Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo
Tóm tắt
It is believed that senescent cells contribute to the progression of primary and metastatic tumors, however, the exact mechanisms of this activity remain elusive. In this report we show that senescent human peritoneal mesothelial cells (HPMCs) alter the secretory profile of ovarian cancer cells (A2780, OVCAR-3, SKOV-3) by increasing the release of four angiogenic agents: CXCL1, CXCL8, HGF, and VEGF. Proliferation and migration of endothelial cells subjected to conditioned medium generated by: cancer cells modified by senescent HPMCs; cancer cells co-cultured with senescent HPMCs; and by early-passage HPMCs from aged donors, were markedly intensified. The same was the case for the vascularization, size and number of tumors that developed in the mouse peritoneum upon injection of ovarian cancer cells with senescent HPMCs. When the identified pro-angiogenic proteins were neutralized in conditioned medium from the cancer cells, both aspects of endothelial cell behavior intensified in vitro in response to senescent HPMCs were markedly reduced. The search for mediators of senescent HPMC activity using specific neutralizing antibodies and recombinant exogenous proteins showed that the intensified angiogenic potential of cancer cells was elicited by IL-6 and TGF-β1. At the transcriptional level, increased proliferation and migration of endothelial cells exposed to cancer cells modified by senescent HPMCs was regulated by HIF-1α, NF-κB/p50 and AP-1/c-Jun. Collectively, our findings indicate that senescent HPMCs may promote the progression of ovarian cancer cells by reprogramming their secretory phenotype towards increased production of pro-angiogenic agents and subsequent increase in the angiogenic capabilities of the vascular endothelium.
Tài liệu tham khảo
Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522
Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118
Lukanova A, Kaaks R (2005) Endogenous hormones and ovarian cancer: epidemiology and current hypotheses. Cancer Epidemiol Biomark Prev 14:98–107
Mikula-Pietrasik J, Sosinska P, Kucinska M, Murias M, Maksin K, Malinska A, Ziolkowska A, Piotrowska H, Wozniak A, Ksiazek K (2014) Peritoneal mesothelium promotes the progression of ovarian cancer cells in vitro and in a mice xenograft model in vivo. Cancer Lett 355:310–315
Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, Lord EM (2006) Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol 169:1739–1752
Sako A, Kitayama J, Yamaguchi H, Kaisaki S, Suzuki H, Fukatsu K, Fujii S, Nagawa H (2003) Vascular endothelial growth factor synthesis by human omental mesothelial cells is augmented by fibroblast growth factor-2: possible role of mesothelial cell on the development of peritoneal metastasis. J Surg Res 115:113–120
Ksiazek K, Jorres A, Witowski J (2008) Senescence induces a proangiogenic switch in human peritoneal mesothelial cells. Rejuvenation Res 11:681–683
Sosinska P, Mikula-Pietrasik J, Ryzek M, Naumowicz E, Ksiazek K (2014) Specificity of cytochemical and fluorescence methods of senescence-associated beta-galactosidase detection for ageing driven by replication and time. Biogerontology 15:407–413
Pronk A, Leguit P, Hoynck van Papendrecht AA, Hagelen E, van Vroonhoven TJ, Verbrugh HA (1993) A cobblestone cell isolated from the human omentum: the mesothelial cell; isolation, identification, and growth characteristics. In Vitro Cell Dev Biol 29A:127–134
Mikula-Pietrasik J, Kuczmarska A, Rubis B, Filas V, Murias M, Zielinski P, Piwocka K, Ksiazek K (2012) Resveratrol delays replicative senescence of human mesothelial cells via mobilization of antioxidative and DNA repair mechanisms. Free Radic Biol Med 52:2234–2245
Mikula-Pietrasik J, Kuczmarska A, Kucinska M, Murias M, Wierzchowski M, Winckiewicz M, Staniszewski R, Breborowicz A, Ksiazek K (2012) Resveratrol and its synthetic derivatives exert opposite effects on mesothelial cell-dependent angiogenesis via modulating secretion of VEGF and IL-8/CXCL8. Angiogenesis 15:361–376
Liu D, Hornsby PJ (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117–3126
Wang X, Lee SO, Xia S, Jiang Q, Luo J, Li L, Yeh S, Chang C (2013) Endothelial cells enhance prostate cancer metastasis via IL-6–>androgen receptor–>TGF-beta–>MMP-9 signals. Mol Cancer Ther 12:1026–1037
Coppe JP, Kauser K, Campisi J, Beausejour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574
Kim E, Rebecca V, Fedorenko IV, Messina JL, Mathew R, Maria-Engler SS, Basanta D, Smalley KS, Anderson AR (2013) Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach. Cancer Res 73:6874–6885
Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98:12072–12077
Taddei ML, Cavallini L, Comito G, Giannoni E, Folini M, Marini A, Gandellini P, Morandi A, Pintus G, Raspollini MR, Zaffaroni N, Chiarugi P (2014) Senescent stroma promotes prostate cancer progression: the role of miR-210. Mol Oncol 8:1729–1746
Domcke S, Sinha R, Levine DA, Sander C, Schultz N (2013) Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun 4:2126
Bobrovnikova-Marjon EV, Marjon PL, Barbash O, Vander Jagt DL, Abcouwer SF (2004) Expression of angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 is highly responsive to ambient glutamine availability: role of nuclear factor-kappaB and activating protein-1. Cancer Res 64:4858–4869
Hoot KE, Oka M, Han G, Bottinger E, Zhang Q, Wang XJ (2010) HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. J Clin Invest 120:3606–3616
Ksiazek K, Piatek K, Witowski J (2008) Impaired response to oxidative stress in senescent cells may lead to accumulation of DNA damage in mesothelial cells from aged donors. Biochem Biophys Res Commun 373:335–339
Książek K, Winckiewicz M, Staniszewski R, Breborowicz A, Witowski J (2007) Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: is TGF-beta1 a link? Exp Gerontol 42:840–843
Steinkamp MP, Winner KK, Davies S, Muller C, Zhang Y, Hoffman RM, Shirinifard A, Moses M, Jiang Y, Wilson BS (2013) Ovarian tumor attachment, invasion, and vascularization reflect unique microenvironments in the peritoneum: insights from xenograft and mathematical models. Front Oncol 3:97
Wang X, Lee SO, Xia S, Jiang Q, Luo J, Li L, Yeh S, Chang C (2013) Endothelial cells enhance prostate cancer metastasis via IL-6–>androgen receptor–>TGF-beta–>MMP-9 signals. Mol Cancer Ther 12:1026–1037
Mikula-Pietrasik J, Sosinska P, Janus J, Rubis B, Brewinska-Olchowik M, Piwocka K, Ksiazek K (2013) Bystander senescence in human peritoneal mesothelium and fibroblasts is related to thrombospondin-1-dependent activation of transforming growth factor-beta1. Int J Biochem Cell Biol 45:2087–2096
Yu B, Miao ZH, Jiang Y, Li MH, Yang N, Li T, Ding J (2009) c-Jun protects hypoxia-inducible factor-1 alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner. Cancer Res 69:7704–7712
Wang L, Walia B, Evans J, Gewirtz AT, Merlin D, Sitaraman SV (2003) IL-6 induces NF-kappa B activation in the intestinal epithelia. J Immunol 171:3194–3201
Gingery A, Bradley EW, Pederson L, Ruan M, Horwood NJ, Oursler MJ (2008) TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival. Exp Cell Res 314:2725–2738