Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

Becker,Marc; Graf,Claudine; Tonak,Marcus; Radsak,Markus  P.; Bopp,Tobias; Bals,Robert; Bohle,Rainer  M.; Theobald,Matthias; Rommens,Pol‑Maria; Proschek,Dirk; Wehler,Thomas  C.

doi:10.3892/ol.2016.4784

Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

Authors:
- Marc Becker
- Claudine Graf
- Marcus Tonak
- Markus P. Radsak
- Tobias Bopp
- Robert Bals
- Rainer M. Bohle
- Matthias Theobald
- Pol‑Maria Rommens
- Dirk Proschek
- Thomas C. Wehler
View Affiliations

Affiliations: Institute of Pathology, Saarland University Medical Center, Homburg, Saarland D‑66421, Germany, III Department of Internal Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Rhineland‑Palatinate D‑55131, Germany, Interdisciplinary Sarcoma Working Group, Center of Orthopaedic and Trauma Surgery, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Rhineland‑Palatinate D‑5513, Germany, Institute for Immunology, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Rhineland‑Palatinate D‑55131, Germany, Department of Internal Medicine V ‑ Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University Medical Center, Homburg, Saarland D‑66421, Germany
Published online on: June 24, 2016 https://doi.org/10.3892/ol.2016.4784
Pages: 1257-1264

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Undifferentiated pleomorphic sarcoma not otherwise specified belongs to the heterogeneous group of soft tissue tumors. It is preferentially located in the upper and lower extremities of the body, and surgical resection remains the only curative treatment. Preclinical animal models are crucial to improve the development of novel chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma. However, this approach has been hampered by the lack of reproducible animal models. The present study established two xenograft animal models generated from stable non‑clonal cell cultures, and investigated the difference in chemotherapeutic effects on tumor growth between undifferentiated pleomorphic sarcoma in vivo and in vitro. The cell cultures were generated from freshly isolated tumor tissues of two patients with undifferentiated pleomorphic sarcoma. For the in vivo analysis, these cells were injected subcutaneously into immunodeficient mice. The mice were monitored for tumor appearance and treated with the most common or innovative chemotherapeutic agents available to date. Furthermore, the same drugs were administered to in vitro cell cultures. The most effective tumor growth inhibition in vitro was observed with doxorubicin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat. In the in vivo xenograft mouse model, the combination of doxorubicin and the tyrosine kinase inhibitor pazopanib induced a significant tumor reduction. By contrast, treatment with vorinostat did not reduce the tumor growth. Taken together, the results obtained from drug testing in vitro differed significantly from the in vivo results. Therefore, the novel and reproducible xenograft animal model established in the present study demonstrated that in vivo models are required to test potential chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma prior to clinical use, since animal models are more similar to humans, compared with in vitro cell cultures.

