Tumour angiogenesis in Epstein-Barr virus-associated post-transplant smooth muscle tumours

Abstract

Epstein-Barr virus (EBV)-associated post-transplant smooth muscle tumours (PTSMT), are rare complications following organ/stem cell transplantation. Despite the mainly benign behaviour of PTSMT, alternative therapies are needed for those patients with progressive tumours. In tumours not approachable by surgery or reduction of immunosuppression, the angiogenic microenvironment might be a potential target of therapy, an approach that is well utilised in other soft tissue neoplasms. In a previous study, we evaluated the expression of EBV-related genes and the microRNA profile in PTSMT, but so far the characteristics of angiogenesis in PTSMT are not known. Therefore, the aim of this study was to evaluate the expression pattern of angiogenesis-related genes in PTSMT, in order to identify potential target molecules for anti-angiogenic therapy.PTSMT (n = 5 tumours) were compared with uterine leiomyomas (n = 7). Analyses included real-time PCR of 45 angiogenesis-associated genes, immunohistochemistry (CD31, prostaglandin endoperoxide synthase 1/PTGS1) and assessment of tumour vascularisation by conventional histopathology.PTSMT showed similar or fewer vessels than leiomyomas. Of the genes under investigation, 23 were down-deregulated (pro-angiogenic and some anti-angiogenic factors) and five were up-regulated (e.g. PTGS1 which is expressed at very low levels in leiomyomas but moderately higher levels in PTSMT).In summary, no particular target molecule could be identified, because tumour angiogenesis in PTSMT is characterised by low levels of major pro-angiogenic factors and there is no prominent increase in tumour vascularisation. EBV can induce angiogenesis via its viral late membrane protein 1 (LMP1) but PTSMT frequently do not express LMP1, which could be an explanation why, despite EBV infection, PTSMT show no exaggerated tumour angiogenesis.

Non-canonical WNT6/WNT10A signal factor expression in EBV+ post-transplant smooth muscle tumors

“…WNT9B (17q21.32), S phase entry blocker growth arrest specific 1 (GAS1) and serine/threonine protein kinase D1 (PRKD1) were expressed at low levels in PTSMT while the other analyzed tumor types showed higher levels, in particular, leiomyosarcomas. Similar to our previous results [ 7 ], fibroblast growth factor receptor 1 (FGFR1) levels are lower in PTSMT as compared to leiomyomas.…”

“…In our previous works, we found a molecular microenvironment which is not related to EBV infection, but rather to smooth muscle differentiation [ 5 ]. In addition, EBV is able to induce neoangiogenesis, but we found only minor changes on the transcriptional level, including increased levels of angiopoietin 2 (ANGPT2) [ 7 ]. Defining driver mutations in PTSMT are still not known.…”

Prolonged response to exemestane following multiple surgical resections and hormonal therapies in a patient with recurrent endometrial stromal sarcoma

“…Aromatase inhibitors have shown clinical benefit in ESSs although data is limited to case reports and small case series. Aromatase inhibitors block the synthesis of estrogen in peripheral adipose tissue, and directly inhibit aromatase activity in tumor tissue ( Thanopoulou et al, 2014 ). There are two categories of AIs based on their chemical structure: type I AIs are steroidal inhibitors and bind aromatase irreversibly by covalent bonds, while type II AIs are nonsteroidal inhibitors that bind reversibly and covalently with aromatase ( Chan and Fan, 2013 ).…”

“…Additionally biologically significant differences in estrogen concentrations with treatment are likely below the threshold of standard immunoassay detection methods at present, and difficult to confirm as a result ( Dowsett, 1999 ). Given the rarity of ESSs, the results from letrozole and anastrozole treatment have often been reported together, and both have demonstrated clinical benefits when used in hormone receptor positive uterine cancers ( Thanopoulou et al, 2014 ). One small retrospective case series reported an overall response rate of 67% (60% partial response rate, 7% complete response rate), and a 20% stable disease rate in 16 patients with ESS treated with AIs ( Altman et al, 2012 ).…”

“…Adjuvant hormonal therapy options include megestrol or medroxyprogesterone, gonadotropin releasing hormone analogs (GnRHs), and aromatase inhibitors (AIs). Exemestane, a type 1 steroidal irreversible AI, is well tolerated and has shown clinical benefit for hormonally sensitive tumors ( Lindemann et al, 2014 , Thanopoulou et al, 2014 ). Exemestane has been used most commonly in the setting of breast cancer treatment or chemoprevention, but has also been used in endometrial carcinoma and leiomyosarcoma ( Lindemann et al, 2014 , Thanopoulou et al, 2014 , Dunn et al, 2013 , Bliss et al, 2012 ).…”