Expression and role of fibroblast activation protein α in acute myeloid leukemia

Mei,Shuchong; Zhang,Yuan; Yu,Li; Chen,Guoan; Zi,Fuming

doi:10.3892/or.2020.7874

Expression and role of fibroblast activation protein α in acute myeloid leukemia

Authors:
- Shuchong Mei
- Yuan Zhang
- Li Yu
- Guoan Chen
- Fuming Zi
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Affiliations: Department of Emergency, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: November 30, 2020 https://doi.org/10.3892/or.2020.7874
Pages: 641-651
Copyright: © Mei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Currently, the prognosis of acute myeloid leukemia (AML) is poor. In the AML microenvironment, bone marrow (BM) mesenchymal stem cells (BMMSCs) serve an important role in protecting AML cells from chemotherapy‑induced apoptosis. The present study aimed to evaluate the expression of fibroblast activation protein α (FAPα) in BMMSCs and BM biopsy samples via flow cytometry, reverse transcription‑quantitative PCR and immunohistochemistry, as well as to identify the correlation between the expression of FAPα in BM with clinical parameters and survival of newly diagnosed patients with AML. Subsequently, the protective effect of FAPα on Cytosine arabinoside (Ara‑C)‑induced apoptosis in Kasumi‑1 cells was investigated via small interfering (si)RNA, and its underlying mechanism was examined by western blotting. The results demonstrated significant differences in FAPα expression in BMMSCs and BM biopsy samples between patients with AML and healthy donors. Furthermore, BMMSCs protected Ara‑C‑induced Kasumi‑1 cells from apoptosis, and knockdown of FAPα using siRNA decreased this protection. It was found that Kasumi‑1 cells expressed β‑catenin, which could be inhibited by Ara‑C, and β‑catenin expression was significantly activated when co‑cultured with BMMSCs, even in the presence of Ara‑C. Knockdown of FAPα with siRNA significantly suppressed the expression of β‑catenin. The present results indicated that FAPα serves an important role in the AML BM microenvironment, and that increased expression of FAPα in BM may be a poor prognostic factor in patients with AML. Moreover, the current findings demonstrated that BMMSCs protected AML cells from apoptosis, which was in part contributed by FAPα, and may occur via the β‑catenin signaling pathway.