View Figures

View References

1	Iwasaki H, Isayama T, Johzaki H and Kikuchi M: Malignant fibrous histiocytoma. Evidence of perivascular mesenchymal cell origin immunocytochemical studies with monoclonal anti-MFH antibodies. Am J Pathol. 128:528–537. 1987.PubMed/NCBI
2	Katenkamp K and Katenkamp D: Soft tissue tumors: New perspectives on classification and diagnosis. Dtsch Arztebl Int. 106:632–636. 2009.PubMed/NCBI
3	Poremba C: Soft tissue sarcomas: The role of histology and molecular pathology for differential diagnosis. Verh Dtsch Ges Pathol. 90:59–72. 2006.(In German). PubMed/NCBI
4	Al-Agha OM and Igbokwe AA: Malignant fibrous histiocytoma: Between the past and the present. Arch Pathol Lab Med. 132:1030–1035. 2008.PubMed/NCBI
5	Matushansky I, Charytonowicz E, Mills J, Siddiqi S, Hricik T and Cordon-Cardo C: MFH classification: Differentiating undifferentiated pleomorphic sarcoma in the 21st Century. Expert Rev Anticancer Ther. 9:1135–1144. 2009. View Article : Google Scholar : PubMed/NCBI
6	Spira AI and Ettinger DS: The use of chemotherapy in soft-tissue sarcomas. Oncologist. 7:348–359. 2002. View Article : Google Scholar : PubMed/NCBI
7	Grimer R, Judson I, Peake D and Seddon B: Guidelines for the management of soft tissue sarcomas. Sarcoma. 2010:5061822010. View Article : Google Scholar : PubMed/NCBI
8	Italiano A, Mathoulin-Pelissier S, Cesne AL, Terrier P, Bonvalot S, Collin F, Michels JJ, Blay JY, Coindre JM and Bui B: Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 117:1049–1054. 2011. View Article : Google Scholar : PubMed/NCBI
9	Daigeler A, Klein-Hitpass L, Stricker I, Müller O, Kuhnen C, Chromik AM, Steinstraesser L, Goertz O, Steinau HU and Lehnhardt M: Malignant fibrous histiocytoma - pleomorphic sarcoma, NOS gene expression, histology, and clinical course. A pilot study. Langenbecks Arch Surg. 395:261–275. 2010. View Article : Google Scholar : PubMed/NCBI
10	Fletcher CDM, Unni KK and Mertens F: World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC Press. (Lyon). 2002.
11	Casali PG and Blay JY: ESMO/CONTICANET/EUROBONET Consensus Panel of experts: Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21(Suppl 5): v198–v203. 2010. View Article : Google Scholar : PubMed/NCBI
12	Italiano A, Le Cesne A, Mendiboure J, Blay JY, Piperno-Neumann S, Chevreau C, Delcambre C, Penel N, Terrier P, Ranchere-Vince D, et al: Prognostic factors and impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the competing risks setting. Cancer. 120:3361–3369. 2014. View Article : Google Scholar : PubMed/NCBI
13	Leahy M, Del Garcia Muro X, Reichardt P, Judson I, Staddon A, Verweij J, Baffoe-Bonnie A, Jönsson L, Musayev A, Justo N, et al: SABINE Investigators: Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol. 23:2763–2770. 2012. View Article : Google Scholar : PubMed/NCBI
14	van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, et al: EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 379:1879–1886. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ray-Coquard I and Thomas D: Targeted therapies: Pazopanib for soft-tissue sarcoma: A PALETTE of data emerges. Nat Rev Clin Oncol. 9:431–432. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nguyen DT and Shayahi S: Pazopanib: Approval for soft-tissue sarcoma. J Adv Pract Oncol. 4:53–57. 2013.PubMed/NCBI
17	Ranieri G, Mammì M, Di Donato Paola E, Russo E, Gallelli L, Citraro R, Gadaleta CD, Marech I, Ammendola M and De Sarro G: Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: A new treatment for metastatic soft tissue sarcoma. Crit Rev Oncol Hematol. 89:322–329. 2014. View Article : Google Scholar : PubMed/NCBI
18	Tavallai S, Hamed HA, Grant S, Poklepovic A and Dent P: Pazopanib and HDAC inhibitors interact to kill sarcoma cells. Cancer Biol Ther. 15:578–585. 2014. View Article : Google Scholar : PubMed/NCBI
19	Schöffski P, Cornillie J, Wozniak A, Li H and Hompes D: Soft tissue sarcoma: An update on systemic treatment options for patients with advanced disease. Oncol Res Treat. 37:355–362. 2014. View Article : Google Scholar : PubMed/NCBI
