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. 1998 Mar;4(3):191–195.

Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

J L Arbiser 1, J D Fine 1, D Murrell 1, A Paller 1, S Connors 1, K Keough 1, E Marsh 1, J Folkman 1
PMCID: PMC2230348  PMID: 9562977

Abstract

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have deficiencies of collagen type VII and have elevated levels of fibroblast collagenase, and a greatly increased risk of cutaneous squamous cell carcinoma. Patients with other genetic blistering disorders do not have elevated collagenase or an increased risk of squamous cell carcinoma, despite chronic wounding. The connection between collagen type VII deficiency, increased collagenase, and squamous cell carcinoma is not understood. MATERIALS AND METHODS: Urine from 81 patients with RDEB (39 patients), junctional epidermolysis bullosa (JEB; 12 patients), and epidermolysis bullosa simplex (EBS; 30 patients), as well as unaffected family members of RDEB patients (33 patients), was tested for the presence of basic fibroblast growth factor (bFGF) using a sensitive radioimmunoassay. These patients included many who were enrolled in the Epidermolysis Bullosa Registry and others who were referred by their physicians. RESULTS: Fifty-one percent of patients with RDEB had elevated levels (> 5000 pg/g) of urinary bFGF. In contrast, none of the patients with JEB had elevated levels of bFGF. Twenty-one percent of clinically unaffected family members had elevated levels of bFGF, and 13% of patients with EBS had elevated levels of bFGF. The frequency of elevated bFGF values among all groups was statistically significant (p = 0.002), and the levels of bFGF in RDEB patients were significantly elevated compared with those of other groups (p < 0.05). CONCLUSIONS: We have found that patients with RDEB have elevated levels of bFGF, which may contribute to increased fibroblast collagenase and the development of squamous cell carcinoma. These results suggest a novel treatment for RDEB, namely, angiogenesis inhibitors, which may antagonize the effects of bFGF in this disorder. There are currently no other means of treatment for this disorder, which has a high morbidity and mortality rate.