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1	Dores GM, Devesa SS, Curtis RE, Linet MS and Morton LM: Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 119:34–43. 2012. View Article : Google Scholar : PubMed/NCBI
2	Montesinos P, Bergua J, Infante J, Esteve J, Guimaraes JE, Sierra J and Sanz MÁ: Update on management and progress of novel therapeutics for R/R AML: An Iberian expert panel consensus. Ann Hematol. 98:2467–2483. 2019. View Article : Google Scholar : PubMed/NCBI
3	Liao Z, Tan ZW, Zhu P and Tan NS: Cancer-associated fibroblasts in tumor microenvironment - Accomplices in tumor malignancy. Cell Immunol. 343:1037292019. View Article : Google Scholar : PubMed/NCBI
4	Shafat MS, Gnaneswaran B, Bowles KM and Rushworth SA: The bone marrow microenvironment - Home of the leukemic blasts. Blood Rev. 31:277–286. 2017. View Article : Google Scholar : PubMed/NCBI
5	Geyh S, Rodríguez-Paredes M, Jäger P, Khandanpour C, Cadeddu RP, Gutekunst J, Wilk CM, Fenk R, Zilkens C, Hermsen D, et al: Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 30:683–691. 2016. View Article : Google Scholar : PubMed/NCBI
6	von der Heide EK, Neumann M, Vosberg S, James AR, Schroeder MP, Ortiz-Tanchez J, Isaakidis K, Schlee C, Luther M, Jöhrens K, et al: Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients. Leukemia. 31:1069–1078. 2017. View Article : Google Scholar : PubMed/NCBI
7	Augsten M: Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol. 4:622014. View Article : Google Scholar : PubMed/NCBI
8	Chaturvedi P, Gilkes DM, Wong CC, Luo W, Zhang H, Wei H, Takano N, Schito L, Levchenko A, Semenza GL and Kshitiz: Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest. 123:189–205. 2013. View Article : Google Scholar : PubMed/NCBI
9	Raz Y, Cohen N, Shani O, Bell RE, Novitskiy SV, Abramovitz L, Levy C, Milyavsky M, Leider-Trejo L, Moses HL, et al: Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J Exp Med. 215:3075–3093. 2018. View Article : Google Scholar : PubMed/NCBI
10	Tao L, Huang G, Song H, Chen Y and Chen L: Cancer associated fibroblasts: An essential role in the tumor microenvironment. Oncol Lett. 14:2611–2620. 2017. View Article : Google Scholar : PubMed/NCBI
11	Zhou P, Xiao N and Wang J, Wang Z, Zheng S, Shan S and Wang J, Du J and Wang J: SMC1A recruits tumor-associated-fibroblasts (TAFs) and promotes colorectal cancer metastasis. Cancer Lett. 385:39–45. 2017. View Article : Google Scholar : PubMed/NCBI
12	Komohara Y and Takeya M: CAFs and TAMs: Maestros of the tumour microenvironment. J Pathol. 241:313–315. 2017. View Article : Google Scholar : PubMed/NCBI
13	Chen X and Song E: Turning foes to friends: Targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 18:99–115. 2019. View Article : Google Scholar : PubMed/NCBI
14	Kalluri R: The biology and function of fibroblasts in cancer. Nat Rev Cancer. 16:582–598. 2016. View Article : Google Scholar : PubMed/NCBI
15	LeBleu VS and Kalluri R: A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis Model Mech. 11:dmm0294472018. View Article : Google Scholar : PubMed/NCBI
16	Higashino N, Koma YI, Hosono M, Takase N, Okamoto M, Kodaira H, Nishio M, Shigeoka M, Kakeji Y and Yokozaki H: Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma. Lab Invest. 99:777–792. 2019. View Article : Google Scholar : PubMed/NCBI
17	Wen X, He X, Jiao F, Wang C, Sun Y, Ren X and Li Q: Fibroblast activation protein-α-positive fibroblasts promote gastric cancer progression and resistance to immune checkpoint blockade. Oncol Res. 25:629–640. 2017. View Article : Google Scholar : PubMed/NCBI
18	Hu M, Qian C, Hu Z, Fei B and Zhou H: Biomarkers in tumor Microenvironment? Upregulation of fibroblast activation protein-α correlates with gastric cancer progression and poor prognosis. OMICS. 21:38–44. 2017. View Article : Google Scholar : PubMed/NCBI
19	Byrling J, Sasor A, Nilsson J, Said Hilmersson K, Andersson R and Andersson B: Expression of fibroblast activation protein and the clinicopathological relevance in distal cholangiocarcinoma. Scand J Gastroenterol. 55:82–89. 2020. View Article : Google Scholar : PubMed/NCBI
20	Zhang L, Yang L, Xia ZW, Yang SC, Li WH, Liu B, Yu ZQ, Gong PF, Yang YL, Sun WZ, et al: The role of fibroblast activation protein in progression and development of osteosarcoma cells. Clin Exp Med. 20:121–130. 2020. View Article : Google Scholar : PubMed/NCBI
21	Pleshkan VV, Alekseenko IV, Tyulkina DV, Kyzmich AI, Zinovyeva MV and Sverdlov ED: Fibroblast activation protein (FAP) as a possible target of an antitumor strategy. Mol Gen Mikrobiol Virusol. 34:90–97. 2016. View Article : Google Scholar : PubMed/NCBI
22	Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, Chen M, Xu G, Ren K and Wei Y: Targeting of cancer associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment. Mol Med Rep. 13:2476–2484. 2016. View Article : Google Scholar : PubMed/NCBI
23	Raffaghello L, Vacca A, Pistoia V and Ribatti D: Cancer associated fibroblasts in hematological malignancies. Oncotarget. 6:2589–2603. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zi FM, He JS, Li Y, Wu C, Wu WJ, Yang Y, Wang LJ, He DH, Yang L, Zhao Y, et al: Fibroblast activation protein protects bortezomib-induced apoptosis in multiple myeloma cells through β-catenin signaling pathway. Cancer Biol Ther. 15:1413–1422. 2014. View Article : Google Scholar : PubMed/NCBI
25	Pittenger MF: Mesenchymal stem cells from adult bone marrow. Mesenchymal Stem Cells. Springer; Basel: pp. 27–44. 2008, View Article : Google Scholar
