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Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Clinical relevance of peroxisome proliferator-activated receptor-gamma expression in myxoid liposarcoma

Authors: Akihiko Takeuchi, Norio Yamamoto, Toshiharu Shirai, Katsuhiro Hayashi, Shinji Miwa, Seiichi Munesue, Yasuhiko Yamamoto, Hiroyuki Tsuchiya

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. PPARγ is essential in adipocyte differentiation from precursor cells. Its antitumorigenic effects are reported in certain malignancies; however, its effects in liposarcoma are unclear.

Methods

We analyzed PPARγ expression using immunohistochemistry (IHC) in 46 patients with myxoid liposarcoma [MLS; median age, 47 years (range, 14–90 years) and mean follow-up period, 91 months (range, 13–358 months)]. PPARγ mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction. Further, we evaluated the correlation of PPARγ expression with clinical outcomes.

Results

We found that the metastasis-free survival rate was significantly higher in lower PPARγ expressers [34 patients with labeling index (LI) <50 %] than in higher expressers (12 patients with LI ≥50 %; p = 0.01). Cox multivariate analysis revealed that a higher PPARγ level was an independent predictor of metastasis (relative risk = 6.945, p = 0.026). Furthermore, using 28 fresh MLS specimens, we confirmed an increased PPARγ mRNA expression level in the higher LI group (p = 0.001).

