The role of basıc fibroblast growth factor receptor (bFGF) and C-kit receptor in progression of cutaneous melanocytic lesions

Objective: We investigated the expression of basic Fibroblast Growth Factor (bFGF) and c-kit proto-oncogene in progression to malignancy and métastases of melanocytic lesions. Methods: lmmunohistochemical detection of bFGF and c-kit receptors were performed by peroxidase- antiperoxidase (PAP) technique on compound nevi, vertical growth phase malignant melanoma and metastatic malignant melanoma in 12, 12 and 15 cases respectively. Clinicopathological correlations were analysed by Paerson's Chi-Square, Student's T-Test and One Way Anova test. Results: bFGF receptor immunoreactivity rates were 83.3%, 83.3% and 80 % in compound nevi, primary MMs and metastatic MMs respectively, c-kit immunoreactivity was absent in nevus cells, but faintly present in 16.6 % (2 cases) of MM cells. Conclusion: The results of our study suggest that loss of c-kit expression is more important in dermal penetration than métastases in melanomas.However, bFGF is not shown to be a prognostic factor for MMs.

___

/. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell. 2nd ed. London: Garland Publishing, Inc. 1989: 681-790. 2. tierlyn M, Mancianti ML, Jambrosic J, Bolen JB, Koprowski H. Regulatory factors that determine growth and phenotype of normal human melanocytes. Exp Cell Res 1988; 179: 322-331. 3. Shih IM, tierlyn M. Autocrine and paracrine roles for growth factors in melanoma. In Vivo 1994; 8:113-123. 4. Halaban R, Fan B, Ahn J, Funasaka Y, Qitay- Goren ti, Heufeld G. Growth factors, receptor kinases, and protein tyrosine phosphatases in normal and malignant melonocytes. J lmmunother 1992; 12:154-161. 5. tialaban R. Growth factors and tyrosine protein kinases in normal and malignant melanocytes. Cancer Metastasis Rev 1991; 10: 129-140. 6. Huang S, Luca M, Qutman M, et al. Enforced c- kit expression renders highly metastatic human melanoma cells susceptible to stem cell factor induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene 1996; 13: 2339-2347. 7. Zakut R, Perlis R, Eliyahu S, et al. KIT ligand (mast cell growth factor) inhibits the growth of KIT-expressing melanoma cells. Oncogene 1993; 8: 2221-2229. 8. Tsuura Y, fliraki fl, Watanabe K, et al. Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin- fixed- paraffin-embedded tissues. Virchows Arch 1994; 424: 135-141. 9. Al-Alousi S, Barnhill R, Blessing K, Barksdale S. The prognostic significance of basic fibroblast growth factor in cutaneous malignant melanoma. J Cutan Pathol 1996; 23:506-510.

10. Luo D, Chen fl, Searles G, Jumbow K. Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanine pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R. Melanoma Res 1995; 5: 303-309. 11. Piatali PQ, Hicotra MR, WinklerAB, Cavaliere R, Bigotti A, Ullrich A. Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 1992; 52: 197-201. 12. Yarden Y, Kuang WJ, Yang-Feng T, e t al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1988; 7:1003- 1011. 13. Giebel IB, Strunk KM, Holmes SA, Spritz RA. Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene 1992:7:2207-2217. 14. Hiroto S, Isozaki K, Moriyama Y, et ah Gain of function mutation of c-kit in human gastrointestinal stromal tumors. Science ' J998;279:577-580

15. Arber DA, Tamayo R, Weiss LM. Paraffin section detection of the c-kit gene product (CD 117) in human tissues: Value in the diagnosis of mast cell disorders. Hum Pathol 1998; 28: 498-504. 16. Ohashi A, Funasaka Y, Veda M, Ichihashi M. C- kit receptor expression in cutaneous malignant melanoma and benign melanocytic naevi. Melanoma Res 1996; 6: 25-30. 17. Lu C, Kerbel RS. Cytokines, growth factors and the loss of negative growth controls in the progression of human cutaneous malignant melanoma. Curr Opin Oncol 1994; 6: 212- 220. 18. Moretti S, Pinzi C, Spallanzani A, et al. Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. Int J Cancer 1999; 84: 160-168. 19. Takahashi H, Saitoh K, Kishi H, Parsons PQ. Immunohistochemical localisation of stem cell factor (SCF) with comparison of its receptor c-Kit proto-oncogene product (c-KIT) in melanocytic tumours. Virchows Arch 1995;42?': 283-288. 20. Welker P, Schadendorf D, Artuc M, Grabbe J, Henz BM. Expression of SCF splice variants in human melonocytes and melanoma cell lines: potential prognostic implications. BrJ Cancer 2000; 82: 1453-1458.

21. Papadimitriou CA, Topp MS, Serve H, et al. Recombinant human stem cell factor does exert minor stimulation of growth in small cell lung cancer and melanoma cell lines. Eur J Cancer 1995; 31 A: 2371-2378. 22. Salama S, Sircar K, Hewlett R. Kit expression in melanocytic lesions: An analysis of conventional nevi, Spitz and Reed's nevi, and melanoma. Am J Dermatopathol 1999; 21: 595. (Abstracts : Joint Meeting of ISD) 23. Shin EY, Lee BH, Yang JH, et al. Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer.J Cancer Res Clin Oncol 2000; 126:519-528. 24. Ropiquet F, Giri D, Kwabi-Addo B, Mansukhani A, Ittmann M. Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer.Cancer Res 2000-,60:4245-4250. 25. Shemirani B,Crowe DL. Head and neck squamous cell carcinoma lines produce biologically active angiogenic factors. Oral Oncol 2000; 36: 61-66. 26. Alanko T, Rosenberg M, Saksela O. FGF expression allows nevus cells to survive in three-dimensional collagen gel under conditions that induce apoptosis in normal human melanocytes. JJnvest Dermatol 1999; 113: 111-116. 27. Meier F, riesbit M, Hsu MY, et al. Human melanoma progression in skin reconstructs : biological significance of bFQF. Am J Pathol 2000; 156: 193-200. 28. Ahmed IiU, Veda M, Ito A, Ohashi A, Funasaka Y, Ichihashi M. Expression of fibroblast growth factor receptors in naevus-cell naevus and malignant melanoma. Melanoma Res 1997; 7: 299-305. 29. Yaguchi H, Tsuboi R, Ueki R, Ogawa H. Immunohistochemical localization of basic fibroblast growth factor in skin diseases. Acta Derm Venereol 1993; 73: 81-83. 30. Birck A, Kirkin AF, Zeuthen J, Hou-Jensen K. Expression of basic fibroblast growth factor and vascular endothelial growth factor in primary and metastatic melanoma from the same patients. Melanoma Res 1999; 9: 375-381. 31. Xerri L, Batty ani Z, Qrob JJ, et al. Expression of FQF1 and FQFR1 in human melanoma tissues. Melanoma Res 1996; 6:223-230. 32. Wang Y, Becker D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Hat Med 1997; 3: 887-893. 33. Rofstad EK, Halsor EF. Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000; 1 -.4932-4938.