p53 expression and relation to human papillomavirus infection in pingueculae, pterygia, and limbal tumors.

BACKGROUND The tumor suppressor gene p53 is expressed without apoptosis in the limbal basal stem cells of all pterygia and limbal tumors and most pingueculae from which these growths seem to originate. Oncogenic human papillomaviruses (HPVs) have been found in pterygia and limbal tumors, and HPV and p53 overexpression commonly coexist in oropharyngeal and penile carcinomas. OBJECTIVE To search for HPV DNA as a cofactor in the development of pingueculae, pterygia, and limbal tumors. METHODS We examined specimens--1 of pinguecula, 13 of pterygia (7 primary, 1 recurrent, 1 with dysplasia, and 4 primary not tested for p53), and 10 of limbal tumors (2 with actinic keratosis dysplasia, 1 with conjunctival intraepithelial neoplasia, 3 with carcinoma in situ, and 4 with squamous cell carcinoma)-expressing p53. Specimens were tested for the presence of HPV DNA by the polymerase chain reaction using degenerate consensus primers for the highly conserved portion of the L1 region that encodes a capsid protein of the virus. This assay has a wide spectrum with capability of detecting essentially all known HPV types. Nested polymerase chain reaction was performed on all specimens. Primers of the cystic fibrosis gene were used to confirm the presence of genomic DNA and to rule out inhibitors. Purified HPV DNA type 11 was the positive control, and HPV-negative genomic DNA was the negative control. RESULTS Using consensus primers for the highly conserved portion of the L1 region, all specimens of pingueculae, pterygia, and limbal tumors studied were negative for HPV DNA by nested polymerase chain reaction. CONCLUSIONS Human papillomavirus DNA is not required as a cofactor in the development of pterygia and limbal tumors. These data support the theory that increased p53 expression in the limbal epithelia of pingueculae, pterygia, and limbal tumors indicates the probable existence of p53 mutations in these cells as an early event in their development, which is consistent with UV irradiation causation. Thus, due to a damaged p53-dependent programmed cell death mechanism, mutations in other genes may be progressively acquired. This would allow for the multistep development of pterygia and limbal tumor cells from p53-mutated limbal epithelial basal stem cells overlying pingueculae.

[1]  I. Cree,et al.  Ophthalmic Pathology—An Atlas and Textbook , 1998 .

[2]  P. McDonnell,et al.  Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia. , 1992, Investigative ophthalmology & visual science.

[3]  A. Schermer,et al.  Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells , 1986, The Journal of cell biology.

[4]  J. Bartek,et al.  An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. , 1992, Journal of immunological methods.

[5]  H. Ridley.  Diseases of Outer Eye , 1965 .

[6]  Z. Karcioglu,et al.  Human papilloma virus in neoplastic and non-neoplastic conditions of the external eye , 1997, The British journal of ophthalmology.

[7]  R. Cote,et al.  Strategies for improving the immunohistochemical staining of various intranuclear prognostic markers in formalin-paraffin sections: androgen receptor, estrogen receptor, progesterone receptor, p53 protein, proliferating cell nuclear antigen, and Ki-67 antigen revealed by antigen retrieval techniques , 1994, Human pathology.

[8]  F. Hu,et al.  Interferon treatment for corneolimbal squamous dysplasia. , 1998, American journal of ophthalmology.

[9]  T. Reid,et al.  Pterygia and limbal epithelial cells: Relationship and molecular mechanisms , 1996, Progress in Retinal and Eye Research.

[10]  G. Demers,et al.  The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest , 1994, Journal of virology.

[11]  C. Shields,et al.  Squamous Cell Carcinoma of the Conjunctiva , 1993, International ophthalmology clinics.

[12]  G. Srivastava,et al.  Expression of p53 and its relationship with human papillomavirus in penile carcinomas. , 1995, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[13]  V. Everts,et al.  Cytokines modulate routes of collagen breakdown. Review with special emphasis on mechanisms of collagen degradation in the periodontium and the burst hypothesis of periodontal disease progression. , 1997, Journal of clinical periodontology.

[14]  S. L. Maskin.  Regression of limbal epithelial dysplasia with topical interferon. , 1994, Archives of ophthalmology.

[15]  K. Kinzler,et al.  Carcinogens leave fingerprints , 1992, Nature.

[16]  Arnold J. Levine,et al.  The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 , 1990, Cell.

[17]  M. Coroneo.  Pterygium as an early indicator of ultraviolet insolation: a hypothesis. , 1993, The British journal of ophthalmology.

[18]  A. Harłozińska,et al.  Expression of p53 and coexistence of HPV in premalignant lesions and in cervical cancer. , 1995, European journal of gynaecological oncology.

[19]  S. Duke-Elder,et al.  Diseases of the outer eye , 1965 .

