Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours.

Abstract

The proto-oncogene c-kit and its ligand stem-cell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit proteins and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens on non-seminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growth-stimulatory effect of high concentrations of SCF on non-seminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.