Differentiation associated modulation of K‐FGF expression in a human teratocarcinoma cell line and in primary germ cell tumours

Abstract

Rcccivcd R Januury 1991The human teratocarcinoma ccl1 line Tcra 2 can bc induced IO di.qcrcJrtiatc in vitro after exposure to rctinoic acid. We show in this pq%r thtrt whereas the K-FGF oncogcnc is cxprrsscd in undiffcrcnti;ited cells, addition of retinoic acid rapidly (~60 min) downrcgulutcs the expression of this pcnc. However, when cells are cultured in AA for an extended pcricsd of timr (> I5 days) KSFGF transcripts rcilppcar. WC also report that K-FGF is expressed in approximately one-third of primary humen gclm cell tumours but no\ in the corrcspondiny normal tcsticuhir tissue. K-FGF; Teralocarcinoma INTRODUCTIONThe heparin binding growth factor family now comprises a number of structurally related polypeptides which influence many aspects of cellular physiology, differentiation and proliferation. The acidic and basic fibroblast growth factors, originally isolated from pituitary and central nervous system respectively, are potent mitogens, both in vitro and in vivo [l] and since their discovery have been shown to stimulate proliferation of a wide variety of cells in tissue and organ culture [2,3]. The FGFs are also interesting in the light of their diveree deve!opmental effects. Synthesis of heparin binding growth factors occurs both in perimplantation stages of mammalian embryogenesis and later during orgsonogenesis. In both these situations there is circumstantial evidence for a pleiotropic response of target cells to the factor: different concentrations of the factor leading to proliferation, cell migration and differentiation f4,5]. Not only are these processes important in morphogenesis but also in the metastasis and angiogenic properties of turnours, and there is strong evidence that FGF or related molecules are potent stimulators of the capillary endothelial cell response to tumours 131.Within recent years the FGF family has expanded to include proteins encoded by at least 7 different genes. In addition, genes encoding FGF-receptors have been recently characterized. Genes encoding the FGF homologues K-FGF?hst, int-2 and FGF-5 were originally isolated as oncogenes by DNA tsansfection assay, Correspondence addrem: W. EngstMm,

FGF4 dissociates anti-tumorigenic from differentiation signals of retinoic acid in human embryonal carcinomas

“…FGF4 expression is repressed in RA-treated NT2/D1 cells but not in di erentiation defective human germ cell tumor lines (Miller and Rizzino, 1996;Miller et al, 1990Miller et al, , 1993Mummery et al, 1993;Scho®eld et al, 1991;Tiesman and Rizzino, 1989;Yoshida et al, 1988a,b). To determine whether FGF4 expression is also repressed in a cell previously responsive to the di erentiationinducing e ects of RA, FGF4 expression was examined in NT2/D1 cells and compared to expression in recently derived retinoid resistant lines, NT2/D1-R1 and NT2/ D1-H1 .…”

“…The FGFs are a large family of growth factors with reported e ects in development, di erentiation, angiogenesis, mitogenesis, and transformation Niswander and Martin, 1993;Sakamoto et al, 1986;Taira et al, 1987;Talarico et al, 1993;Tiesman and Rizzino, 1989;Velcich et al, 1989). Of these diverse functions, FGF4 signals are especially interesting to examine in germ cell tumors since expression of FGF4 is tightly regulated during development and restricted to undi erentiated ECs (Miller and Rizzino, 1996;Miller et al, 1990;Mummery et al, 1993;Scho®eld et al, 1991;Strohmeyer et al, 1991;Tiesman and Rizzino, 1989;Yoshida et al, 1988a,b). Cell stage-speci®c expression depends on an enhancer element present 3' to FGF4 coding sequences, which contains an octamer binding site (Ambrosetti et al, 1997;Curatola and Basilico, 1990;Dailey et al, 1994;Yuan et al, 1995).…”

“…Cell stage-speci®c expression depends on an enhancer element present 3' to FGF4 coding sequences, which contains an octamer binding site (Ambrosetti et al, 1997;Curatola and Basilico, 1990;Dailey et al, 1994;Yuan et al, 1995). RAtreatment represses FGF4 expression in di erentiation sensitive but not resistant human ECs (Miller and Rizzino, 1996;Miller et al, 1990Miller et al, , 1993Mummery et al, 1993;Scho®eld et al, 1991;Tiesman and Rizzino, 1989;Yoshida et al, 1988a,b). As shown in Figure 1, NT2/D1 cells rendered RA resistant all fail to repress FGF4 expression, despite RA-treatment.…”

“…FGF4 expression is restricted to undi erentiated murine and human embryonal carcinomas (ECs). During induced di erentiation, FGF4 expression is repressed (Miller and Rizzino, 1996;Miller et al, 1990Miller et al, , 1993; Mummery et al, 1993;Scho®eld et al, 1991;Tiesman and Rizzino, 1989;Yoshida et al, 1988a, b). FGF4 expression is repressed during induced di erentiation of maturation sensitive but not resistant human germ cell tumor cell lines .…”

Heparin Binding Growth Factors and the Control of Teratoma Cell Proliferation

“…a derivative of Tera-2 [17], but we have detected no change in bFGF transcript levels on differentiation of Tera-2 [13]. The possibility remains that the physiological ligand for the Tera-2 recep tor is a related molecule such as K-FGF, which is expressed by Tera-2 and is present in all embryonal carcinomas studied [21],…”