[20]  T. Sun,et al.  Relative proliferative rates of limbal and corneal epithelia. Implications of corneal epithelial migration, circadian rhythm, and suprabasally located DNA-synthesizing keratinocytes. , 1991, Investigative ophthalmology & visual science.

[21]  J. Friedenwald,et al.  Effects of ultraviolet irradiation on corneal epithelium; mitosis, nuclear fragmentation, post-traumatic cell movements, loss of tissue cohesion. , 1945, Journal of cellular and comparative physiology.

[22]  A. Levine,et al.  Association of human papillomavirus types 16 and 18 E6 proteins with p53. , 1990, Science.

[23]  W. Sekundo,et al.  Capillaries in the epithelium of pterygium , 1998, The British journal of ophthalmology.

[24]  B. Geiger,et al.  Cytokeratin expression in squamous metaplasia of the human uterine cervix. , 1986, Differentiation; research in biological diversity.

[25]  T. Reid,et al.  Immunohistochemical evidence that human pterygia originate from an invasion of vimentin-expressing altered limbal epithelial basal cells. , 1994, Current eye research.

[26]  M. Manos,et al.  42 – DETECTION AND TYPING OF GENITAL HUMAN PAPILLOMAVIRUSES , 1990 .

[27]  H. Jampel,et al.  Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye. , 1993, Investigative ophthalmology & visual science.

[28]  P. Anthony.  Robbins' Pathologic Basis of Disease , 1990 .

[29]  S. Baron,et al.  The interferons. Mechanisms of action and clinical applications. , 1991, JAMA.

[30]  H. Birkedal‐Hansen,et al.  Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. , 1991, The Journal of biological chemistry.

[31]  B. Munoz,et al.  Corneal changes associated with chronic UV irradiation. , 1989, Archives of ophthalmology.

[32]  J. Simon,et al.  A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[33]  H. Taylor,et al.  Human papillomavirus in corneal and conjunctival carcinoma. , 1997, Australian and New Zealand journal of ophthamology (Print).

[34]  M. Matsubara,et al.  Unique regulation of the matrix metalloproteinase, gelatinase B. , 1995, Investigative ophthalmology & visual science.

[35]  K. Park,et al.  Indirect mitogenic effect of transforming growth factor-beta on cell proliferation of subconjunctival fibroblasts. , 1998, Investigative ophthalmology & visual science.

[36]  C. Sutter,et al.  Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. , 1992, Cancer research.

[37]  L. Liotta,et al.  Metastasis suppressor genes. , 1991, Important advances in oncology.

[38]  G. Giannelli,et al.  Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. , 1997, Science.

[39]  Harold Francis Blum,et al.  Carcinogenesis by Ultraviolet Light , 1959 .

[40]  R. Weinberg,et al.  Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. , 1989, Cancer research.

[41]  M. Sporn,et al.  Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[42]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[43]  S. Tsao,et al.  Prevalence of HPV infection in esophageal squamous cell carcinoma in Chinese patients and its relationship to the p53 gene mutation , 1997, International journal of cancer.

[44]  T. Sun,et al.  In vitro growth and differentiation of rabbit bulbar, fornix, and palpebral conjunctival epithelia. Implications on conjunctival epithelial transdifferentiation and stem cells. , 1993, Investigative ophthalmology & visual science.

[45]  C. Karp,et al.  Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. , 1999, Ophthalmology.

[46]  S. Robbins,et al.  Pathologic basis of disease , 1974 .

[47]  M. Chirambo,et al.  Solar keratosis, pterygium, and squamous cell carcinoma of the conjunctiva in Malawi. , 1979, The British journal of ophthalmology.

[48]  T. Sun,et al.  Keratinocyte stem cells of cornea, skin and hair follicle: common and distinguishing features , 1993 .

[49]  T. Amemiya,et al.  Immunohistochemical localization of basic fibroblast growth factor, platelet derived growth factor, transforming growth factor-β and tumor necrosis factor-α in the pterygium , 1996 .

[50]  A. Ziegler,et al.  Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[51]  L. Crawford,et al.  Human Papillomavirus E6 and E7: Proteins which deregulate the cell cycle , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[52]  Kathleen R. Cho,et al.  Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[53]  K. Kinzler,et al.  Life (and death) in a malignant tumour , 1996, Nature.

[54]  F. Blodi,et al.  Metastatic squamous cell carcinoma of the conjunctiva. , 1988, Ophthalmology.

[55]  T. Reid,et al.  P53 expression in altered limbal basal cells of pingueculae, pterygia, and limbal tumors. , 1997, Current eye research.

[56]  M. Stanley,et al.  Abnormal expression and mutation of p53 in cervical cancer--a study at protein, RNA and DNA levels. , 1997, Genitourinary medicine.