A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts

Abstract

In addition to its role in invasion and metastasis of several tumors, the multifunctional urokinase receptor uPAR (urokinase plasminogen activator receptor) is directly involved in the growth of several cancer cells in vitro and in vivo. We have compared growth rate and oncogenic transformation in wild-type (wt) or uPAR À/À mouse embryonic fibroblasts (MEFs). Surprisingly, uPAR À/À MEFs grew faster than wt MEFs. This agreed with elevated levels of cell cycle mediators like extracellular signal-regulated protein kinase, p38, AP1 and Cyclin D1. Infection with a uPAR retrovirus reverted the effect, decreasing the growth rate.When MEFs were transformed with H-Ras V12 and E1A oncogenes, the efficiency of transformation in uPAR À/À MEFs was higher than in wt. UPAR À/À MEFs grew faster at low serum, produced more colonies in agar and produced tumors in vivo in nude mice with a lower latency period. The properties of the heterozygous uPAR þ /À MEFs were always intermediate. We conclude therefore that in MEFs uPAR concentration controls cell proliferation and the transforming activity of some oncogenes.

Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells

“…Our findings do not allow us to conclude that expression of M uPAR on HSPCs per se regulates the anchorage-dependent cell cycle, even though M uPAR can regulate the cell cycle (47). Rather, we favor the interpretation that the observed differences in the proliferation status between M uPAR + and M uPAR -HSPCs might be explained, at least in part, by assuming that the M uPAR + HSPC is a different type of progenitor.…”

Co-Depletion of Cathepsin B and uPAR Induces G0/G1 Arrest in Glioma via FOXO3a Mediated p27Kip1 Upregulation

“…Likewise, an 88% inhibition of proliferating cancer cells in colorectal carcinoma in vivo when treated with uPAR monoclonal antibody (ATN658) has been reported recently [67]. In contrast, uPAR overexpression inhibited cell growth in murine embryonic fibroblast cells and induced cell growth in keratinocytes [68]. uPAR has been detected as a potential cooperating oncogene in Ink4a KO mice, which are deficient in cell growth control [69].…”

Urokinase receptor primes cells to proliferate in response to epidermal growth factor

“…Furthermore, our c-Src overexpression experiments prove that under specific conditions, the requirement for uPAR in supporting EGF mitogenic activity is eliminated. Mazzieri et al (2006) reported that uPARÀ/À MEFs demonstrate more rapid proliferation and oncogenic transformation, compared with uPAR-positive cells; however, their MEFs were not transformed with SV40 large T antigen. As our MEFs were transformed, the tumor suppressor gene p53 is inactivated (O'Reilly, 1986), as may be observed in human cancers and cancer cell lines.…”