Conclusions

In this study, higher PPARγ expression in MLS was a risk factor associated with distant metastasis; therefore, it would be a novel prognostic marker for MLS. Further analyses will help to understand the correlation between PPARγ expression and tumor malignancy in liposarcoma.
Literature
1.
go back to reference Goldblum JR, Folpe AL, Weiss SW. Liposarcoma. In: Goldblum JR, Folpe AL, Weiss SW, editors. Enzinger & Weiss’s soft tissue tumors. 6th ed. Philadelphia: Elsevier; 2013. p. 484–523. Goldblum JR, Folpe AL, Weiss SW. Liposarcoma. In: Goldblum JR, Folpe AL, Weiss SW, editors. Enzinger & Weiss’s soft tissue tumors. 6th ed. Philadelphia: Elsevier; 2013. p. 484–523.
2.
go back to reference Antonescu CR, Ladanyi M. Myxoid liposarcoma. In: Fletcher CD, Hogendoorn P, Mertens F, Bridge J, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 39–41. Antonescu CR, Ladanyi M. Myxoid liposarcoma. In: Fletcher CD, Hogendoorn P, Mertens F, Bridge J, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 39–41.
3.
go back to reference Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol. 1996;20:171–80.CrossRefPubMed Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol. 1996;20:171–80.CrossRefPubMed
4.
go back to reference Grozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993;363:640–4.CrossRef Grozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993;363:640–4.CrossRef
5.
go back to reference Rabbitts TH, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 1993;4:175–80.CrossRefPubMed Rabbitts TH, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 1993;4:175–80.CrossRefPubMed
6.
go back to reference Demicco EG, Torres KE, Ghadimi MP, Colombo C, Bolshakov S, Hoffman A, et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod Pathol. 2012;25:212–21.CrossRefPubMed Demicco EG, Torres KE, Ghadimi MP, Colombo C, Bolshakov S, Hoffman A, et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod Pathol. 2012;25:212–21.CrossRefPubMed
7.
go back to reference Pitson G, Robinson P, Wilke D, Kandel RA, White L, Griffin AM, et al. Radiation response: an additional unique signature of myxoid liposarcoma. Int J Radiat Oncol Biol Phys. 2005;60:522–6.CrossRef Pitson G, Robinson P, Wilke D, Kandel RA, White L, Griffin AM, et al. Radiation response: an additional unique signature of myxoid liposarcoma. Int J Radiat Oncol Biol Phys. 2005;60:522–6.CrossRef
8.
go back to reference Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41:2853–60.CrossRefPubMed Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41:2853–60.CrossRefPubMed
9.
go back to reference Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, et al. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 2002;16:22–6.CrossRefPubMedPubMedCentral Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, et al. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 2002;16:22–6.CrossRefPubMedPubMedCentral
10.
go back to reference Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, et al. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998;1:465–70.CrossRefPubMed Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, et al. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998;1:465–70.CrossRefPubMed
11.
go back to reference Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell. 1999;3:799–804.CrossRefPubMed Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell. 1999;3:799–804.CrossRefPubMed
12.
go back to reference Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A. 2000;97:10990–5.CrossRefPubMedPubMedCentral Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A. 2000;97:10990–5.CrossRefPubMedPubMedCentral
13.
go back to reference Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science. 2000;289:1357–60.CrossRefPubMed Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science. 2000;289:1357–60.CrossRefPubMed
14.
go back to reference Takeuchi A, Yamamoto N, Nishida H, Kimura H, Ikeda H, Tsuchiya H. Complete necrosis of a giant cell tumor with high expression of PPARγ: a case report. Anticancer Res. 2013;33:2169–74.PubMed Takeuchi A, Yamamoto N, Nishida H, Kimura H, Ikeda H, Tsuchiya H. Complete necrosis of a giant cell tumor with high expression of PPARγ: a case report. Anticancer Res. 2013;33:2169–74.PubMed
15.
go back to reference Tajima T, Morii T, Kikuchi F, Matsumine A, Murata H, Nobuto H, et al. Significance of LRP and PPAR-gamma expression in lipomatous soft tissue tumors. Open Orthop J. 2010;4:48–55.CrossRefPubMedPubMedCentral Tajima T, Morii T, Kikuchi F, Matsumine A, Murata H, Nobuto H, et al. Significance of LRP and PPAR-gamma expression in lipomatous soft tissue tumors. Open Orthop J. 2010;4:48–55.CrossRefPubMedPubMedCentral
16.
go back to reference Green FL, Page DL, Fleming ID, Fritz AG, Balch CM, et al. Soft tissue sarcoma. In: AJCC (American Joint Committee on Cancer) cancer staging manual. 6th ed. New York: Springer; 2002. p. 193–200.CrossRef Green FL, Page DL, Fleming ID, Fritz AG, Balch CM, et al. Soft tissue sarcoma. In: AJCC (American Joint Committee on Cancer) cancer staging manual. 6th ed. New York: Springer; 2002. p. 193–200.CrossRef
17.
go back to reference Scotlandi K, Serra M, Manara MC, Maurici D, Benini S, Nini G, et al. Clinical relevance of Ki-67 expression in bone tumors. Cancer. 1995;75:806–14.CrossRefPubMed Scotlandi K, Serra M, Manara MC, Maurici D, Benini S, Nini G, et al. Clinical relevance of Ki-67 expression in bone tumors. Cancer. 1995;75:806–14.CrossRefPubMed
18.
go back to reference Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997;94:237–41.CrossRefPubMedPubMedCentral Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997;94:237–41.CrossRefPubMedPubMedCentral
19.
go back to reference Nishida Y, Tsukushi S, Nakashima H, Ishiguro N. Clinicopathologic prognostic factors of pure myxoid liposarcoma of the extremities and trunk wall. Clin Orthop Relat Res. 2010;468:3041–6.CrossRefPubMedPubMedCentral Nishida Y, Tsukushi S, Nakashima H, Ishiguro N. Clinicopathologic prognostic factors of pure myxoid liposarcoma of the extremities and trunk wall. Clin Orthop Relat Res. 2010;468:3041–6.CrossRefPubMedPubMedCentral