26	Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M and Vardiman JW: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127:2391–2405. 2016. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Yang Y, Mallampati S, Sun B, Zhang J, Kim SB, Lee JS, Gong Y, Cai Z and Sun X: Wnt pathway contributes to the protection by bone marrow stromal cells of acute lymphoblastic leukemia cells and is a potential therapeutic target. Cancer Lett. 333:9–17. 2013. View Article : Google Scholar : PubMed/NCBI
29	Abramoff MD, Magalhaes PJ and Ram SJ: Image processing with ImageJ. Biophoton Int. 11:36–42. 2004.
30	Caplan AI: Mesenchymal stem cells. J Orthop Res. 9:641–650. 1991. View Article : Google Scholar : PubMed/NCBI
31	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
32	Rettig WJ, Chesa PG, Beresford HR, Feickert HJ, Jennings MT, Cohen J, Oettgen HF and Old LJ: Differential expression of cell surface antigens and glial fibrillary acidic protein in human astrocytoma subsets. Cancer Res. 46:6406–6412. 1986.PubMed/NCBI
33	Rettig WJ, Su SL, Fortunato SR, Scanlan MJ, Raj BK, Garin-Chesa P, Healey JH and Old LJ: Fibroblast activation protein: Purification, epitope mapping and induction by growth factors. Int J Cancer. 58:385–392. 1994. View Article : Google Scholar : PubMed/NCBI
34	Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, Old LJ and Rettig WJ: Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA. 91:5657–5661. 1994. View Article : Google Scholar : PubMed/NCBI
35	Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP and Old LJ: Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 53:3327–3335. 1993.PubMed/NCBI
36	Keane FM, Yao TW, Seelk S, Gall MG, Chowdhury S, Poplawski SE, Lai JH, Li Y, Wu W, Farrell P, et al: Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio. 4:43–54. 2013. View Article : Google Scholar : PubMed/NCBI
37	Jacob M, Chang L and Puré E: Fibroblast activation protein in remodeling tissues. Curr Mol Med. 12:1220–1243. 2012. View Article : Google Scholar : PubMed/NCBI
38	Chung KM, Hsu SC, Chu YR, Lin MY, Jiaang WT, Chen RH and Chen X: Fibroblast activation protein (FAP) is essential for the migration of bone marrow mesenchymal stem cells through RhoA activation. PLoS One. 9:e887722014. View Article : Google Scholar : PubMed/NCBI
39	Hamson EJ, Keane FM, Tholen S, Schilling O and Gorrell MD: Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 8:454–463. 2014. View Article : Google Scholar : PubMed/NCBI
40	Zi F, He J, He D, Li Y, Yang L and Cai Z: Fibroblast activation protein α in tumor microenvironment: Recent progression and implications (Review). Mol Med Rep. 11:3203–3211. 2015. View Article : Google Scholar : PubMed/NCBI
41	Tian K, Yang S, Ren Q and Han Z, Lu S, Ma F, Zhang L and Han Z: p38 MAPK contributes to the growth inhibition of leukemic tumor cells mediated by human umbilical cord mesenchymal stem cells. Cell Physiol Biochem. 26:799–808. 2010. View Article : Google Scholar : PubMed/NCBI
42	Liu F, Qi L, Liu B, Liu J, Zhang H, Che D, Cao J, Shen J, Geng J, Bi Y, et al: Fibroblast activation protein overexpression and clinical implications in solid tumors: A meta-analysis. PLoS One. 10:e01166832015. View Article : Google Scholar : PubMed/NCBI
43	Traer E, Martinez J, Javidi-Sharifi N, Agarwal A, Dunlap J, English I, Kovacsovics T, Tyner JW, Wong M and Druker BJ: FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res. 76:6471–6482. 2016. View Article : Google Scholar : PubMed/NCBI
44	Fathi E, Sanaat Z and Farahzadi R: Mesenchymal stem cells in acute myeloid leukemia: A focus on mechanisms involved and therapeutic concepts. Blood Res. 54:165–174. 2019. View Article : Google Scholar : PubMed/NCBI
45	Brenner AK, Nepstad I and Bruserud Ø: Mesenchymal stem cells support survival and proliferation of primary human acute myeloid leukemia cells through heterogeneous molecular mechanisms. Front Immunol. 8:1062017. View Article : Google Scholar : PubMed/NCBI
46	Li Q, Pang Y, Liu T, Tang Y, Xie J, Zhang B and Chen H: Effects of human umbilical cord-derived mesenchymal stem cells on hematologic malignancies. Oncol Lett. 15:6982–6990. 2018.PubMed/NCBI
47	Yang X, Sexauer A and Levis M: Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase. Br J Haematol. 164:61–72. 2014. View Article : Google Scholar : PubMed/NCBI
48	Tian C, Zheng G, Zhuang H, Li X, Hu D, Zhu L, Wang T, You MJ and Zhang Y: MicroRNA-494 activation suppresses bone marrow stromal cell-mediated drug resistance in acute myeloid leukemia cells. J Cell Physiol. 232:1387–1395. 2017. View Article : Google Scholar : PubMed/NCBI
49	Guo F, Wang Y, Liu J, Mok SC, Xue F and Zhang W: CXCL12/CXCR4: A symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 35:816–826. 2016. View Article : Google Scholar : PubMed/NCBI
50	Malfuson JV, Boutin L, Clay D, Thépenier C, Desterke C, Torossian F, Guerton B, Anginot A, de Revel T, Lataillade JJ, et al: SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis. Leukemia. 28:853–864. 2014. View Article : Google Scholar : PubMed/NCBI
51	Battula VL, Benito J, Somanchi AG, Duvvuri S, Hodgson L, Chen Y, Ma W, Davis RE, McNiece I, Shpall EJ, et al: Acute myeloid leukemia cells acquire stem cell features in the bone marrow microenvironment. Clin Lymphoma Myeloma Leuk. 14:S119–S120. 2014. View Article : Google Scholar
52	Nusse R and Clevers H: Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 169:985–999. 2017. View Article : Google Scholar : PubMed/NCBI
53	Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI and Armstrong SA: The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 327:1650–1653. 2010. View Article : Google Scholar : PubMed/NCBI