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Selected References

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  1. Bauer E. A., Cooper T. W., Tucker D. R., Esterly N. B. Phenytoin therapy of recessive dystrophic epidermolysis bullosa. Clinical trial and proposed mechanism of action on collagenase. N Engl J Med. 1980 Oct 2;303(14):776–781. doi: 10.1056/NEJM198010023031402. [DOI] [PubMed] [Google Scholar]
  2. Bruckner-Tuderman L., Winberg J. O., Anton-Lamprecht I., Schnyder U. W., Gedde-Dahl T., Jr Anchoring fibrils, collagen VII, and neutral metalloproteases in recessive dystrophic epidermolysis bullosa inversa. J Invest Dermatol. 1992 Nov;99(5):550–558. doi: 10.1111/1523-1747.ep12667372. [DOI] [PubMed] [Google Scholar]
  3. Caldwell-Brown D., Stern R. S., Lin A. N., Carter D. M. Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. Epidermolysis Bullosa Study Group. N Engl J Med. 1992 Jul 16;327(3):163–167. doi: 10.1056/NEJM199207163270305. [DOI] [PubMed] [Google Scholar]
  4. Christiano A. M., Anhalt G., Gibbons S., Bauer E. A., Uitto J. Premature termination codons in the type VII collagen gene (COL7A1) underlie severe, mutilating recessive dystrophic epidermolysis bullosa. Genomics. 1994 May 1;21(1):160–168. doi: 10.1006/geno.1994.1238. [DOI] [PubMed] [Google Scholar]
  5. Cooper T. W., Bauer E. A. Therapeutic efficacy of phenytoin in recessive dystrophic epidermolysis. A comparison of short- and long-term treatment. Arch Dermatol. 1984 Apr;120(4):490–495. [PubMed] [Google Scholar]
  6. D'Armiento J., DiColandrea T., Dalal S. S., Okada Y., Huang M. T., Conney A. H., Chada K. Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis. Mol Cell Biol. 1995 Oct;15(10):5732–5739. doi: 10.1128/mcb.15.10.5732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dunnill M. G., McGrath J. A., Richards A. J., Christiano A. M., Uitto J., Pope F. M., Eady R. A. Clinicopathological correlations of compound heterozygous COL7A1 mutations in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 1996 Aug;107(2):171–177. doi: 10.1111/1523-1747.ep12329570. [DOI] [PubMed] [Google Scholar]
  8. Dunnill M. G., Richards A. J., Milana G., Mollica F., Atherton D., Winship I., Farrall M., al-Imara L., Eady R. A., Pope F. M. Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities. J Med Genet. 1994 Oct;31(10):745–748. doi: 10.1136/jmg.31.10.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eisen A. Z. Human skin collagenase: relationship to the pathogenesis of epidermolysis bullosa dystrophica. J Invest Dermatol. 1969 May;52(5):449–453. doi: 10.1038/jid.1969.77. [DOI] [PubMed] [Google Scholar]
  10. Fine J. D., Bauer E. A., Briggaman R. A., Carter D. M., Eady R. A., Esterly N. B., Holbrook K. A., Hurwitz S., Johnson L., Lin A. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry. J Am Acad Dermatol. 1991 Jan;24(1):119–135. doi: 10.1016/0190-9622(91)70021-s. [DOI] [PubMed] [Google Scholar]
  11. Fine J. D., Johnson L. Efficacy of systemic phenytoin in the treatment of junctional epidermolysis bullosa. Arch Dermatol. 1988 Sep;124(9):1402–1406. [PubMed] [Google Scholar]
  12. Folkman J., Ingber D. Inhibition of angiogenesis. Semin Cancer Biol. 1992 Apr;3(2):89–96. [PubMed] [Google Scholar]
  13. Goldberg G. I., Eisen A. Z., Bauer E. A. Tissue stress and tumor promotion. Possible relevance to epidermolysis bullosa. Arch Dermatol. 1988 May;124(5):737–741. [PubMed] [Google Scholar]
  14. Levitzki A., Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science. 1995 Mar 24;267(5205):1782–1788. doi: 10.1126/science.7892601. [DOI] [PubMed] [Google Scholar]
  15. Nguyen M., Watanabe H., Budson A. E., Richie J. P., Hayes D. F., Folkman J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst. 1994 Mar 2;86(5):356–361. doi: 10.1093/jnci/86.5.356. [DOI] [PubMed] [Google Scholar]
  16. O'Keefe E. J., Chiu M. L., Payne R. E., Jr Stimulation of growth of keratinocytes by basic fibroblast growth factor. J Invest Dermatol. 1988 May;90(5):767–769. doi: 10.1111/1523-1747.ep12560956. [DOI] [PubMed] [Google Scholar]
  17. Parente M. G., Chung L. C., Ryynänen J., Woodley D. T., Wynn K. C., Bauer E. A., Mattei M. G., Chu M. L., Uitto J. Human type VII collagen: cDNA cloning and chromosomal mapping of the gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6931–6935. doi: 10.1073/pnas.88.16.6931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Singh R. K., Gutman M., Bucana C. D., Sanchez R., Llansa N., Fidler I. J. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4562–4566. doi: 10.1073/pnas.92.10.4562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Smoller B. A., McNutt N. S., Carter D. M., Gottlieb A. B., Hsu A., Krueger J. Recessive dystrophic epidermolysis bullosa skin displays a chronic growth-activated immunophenotype. Implications for carcinogenesis. Arch Dermatol. 1990 Jan;126(1):78–83. [PubMed] [Google Scholar]
  20. Tsuboi R., Sato Y., Rifkin D. B. Correlation of cell migration, cell invasion, receptor number, proteinase production, and basic fibroblast growth factor levels in endothelial cells. J Cell Biol. 1990 Feb;110(2):511–517. doi: 10.1083/jcb.110.2.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Uitto J., Christiano A. M. Molecular genetics of the cutaneous basement membrane zone. Perspectives on epidermolysis bullosa and other blistering skin diseases. J Clin Invest. 1992 Sep;90(3):687–692. doi: 10.1172/JCI115938. [DOI] [PMC free article] [PubMed] [Google Scholar]

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