20.
go back to reference ten Heuvel SE, Hoekstra HJ, van Ginkel RJ, Bastiaannet E, Suurmeijer AJ. Clinicopathologic prognostic factors in myxoid liposarcoma: a retrospective study of 49 patients with long-term follow-up. Ann Surg Oncol. 2007;14:222–9.CrossRefPubMed ten Heuvel SE, Hoekstra HJ, van Ginkel RJ, Bastiaannet E, Suurmeijer AJ. Clinicopathologic prognostic factors in myxoid liposarcoma: a retrospective study of 49 patients with long-term follow-up. Ann Surg Oncol. 2007;14:222–9.CrossRefPubMed
21.
go back to reference Kilpatrick SE, Doyon J, Choong PF, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996;77:1450–8.CrossRefPubMed Kilpatrick SE, Doyon J, Choong PF, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996;77:1450–8.CrossRefPubMed
22.
go back to reference Cheng EY, Springfield DS, Mankin HJ. Frequent incidence of extrapulmonary sites of initial metastasis in patients with liposarcoma. Cancer. 1995;75:1120–7.CrossRefPubMed Cheng EY, Springfield DS, Mankin HJ. Frequent incidence of extrapulmonary sites of initial metastasis in patients with liposarcoma. Cancer. 1995;75:1120–7.CrossRefPubMed
23.
go back to reference Asano N, Susa M, Hosaka S, Nakayama R, Kobayashi E, Takeuchi K, et al. Metastatic patterns of myxoid/round cell liposarcoma: a review of a 25-year experience. Sarcoma. 2012;2012:345161.CrossRefPubMedPubMedCentral Asano N, Susa M, Hosaka S, Nakayama R, Kobayashi E, Takeuchi K, et al. Metastatic patterns of myxoid/round cell liposarcoma: a review of a 25-year experience. Sarcoma. 2012;2012:345161.CrossRefPubMedPubMedCentral
24.
go back to reference Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest. 2002;110:923–32.CrossRefPubMedPubMedCentral Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest. 2002;110:923–32.CrossRefPubMedPubMedCentral
25.
go back to reference Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, et al. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A. 1998;95:8806–11.CrossRefPubMedPubMedCentral Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, et al. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A. 1998;95:8806–11.CrossRefPubMedPubMedCentral
26.
go back to reference Kristiansen G, Jacob J, Buckendahl AC, Grützmann R, Alldinger I, Sipos B, et al. Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res. 2006;12:6444–51.CrossRefPubMed Kristiansen G, Jacob J, Buckendahl AC, Grützmann R, Alldinger I, Sipos B, et al. Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res. 2006;12:6444–51.CrossRefPubMed
27.
go back to reference Forootan FS, Forootan SS, Malki MI, Chen D, Li G, Lin K, et al. The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer. Int J Oncol. 2014;44:265–75.PubMed Forootan FS, Forootan SS, Malki MI, Chen D, Li G, Lin K, et al. The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer. Int J Oncol. 2014;44:265–75.PubMed
28.
go back to reference Zhang GY, Ahmed N, Riley C, Oliva K, Barker G, Quinn MA, et al. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer. 2005;92:113–9.CrossRefPubMed Zhang GY, Ahmed N, Riley C, Oliva K, Barker G, Quinn MA, et al. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer. 2005;92:113–9.CrossRefPubMed
29.
go back to reference Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.CrossRefPubMed Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.CrossRefPubMed
30.
go back to reference Debrock G, Vanhentenrijk V, Sciot R, Debiec-Rychter M, Oyen R, Van Oosterom A. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer. 2003;89:1409–12.CrossRefPubMedPubMedCentral Debrock G, Vanhentenrijk V, Sciot R, Debiec-Rychter M, Oyen R, Van Oosterom A. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer. 2003;89:1409–12.CrossRefPubMedPubMedCentral
31.
go back to reference Pishvaian MJ, Marshall JL, Wagner AJ, Hwang JJ, Malik S, Cotarla I, et al. A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies. Cancer. 2012;118:5403–13.CrossRefPubMedPubMedCentral Pishvaian MJ, Marshall JL, Wagner AJ, Hwang JJ, Malik S, Cotarla I, et al. A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies. Cancer. 2012;118:5403–13.CrossRefPubMedPubMedCentral
32.
go back to reference Pérez-Losada J, Pintado B, Gutiérrez-Adán A, Flores T, Bañares-González B, del Campo JC, et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene. 2000;19:2413–22.CrossRefPubMed Pérez-Losada J, Pintado B, Gutiérrez-Adán A, Flores T, Bañares-González B, del Campo JC, et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene. 2000;19:2413–22.CrossRefPubMed
33.
go back to reference Gronchi A, Bui BN, Bonvalot S, Pilotti S, Ferrari S, Hohenberger P, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol. 2012;23:771–6.CrossRefPubMed Gronchi A, Bui BN, Bonvalot S, Pilotti S, Ferrari S, Hohenberger P, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol. 2012;23:771–6.CrossRefPubMed
34.
go back to reference Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, et al. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther. 2009;8:449–57.CrossRefPubMed Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, et al. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther. 2009;8:449–57.CrossRefPubMed
35.
go back to reference Guo S, Lopez-Marquez H, Fan KC, Choy E, Cote G, Harmon D, et al. Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma. PLoS One. 2014;9:e93996.CrossRefPubMedPubMedCentral Guo S, Lopez-Marquez H, Fan KC, Choy E, Cote G, Harmon D, et al. Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma. PLoS One. 2014;9:e93996.CrossRefPubMedPubMedCentral
Metadata
Title
Clinical relevance of peroxisome proliferator-activated receptor-gamma expression in myxoid liposarcoma
Authors
Akihiko Takeuchi
Norio Yamamoto
Toshiharu Shirai
Katsuhiro Hayashi
Shinji Miwa
Seiichi Munesue
Yasuhiko Yamamoto
Hiroyuki Tsuchiya
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2524-6

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