Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts.
Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it.
Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, F-69000, France.
David
D
Vindrieux
Baptiste
B
Gras
Merce
M
Garcia-Belinchon
Samia
S
Mourah
Céleste
C
Lebbe
Arnaud
A
Augert
David
D
Bernard
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D020574:Proto-Oncogene Proteins c-sis; D016159:Tumor Suppressor Protein p53