Nuclear 24 kD fibroblast growth factor (FGF)-2 confers metastatic properties on rat bladder carcinoma cells

Abstract

The tumorigenic and metastatic properties of rat bladder carcinoma NBT-II cells transfected with a cDNA encoding the 24 kD nuclear isoform of human ®broblast growth factor-2 (FGF-2) were analysed and compared with those cells producing the 18 kD cytoplasmic isoform FGF-2. In transfected clones, 24 kD FGF-2 was found in the nucleus, and no FGF-2 was secreted. RT ± PCR analysis showed no upregulation of FGF-2-speci®c receptor FGFR2c expression in these proliferating transfected cells. A shorter latency period for in vivo tumor formation and abundant spontaneous lung metastases were only seen if nuclear FGF-2-producing cells were injected subcutaneously into nude mice. Intravenous injection of 24 kD FGF-2-producing cells led to extensive experimental lung metastases whereas injection of control NBT-II cells or 18 kD FGF-2-producing cells did not. As FGF-2-producing cells have no speci®c FGF-2 receptors, our results suggest that the 24 kD FGF-2 has nuclear targets, and activates metastatic property of carcinoma cells via a mechanism other than the conventional FGF receptor-mediated signaling pathway.

Nuclear FGF-2 facilitates cell survival in vitro and during establishment of metastases

“…In contrast, the NBT-II Tet-Off GF12 clone grew faster in the absence of doxycycline than in the presence of the antibiotic, indicating that expression of the 24 kDa FGF-2 enhances the tumor growth properties of the cells. These results are in accordance with the tumor growth properties of the NLS42 clone of NBT-II cells, which constitutively express nuclear 24 kDa FGF-2, with the smaller primary tumors from mice injected with the Tet-Off GF12 cells likely to be due to clonal variation (Okada-Ban et al, 1999).…”

“…The doubling time of the cells grown in vitro can be estimated to be approximately 24 h in 10% FBS-containing medium. In vivo NLS42 cells formed tumors more quickly than the NBT-II cells (Okada-Ban et al, 1999) and the labeled cells behaved in a manner similar to that seen with unlabeled tumor cells (data not shown).…”

“…We have previously reported that expression of the nuclear 24 kDa FGF-2 allows NBT-II carcinoma cells to give rise to metastatic foci in the lungs of nude mice that have been subcutaneously (s.c.) injected (Okada-Ban et al, 1999). In order to elucidate the specific role of nuclear FGF-2 and to determine potential nuclear targets, we have generated cells that conditionally express the 24 kDa FGF-2 with the Tet-Off system, and have studied the metastatic ability of these cells.…”

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

“…Western blot analysis showed high levels of both nuclear (22,22.5,and 24 kDa) and cytoplasmic isoforms (18 kDa) of bFGF in DU-145 and vector transfected DU-145 cells. Reexpression of DPPIV in DU-145 cells greatly decreased the levels of nuclear bFGF isoforms; the levels of low molecular weight cytoplasmic isoform were also decreased (Fig.…”

“…The high molecular weight isoforms possess the NH 2 -terminal nuclear localization signal and are exclusively localized to the nucleus (19)(20)(21). Recent data indicate that increased expression of bFGF promotes tumorigenic and metastatic properties of various malignancies including prostate cancer and is associated with inferior survival of prostate cancer patients (2,3,19,(21)(22)(23)(24)(25)(26). Furthermore, loss of even one allele of bFGF in the transgenic adenocarcinoma of the mouse prostate model increases their survival by suppressing metastasis (27).…”