bodies derived from transdifferentiated retinal pigment epithelium (RPE) and retina in vitro .[27]
Further, signaling processes between the lens capsule and the tumour cells could also be studied, these might also reveal interesting new concepts relating to why the lens seems to have such a strong barrier against tumour invasion.
The body of data from the past 50 years or so shows that the enigma of lenticular oncology still exists and may have several possible explanations. For one, we now know that lens subcapsular epithelial cells themselves are not immune to neoplastic transformation in vitro , given the right circumstances. Therefore, it is the in vivo ocular environment and/or an intact lens capsule that seem to inhibit both the neoplastic transformation of lens subcapsular epithelial cells, as well as the breach of the lens capsule by invading tumour cells. Further characterisation of the lens capsule and its ocular environment may shed more light on its unique role in anti-tumourigenesis.
| References | |  |
| 1. | Mann I. Introduction of an experimental tumour of the lens. Trans Ophthalm Soc UK 1948;67:141-53.  |
| 2. | Wride MA. Cellular and molecular features of lens differentiation: A review of recent advances. Differentiation 1996;61:77-93. [ PUBMED] [ FULLTEXT] |
| 3. | Wride WA. Minireview. Apoptosis as seen through a lens. Apoptosis 2000;5:203-9. |
| 4. | Ishizaki Y, Jacobson MD, Raff MC. A role of caspases in lens differentiation. J Cell Biol 1998;140:153-58. [ PUBMED] [ FULLTEXT] |
| 5. | Chen Q, Hung FC, Fromm L, Overbeek PA. Induction of cell cycle entry and cell death in postmitotic lens fiber cells by over expression of E2F1 or E2F2. Invest Ophthalmol Vis Sci 2000;41:4223-31. [ PUBMED] [ FULLTEXT] |
| 6. | Courtosis Y, Simonneau L, Tassin L, Laurent WV, Malaise E. Spontaneous transformation of bovine lens epithelial cells. Differentiation 1978;10:23-30. |
| 7. | Messiaen L, Qian S, De Bruyne, Boghaert E, Moens T, Rabaey M, et al. Spontaneous acquisition of tumorigenicity and invasiveness by mouse lens explant cells during culture in vitro. In Vitro Cell Dev Biol 1991;27A:369-80. |
| 8. | Lenstra JA, Hukkelhoven MWCA, Groeneveld AA, Smits RAMM, Weterings PJJM, Bloemendal H. Gene expression of transformed lens cells. Exp Eye Res 1982;35:549-54. |
| 9. | Gotz W, Theuring F, Favor J, Herken R. Eye pathology in transgenic mice carrying a MSV-SV 40 large T-construct. Exp Eye Res 1991;52:41-49. [ PUBMED] |
| 10. | Nakamura T, Mahon KA, Miskin R, Dey A, Kuwubara T, Westphal H. Differentiation and oncogenesis - phenotypically distinct lens tumours in transgenic mice. New Biol 1989;1:193-204. |
| 11. | Mahon KA, Chepelinsky AB, Khillan JS, Overbeek PA, Piatigorsky J, Westphal H. Science 1987;235:1622-28. [ PUBMED] |
| 12. | Davson H. The lens. In: Physiology of the Eye , 5th edition, New York: Pergamon Press; 1990, pp 145-149. |
| 13. | Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumour factor responsible for angiogenesis. Exp Med 1971;133:275-88. [ PUBMED] [ FULLTEXT] |
| 14. | Langer R, Brem H, Falterman K, Klein M, Folkamn J. Isolation of a cartilage factor that inhibits tumour neovascularization. Science 1976;193:70-72. |
| 15. | Pettenati MJ, Sweatt AJ, Lantz, Stanton CA, Reynolds J, Rao PN, et al. The human cornea has a high incidence of acquired chromosome abnormalities. Hum Genet 1997;101:26-29. |
| 16. | Marshall GE, Konstas AG, Bechrakis NE, Lee WR. An immunoelectron microscopy study of the aged human lens capsule. Exp Eye Res 1992;54:393-401. [ PUBMED] |
| 17. | Schmut O. The organization of the tissues of the eye by the different collagan types. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1978;207:189-99. [ PUBMED] |
| 18. | Cammarata PR, Cantu-Crouch D, Oakford L, Morrill A. Macromolecular organization of bovine lens capsule. Tissue Cell 1986;18:83-97. [ PUBMED] |
| 19. | Sasaki T, Larsson H, Tisi D, Claesson-Welsh, Hohenester E, Timpl R. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J Mol Biol 2000;301:1179-90. |
| 20. | Kefalides NA, Monboisse JC, Bellon G, Ohno N, Ziaie Z, Shahan TA. Suppression of tumour cell growth by type IV collagen and a peptide from the NCI domain of the alpha 3 [IV] chain. Medicina {B Aires} 1999;59:553. [ PUBMED] |
| 21. | Pasco S, Han J, Gillery P, Bellon G, Maquart FX, Borel JP, et al. A specific sequence of the noncollagenous domain of the alpha 3 [IV] chain of type IV collagen inhibits expression and activation of matrix metalloproteinases by tumour cells. Cancer Res 2000;60:467-73. [ PUBMED] [ FULLTEXT] |
| 22. | Starkey JR, Hosick HL, Stanford DR, Liggit HD. Interaction of metastatic tumour cells with bovine lens capsule basement membrane. Cancer Res 1984;44:1585-94. |
| 23. | Starkey JR, Stanford DR, Magnuson JA, Hammer S, Robertson NP, Gasic GJ. Comparison of basement membrane matrix degradation by purified proteases and by metastatic tumour cells. J Cell Biochem 1987;35:31-49. |
| 24. | Mainardi CL, Dixit SN, Kang AH. Degradation of type IV [basement membrane] collagen by a proteinase isolated from human polymorphonuclear leukocyte granules. J Biol Chem 1980;255:5435-41. [ PUBMED] [ FULLTEXT] |
| 25. | Von Hallermann W, Meisner G. Die umstrittene tumorimmunitaet der Linse (Translation: The controversial tumour immunity of the lens) Monatsblaetter fuer Augenheilkunde [German] 1954;124 Bd:159-64. |
| 26. | Grossniklaus HE, Zimmerman LE, Kachmer ML. Pleomorphic adenocarcinoma of the ciliary body. Ophthalmology 1990;97:763-68. [ PUBMED] |
| 27. | Pritchard DJ, Clayton RM, De Pomerai DI. 'Transdifferentiation' of chicken neural retina into lens and pigment epithelium in culture; controlling influences. J Embryol Exp Morphol 1978;48:1-21. [ PUBMED] |
[Figure - 1], [Figure - 2]
|
Search Pubmed for