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Non-Canonical WNT6/WNT10A Signal Factor Expression in EBV+ Post Teiken et al. Clin Sarcoma Res (2018) 8:10 https://doi.org/10.1186/s13569-018-0096-8 Clinical Sarcoma Research RESEARCH Open Access Non‑canonical WNT6/WNT10A signal factor expression in EBV post‑transplant smooth muscle tumors + Kristin Teiken1*†, Mark Kuehnel1†, Jan Rehkaemper2, Hans Kreipe1, Florian Laenger1, Kais Hussein1 and Danny Jonigk1 Abstract Post-transplant smooth muscle tumors (PTSMTs) are rare mesenchymal neoplasms which occur after solid organ or haematopoietic stem cell transplantation. PTSMT typically consist of Epstein–Barr-virus (EBV) smooth muscle-like cells and show an intermediate malignancy. Their main occurrences are visceral organs, especially+ the liver, but intrac- ranial appearances are described and associated with a poor prognosis. EBV drives the growth of PTSMT; however, the underlying molecular mechanisms still remain unclear. Gene expression analysis of a set of morphologically similar tumors (leiomyomas, leiomyosarcomas, angioleiomyomas and endothelial haemangiomas) from patients without immunosuppression or EBV-association was performed. Our fndings indicate that PTSMT’s growth is driven by two factors of the wingless-type protein family: WNT6 and WNT10A. We are frst to report that in PTSMTs, a non-canonical activation of WNT, independent of beta-catenin, drives tumor cell proliferation via MTOR/AKT1, MYC and Cyclin D2. Keywords: PTSMT, Post-transplant smooth muscle tumors, Angioleiomyomas, EBV, WNT Background patients [5]) but represent an important clinical and radi- Tumors with predominant or partial smooth muscle dif- ological diferential diagnosis in immune-compromised ferentiation make up a broad spectrum of mesenchymal patients, particularly to post-transplant lymphoprolifera- neoplasms. Most of these tumors are based on sponta- tive diseases (PTLD). In PTSMT, the site of manifesta- neous mutations of a mesenchymal stem cell. A rare and tion determines the patients’ outcome [2]. In particular, virus-associated entity are the post-transplant smooth cerebral PTSMT has a poor prognosis, while histological muscle tumors (PTSMT) [1, 2]. Tese tumors are typi- features (mitotic rate, cellular atypia, and necrosis) have cally positive for the Epstein–Barr virus (EBV) and can no prognostic impact [1]. manifest themselves at any time and in any organ after Epstein–Barr virus is specialized to infect B cells and transplantation [1]. Similar neoplasms can also occur almost all adults harbor a small population of EBV+ non- in any other immunosuppressive condition, in particu- neoplastic B cells, which are controlled by T cell homeo- lar after infection with human immunodefciency virus stasis. It is not known how EBV enters non-B cell tissues, (HIV; HIV-SMT) or congenital immune defects (CI- such as mesenchymal cells. It is thought that the PTSMT SMT) [1, 3, 4]. cell of origin is derived from a perivascular non-endothe- Post-transplant smooth muscle tumors are rare in lial mesenchymal smooth muscle stem cell. EBV+ regard to the total population (< 1% of transplanted PTSMT have a type III-like latency with expression of EBV protein EBNA (Epstein–Barr nuclear antigen) but often lack EBV latent membrane protein 1 (LMP1) *Correspondence: Teiken.Kristin@mh‑hannover.de expression [6]. Te tumorigenic role of EBV in smooth † Kristin Teiken and Mark Kuehnel contributed equally to this work muscle neoplasms is not clear because particularly HIV- 1 Institute of Pathology, Hannover Medical School (MHH), Carl‑Neuberg‑Str. 1, 30625 Hannover, Germany SMT can be EBV negative, indicating that the virus is not Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Teiken et al. Clin Sarcoma Res (2018) 8:10 Page 2 of 8 absolutely necessary for aberrant smooth muscle prolif- uncertain and aberrant myogenous venous wall cells eration [1]. are still under discussion as the cells of origin [2, 8]. In our previous works, we found a molecular microenvi- Before performing molecular analysis, the angioleio- ronment which is not related to EBV infection, but rather myomas were histologically sub grouped according to to smooth muscle diferentiation [5]. In addition, EBV is the old but current standard of Morimoto [9] (13/28 able to induce neoangiogenesis, but we found only minor capillary solid, 7/28 venous, 5/28 cavernous, 3/28 changes on the transcriptional level, including increased mixed capillary-cavernous). All samples of forma- levels of angiopoietin 2 (ANGPT2) [7]. Defning