20	Nakatani T, Marui T, Yamamoto T, Kurosaka M, Akisue T and Matsumoto K: Establishment and characterization of cell line TNMY1 derived from human malignant fibrous histiocytoma. Pathol Int. 51:595–602. 2001. View Article : Google Scholar : PubMed/NCBI
21	Krause AK, Hinrichs SH, Orndal C, DeBoer J, Neff JR and Bridge JA: Characterization of a human myxoid malignant fibrous histiocytoma cell line, OH931. Cancer Genet Cytogenet. 94:138–143. 1997. View Article : Google Scholar : PubMed/NCBI
22	Mairal A, Chibon F, Rousselet A, Couturier J, Terrier P and Aurias A: Establishment of a human malignant fibrous histiocytoma cell line, COMA. Characterization by conventional cytogenetics, comparative genomic hybridization, and multiplex fluorescence In situ hybridization. Cancer Genet Cytogenet. 121:117–123. 2000. View Article : Google Scholar : PubMed/NCBI
23	Hakozaki M, Hojo H, Sato M, Tajino T, Yamada H, Kikuchi S and Abe M: Establishment and characterization of a new cell line, FPS-1, derived from human undifferentiated pleomorphic sarcoma, overexpressing epidermal growth factor receptor and cyclooxygenase-2. Anticancer Res. 26(5A): 3393–3401. 2006.PubMed/NCBI
24	Nishio J, Iwasaki H, Nabeshima K, Ishiguro M, Isayama T and Naito M: Establishment of a new human pleomorphic malignant fibrous histiocytoma cell line, FU-MFH-2: Molecular cytogenetic characterization by multicolor fluorescence in situ hybridization and comparative genomic hybridization. J Exp Clin Cancer Res. 29:1532010. View Article : Google Scholar : PubMed/NCBI
25	Steinstraesser L, Jacobsen F, Schubert C, Gevers K, Stricker I, Steinau HU and Al-Benna S: Establishment of a primary human sarcoma model in athymic nude mice. Hum Cell. 23:50–57. 2010. View Article : Google Scholar : PubMed/NCBI
26	Tilkorn DJ, Daigeler A, Hauser J, Ring A, Stricker I, Schmitz I, Steinstraesser L, Steinau HU and Al-Benna S: A novel xenograft model with intrinsic vascularisation for growing undifferentiated pleomorphic sarcoma NOS in mice. J Cancer Res Clin Oncol. 138:877–884. 2012. View Article : Google Scholar : PubMed/NCBI
27	Tilkorn DJ, Stricker I, Hauser J, Ring A, Schmitz I, Steinstraesser L, Steinau HU, Daigeler A and Al-Benna S: Experimental murine model of primary high grade undifferentiated pleomorphic sarcoma not otherwise specified. In Vivo. 26:559–563. 2012.PubMed/NCBI
28	Fletcher CDM, Bridge JA, Hogendoorn P and Mertens F: World Health Organization Classification of Tumours of Soft Tissue and Bone (4th). 5:IARC. Lyon: 2013.
29	Radaelli S, Stacchiotti S, Casali PG and Gronchi A: Emerging therapies for adult soft tissue sarcoma. Expert Rev Anticancer Ther. 14:689–704. 2014. View Article : Google Scholar : PubMed/NCBI
30	Reichardt P: Soft tissue sarcomas, a look into the future: Different treatments for different subtypes. Future Oncol. 10(Suppl 8): s19–s27. 2014. View Article : Google Scholar : PubMed/NCBI
31	Villacis RA, Silveira SM, Barros-Filho MC, Marchi FA, Domingues MA, Scapulatempo-Neto C, Aguiar S Jr, Lopes A, Cunha IW and Rogatto SR: Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker. PLoS One. 9:e1022812014. View Article : Google Scholar : PubMed/NCBI
32	Villacis RA, Silveira SM, Barros-Filho MC, Marchi FA, Domingues MA, Scapulatempo-Neto C, Aguiar S Jr, Lopes A, Cunha IW and Rogatto SR: Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker. PLoS One. 9:e1022812014. View Article : Google Scholar : PubMed/NCBI
33	Versleijen-Jonkers YM, Vlenterie M, van de Luijtgaarden AC and van der Graaf WT: Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit Rev Oncol Hematol. 91:172–185. 2014. View Article : Google Scholar : PubMed/NCBI
34	Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA and Eckhardt SG: Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol. 9:338–350. 2012. View Article : Google Scholar : PubMed/NCBI