Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells

Lai,Dongmei; Ma,Li; Wang,Fangyuan

doi:10.3892/ijo.2012.1475

Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells

Authors:
- Dongmei Lai
- Li Ma
- Fangyuan Wang
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Affiliations: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China, Zhangshan Hospital, Fudan University, Shanghai, P.R. China
Published online on: May 14, 2012 https://doi.org/10.3892/ijo.2012.1475
Pages: 541-550

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Abstract

The fibroblast activation protein (FAP) is a cell surface serine protease which has emerged as a specific marker of tumor-associated fibroblasts (TAFs). FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity. However, the biological function of FAP in the tumor microenvironment is largely unknown. In this study, we first show that TAFs isolated from ovarian cancer samples have the characteristics of stem cells. To explore the functional role of FAP, the protein was silenced by siRNA lentiviral vector transfection. FAP silencing inhibited the growth of TAFs in vitro, accompanied with cell cycle arrest at the G2 and S phase in TAFs. FAP silencing also reduced the stem cell marker gene expression in TAFs. SKOV3 cells do not express FAP. Although FAP-silenced SKOV3 cells induced ovarian tumors, the rate of tumor growth was significantly decreased, as shown in the xenograft mouse model. TAF phenotypes in the xenograft tumor tissues were further assayed by immunohistochemistry. The expression of TAF markers, including fibroblast-specific protein, FAP, smooth muscle actin, desmin, vascular endothelial growth factor and fibroblast growth factor was decreased in the tumor stroma induced by FAP-silenced SKOV3 cells. In conclusion, FAP is an important regulator of the microenvironment in tumor formation and targeting FAP is a potential therapeutic strategy to combat ovarian cancer.

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1	Kunz-Schughart LA and Knuechel R: Tumor-associated fibroblasts (part I): active stromal participants in tumor development and progression? Histol Histopathol. 17:599–621. 2002.PubMed/NCBI
2	Kunz-Schughart LA and Knuechel R: Tumor-associated fibroblasts (part II): functional impact on tumor tissue. Histol Histopathol. 17:623–637. 2002.PubMed/NCBI
3	Orimo A, Gupta PB, Sgroi DC, et al: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar
4	Rowley DR: What might a stromal response mean to prostate cancer progression? Cancer Metastasis Rev. 17:411–419. 1998. View Article : Google Scholar : PubMed/NCBI
5	Ostermann E, Garin-Chesa P, Heider KH, et al: Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res. 14:4584–4592. 2008. View Article : Google Scholar : PubMed/NCBI
6	Garin-Chesa P, Old LJ and Rettig WJ: Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 87:7235–7239. 1990. View Article : Google Scholar : PubMed/NCBI
7	Christiansen V, Jackson KW, Lee KN and McKee PA: Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys. 457:177–186. 2007. View Article : Google Scholar : PubMed/NCBI
8	Aggarwal S, Brennen WN, Kole TP, et al: Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites. Biochemistry. 47:1076–1086. 2008. View Article : Google Scholar
9	Piñeiro-Sánchez ML, Goldstein LA, Dodt J, et al: Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem. 272:7595–7601. 1997.PubMed/NCBI
10	Park JE, Lenter MC, Zimmermann RN, et al: Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 274:36505–36512. 1999. View Article : Google Scholar : PubMed/NCBI
11	Santos AM, Jung J, Aziz N, Kissil JL and Puré E: Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 119:3613–3625. 2009. View Article : Google Scholar
12	Liu T, Cheng WW, Lai DM, Huang Y and Guo LH: Characterization of primary ovarian cancer cells in different culture systems. Oncol Rep. 23:1277–1284. 2010.PubMed/NCBI
13	Ma L, Lai DM, Liu T, Cheng WW and Guo LH: Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3. Acta Biochim Biophys Sin. 42:593–602. 2010. View Article : Google Scholar : PubMed/NCBI
14	Giannoni E, Bianchini F, Calorini L and Chiarugi P: Associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal. 14:2361–2371. 2011. View Article : Google Scholar
15	Studeny M, Marini FC, Champlin RE, et al: Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 62:3603–3608. 2002.PubMed/NCBI
16	Nakamizo A, Marini F, Amano T, et al: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 65:3307–3318. 2005.PubMed/NCBI
17	Al-Hajj M and Clarke MF: Self-renewal and solid tumor stem cells. Oncogene. 23:7274–7282. 2004. View Article : Google Scholar : PubMed/NCBI
18	Fang D, Nguyen TK, Leishear K, et al: A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 65:9328–9237. 2005. View Article : Google Scholar : PubMed/NCBI
19	Bapat SA, Mali AM, Koppikar CB and Kurrey NK: Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 65:3025–3029. 2005.PubMed/NCBI
20	Baglole CJ, Maggirwar SB, Gasiewicz TA, et al: The aryl hydrocarbon receptor attenuates tobacco smoke-induced cyclooxygenase-2 and prostaglandin production in lung fibroblasts through regulation of the NF-kappaB family member RelB. J Biol Chem. 283:28944–28957. 2008. View Article : Google Scholar
21	Trimboli AJ, Cantemir-Stone CZ, Li F, et al: Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature. 461:1084–1091. 2009. View Article : Google Scholar : PubMed/NCBI
22	Studeny M, Marini FC, Dembinski JL, et al: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst. 96:1593–1603. 2004. View Article : Google Scholar : PubMed/NCBI
23	Spaeth EL, Dembinski JL, Sasser AK, et al: Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One. 4:e49922009. View Article : Google Scholar : PubMed/NCBI
24	Mimeault M and Batra SK: Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol. 18:1605–1619. 2007. View Article : Google Scholar
25	Giannoni E, Bianchini F, Masieri L, et al: Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 70:6945–6956. 2010. View Article : Google Scholar
26	Pirzio LM, Freulet-Marrière MA, Bai Y, et al: Human fibroblasts expressing hTERT show remarkable karyotype stability even after exposure to ionizing radiation. Cytogenet Genome Res. 104:87–94. 2004. View Article : Google Scholar : PubMed/NCBI
27	Cheng JD, Dunbrack RL Jr, Valianou M, et al: Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res. 62:4767–4772. 2002.PubMed/NCBI
28	Cheng JD, Valianou M, Canutescu AA, et al: Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol Cancer Ther. 4:351–360. 2005.PubMed/NCBI
29	Mentlein R, Hattermann K, Hemion C, Jungbluth AA and Held-Feindt J: Expression and role of the cell surface protease seprase/ fibroblast activation protein-α (FAP-α) in astroglial tumors. Biol Chem. 392:199–207. 2011.PubMed/NCBI
30	Littlepage LE, Egeblad M and Werb Z: Coevolution of cancer and stromal cellular responses. Cancer Cell. 7:499–500. 2005. View Article : Google Scholar : PubMed/NCBI
31	Lazarides E, Granger BL, Gard DL, et al: Desmin- and vimentin-containing filaments and their role in the assembly of the Z disk in muscle cells. Cold Spring Harbor Symp Quant Biol. 46:351–378. 1982. View Article : Google Scholar : PubMed/NCBI
32	Kraman M, Bambrough PJ, Arnold JN, et al: Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 330:827–830. 2010. View Article : Google Scholar : PubMed/NCBI