Senescent stromal-derived osteopontin promotes preneoplastic cell growth.
Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies showing that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole-genome transcriptional profiling and compared senescent fibroblasts with their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNA interference did not affect senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, showing that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we show that OPN is expressed in senescent stroma within preneoplastic lesions that arise following 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatment of mice, suggesting that stromal-derived OPN-mediated signaling events affect neoplastic progression.
Pazolli
Ermira
E
Department of Cell Biology and Physiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Luo
Xianmin
X
Brehm
Sarah
S
Carbery
Kelly
K
Chung
Jun-Jae
JJ
Prior
Julie L
JL
Doherty
Jason
J
Demehri
Shadmehr
S
Salavaggione
Lorena
L
Piwnica-Worms
David
D
Stewart
Sheila A
SA
D048708:Cell Growth Processes; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000096:biosynthesis* / Q000494:pharmacology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D011994:Recombinant Proteins; D053495:Osteopontin