driver lin fixed and paraffin-embedded (FFPE) tumors were mutations in PTSMT are still not known. However, we selected from the archive of the Institutes of Pathology and others found up-regulation of MYC proto-oncogene in Muenster (12/28 angioleiomyomas) and Hannover transcripts, protein expression of phosphorylated mecha- (all other samples). nistic target of rapamycin kinase (MTOR) and phospho- rylated AKT serine/threonine kinase 1 (AKT1) signaling Transcript expression analysis factors [2, 6]. Samples contained > 80% tumor tissue and RNA was In the present analyses we wanted to asses if and which extracted and purifed with our established mineral oil transcript profle of mesenchymal stem cell and signaling method and RNeasy Mini Kit (Qiagen, Hilden, Ger- factors difer between PTSMT and other neoplasms with many) via Maxwell ® system (Promega cooperation, smooth muscle diferentiation. Mannheim, Germany). RNA was quantifed by Qubit® 2.0 fuorometer (Life Technologies/Termo Fisher Sci- Methods entifc, Waltham, MA, USA). Transcript expression Tumor samples analysis was performed via NanoString nCounter™ sys- EBV+ PTSMTs comprised six tumors from fve patients; tem. NanoString uses digital fuorescent reporters for one patient had a tumor in the spleen and another in a gene detection and enables analysis of small amount of cerebral sinus. We previously reported the clinical and RNA while minimizing background signals. We used histopathological characteristics of four of these patients the prefabricated stem cell panel (includes 193 target [2]. Te ffth patient was a female (age: 61 years) who genes and six endogenous control genes) as described developed a PTSMT in the liver 5 years after kidney in the manufacturer’s protocol (NanoString Technolo- transplantation (tumor diameter 3.1 cm, 10% Ki67, posi- gies, Seattle, WA, USA). Endogenous control genes were tive for EBV in situ hybridization (EBER), smooth muscle glucuronidase beta (GUSB), glyceraldehyde-3-phosphate actin, caldesmon and desmin). dehydrogenase (GAPDH), clathrin heavy chain (CLTC), For control purposes, the following tumors were hypoxanthine phosphoribosyltransferase 1 (HPRT1), analyzed (Table 1, Fig. 1): (i) smooth muscle tumors phosphoglycerate kinase 1 (PGK1) and tubulin beta class (nine visceral leiomyomas and four central venous I (TUBB). G1–2 leiomyosarcomas) and (ii) mixed smooth mus- cle and vascular tumors (28 with different histological Immunohistochemistry subtypes of angioleiomyomas). Additionally, we added Deparafnized and rehydrated FFPE tissue sections (iii) a vascular tumor control group (five endothelial (1–2 μm) were processed in an automated staining sys- haemangiomas), as the actual origin of PTSMT is still tem (Benchmark ULTRA, Ventana Medical Systems, Inc., Table 1 Sample set and clinical data Entities PTSMT Leiomyoma (LM) Leiomyosarcoma (LMS) Angioleiomyoma Endothelial haeman- (ALM) gioma (EHA) Number of n 6 (5 patients) n 9 n 4 n 28 n 5 tumors = = = = = Age (median, 11.5 (6–61) 60 (29–71) 63 (45–71) 60 (23–79) 48 (32–58) range) Gender ♀ 100% ♀ 89% ♀ 75% ♀ 64% ♀ 60% ♂ 0% ♂ 11% ♂ 25% ♂ 36% ♂ 40% Tumor localisation Kidney (n 2) Stomach (n 3) Pulmonary artery (n 2) Lower extremities Lower extremities (n 3) Lung (n = 1) Kidney (n =2) Right atrium (n 1) = (n 13) Head–Neck (n 1) = Colon (n= 1) Skin (n 2)= Adrenal gland vein= Upper= extremities (n 2) Mediastinal (n = 1) Spleen (n= 1) Esophagus= (n 1) (n 1) Head–Neck (n 3) = = = = = = Confuens sinuum (n 1) Mesenterium (n 1) Genital ♀ (n 2) = = Skin/soft tissue= (n 8) = Teiken et al. Clin Sarcoma Res (2018) 8:10 Page 3 of 8 Fig. 1 Histological appearance of the fve diferent entities. a Post transplant smooth muscle tumor (haematoxylin–eosin stain (HE stain, 100 ) × with inserted positive EBV-in situ hybridization (EBER), b visceral leiomyoma (HE stain, 100 ), c visceral leiomyosarcoma of the central venous tract × (right atrium, HE stain, 100 ) with prominent atypia and increased level of mitosis fgures, d endothelial haemangioma (HE stain, 100 ) with promi- × × nent vessels, e angioleiomyoma (HE stain, 50 ), in particular venous subtype with prominently walled vessels (arrows) × Tucson, AZ, USA). A monoclonal anti-beta-catenin anti- comparisons. P values < 0.05 were considered as statisti- body was used. cally signifcant. Heatmaps were generated using R. Data analysis Results Raw data of transcript target gene expression were ana- Increased WNT6/WNT10A levels in PTSMT lyzed by nSolver™ software (NanoString Technologies)
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