Cancer stem cells (CSCs) are a distinct population in tumors and cause cancer relapse and metastasis. Thus, treating CSCs are believed to be potential to cure rapidly growing and highly metastatic cancers. To date, CSCs in esophageal cancer have not been characterized. In the current study, we detected significant higher levels of placental growth factor (PLGF) and matrix metalloproteinase 9 (MMP9) in the esophageal cancers with metastasis, compared to those without metastasis, in which the expression levels of PLGF and MMP9 strongly correlated with each other. Thus, we used a human esophageal cancer cell line, TE-1, to examine the cross talk of PLGF and MMP9. We found that the levels of PLGF in TE-1 cells positively affected the levels of MMP9, while the levels of MMP9 did not affected the levels of PLGF, suggesting that PLGF may activate MMP9 in esophageal cancer cells. Then, we separated PLGF-positive and PLGF-negative TE-1 cells that had been transfected with a GFP reporter under a PLGF promoter by flow cytometry. We found that PLGF-positive cells grew significantly faster than PLGF-negative cells both in vitro and in vivo in a stereotactical implantation model, suggesting that PLGF-positive cells are likely CSCs in esophageal cancer. Taken together, we demonstrate that PLGF-positive cells appear to be CSCs in esophageal cancer, and they may release PLGF to promote cancer metastasis through MMP9 activation.
Esophageal cancer Cancer stem cells Placental growth factor Matrix metalloproteinases 9 Metastasis
This is a preview of subscription content, log in to check access.
This work was financially supported by the Shanghai Municipal Commission of Health and Family Planning Foundation No. 20134036.
Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, et al. Pancreatic duct cells as a source of VEGF in mice. Diabetologia. 2014;57:991–1000.PubMedCrossRefGoogle Scholar
Xiao X, Guo P, Chen Z, El-Gohary Y, Wiersch J, Gaffar I, et al. Hypoglycemia reduces vascular endothelial growth factor a production by pancreatic beta cells as a regulator of beta cell mass. J Biol Chem. 2013;288:8636–46.PubMedCentralPubMedCrossRefGoogle Scholar
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7:575–83.PubMedCrossRefGoogle Scholar
Eriksson A, Cao R, Pawliuk R, Berg SM, Tsang M, Zhou D, et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell. 2002;1:99–108.PubMedCrossRefGoogle Scholar
Davidson B, Reich R, Risberg B, Nesland JM. The biological role and regulation of matrix metalloproteinases (MMP) in cancer. Arkh Patol. 2002;64:47–53.PubMedGoogle Scholar
Rhee JS, Coussens LM. RECKing MMP function: implications for cancer development. Trends Cell Biol. 2002;12:209–11.PubMedCrossRefGoogle Scholar
Li B, Tsao SW, Li YY, Wang X, Ling MT, Wong YC, et al. Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway. Int J Cancer. 2009;125:2576–85.PubMedCrossRefGoogle Scholar
Mroczko B, Kozlowski M, Groblewska M, Lukaszewicz M, Niklinski J, Laudanski J, et al. Expression of matrix metalloproteinase-9 in the neoplastic and interstitial inflammatory infiltrate cells in the different histopathological types of esophageal cancer. Folia Histochem Cytobiol. 2008;46:471–8.PubMedGoogle Scholar
Kataoka M, Yamagata S, Takagi H, Thant A, Akiyama S, Iida K, et al. Matrix metalloproteinase 2 and 9 in esophageal cancer. Int J Oncol. 1996;8:773–9.PubMedGoogle Scholar
Shima I, Sasaguri Y, Arima N, Yamana H, Fujita H, Morimatsu M, et al. Expression of epidermal growth-factor (EGF), matrix metalloproteinase-9 (mmp-9) and proliferating cell nuclear antigen (pcna) in esophageal cancer. Int J Oncol. 1995;6:833–9.PubMedGoogle Scholar
Hori T, Yamashita Y, Ohira M, Matsumura Y, Muguruma K, Hirakawa K. A novel orthotopic implantation model of human esophageal carcinoma in nude rats: CD44H mediates cancer cell invasion in vitro and in vivo. Int J Cancer. 2001;92:489–96.PubMedCrossRefGoogle Scholar
Zins K, Thomas A, Lucas T, Sioud M, Aharinejad S, Abraham D. Inhibition of stromal PlGF suppresses the growth of prostate cancer xenografts. Int J Mol Sci. 2013;14:17958–71.PubMedCentralPubMedCrossRefGoogle Scholar
Li B, Wang C, Zhang Y, Zhao XY, Huang B, Wu PF, et al. Elevated PLGF contributes to small-cell lung cancer brain metastasis. Oncogene. 2013;32:2952–62.PubMedCrossRefGoogle Scholar
Laurent J, Hull EF, Touvrey C, Kuonen F, Lan Q, Lorusso G, et al. Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. Cancer Res. 2011;71:3781–91.PubMedCrossRefGoogle Scholar
Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell. 2010;141:178–90.PubMedCrossRefGoogle Scholar
Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene. 1999;18:2883–91.PubMedCrossRefGoogle Scholar
Holland JD, Klaus A, Garratt AN, Birchmeier W. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25:254–64.PubMedCrossRefGoogle Scholar