Date Published: April 24, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Susanna Mannucci, Anna Luzzi, Alessandro Carugi, Alessandro Gozzetti, Stefano Lazzi, Valeria Malagnino, Monique Simmonds, Maria Grazia Cusi, Lorenzo Leoncini, Cornelia A. van den Bosch, Giulia De Falco.
Burkitt lymphoma is endemic in the Equatorial Belt of Africa, its molecular hallmark is an activated, MYC gene mostly due to a chromosomal translocation. Especially in its endemic clinical variant, Burkitt lymphoma is associated with the oncogenic Epstein-Barr virus (EBV), and holoendemic malaria acts as an amplifier. Environmental factors may also cooperate in Burkitt lymphomagenesis in the endemic regions, such as plants used as traditional herbal remedies. Euphorbia tirucalli, a plant known to possess EBV-activating substances, has a similar geographical distribution to endemic Burkitt’s Lymphoma and is used as a hedge, herbal remedy and toy in the Lymphoma BeltI. In this study we aimed at determining if exposure to Euphorbia tirucalli could contribute to lymphomagenesis, and at which extent. Lymphoblastoid and cord blood-derived cell lines were treated with plant extracts, and the expression of EBV-coded proteins was checked, to assess EBV reactivation. The occurrence of chromosomal translocations was then investigated by FISH. Our preliminary results suggest that E. tirucalli is able to reactivate EBV and determine chromosomal alterations, which leads to c-MYC altered expression. The existence of genomic alterations might determine the accumulation of further genetic alteration, which could eventually lead to a transformed phenotype.
Burkitt’s Lymphoma (BL), a high-grade Non-Hodgkin’s lymphoma, is endemic in the Lymphoma Belt of Africa, which lies between 10°N and 10°S of the Equator [1, 2]. Within these geographical boundaries, BL accounts for up to 70% of children cancer with rates up to 10 cases of Burkitt’s Lymphoma per 100,000 children under the age of 14 years . Burkitt’s Lymphoma characteristically has a translocation involving a deregulated, activated, MYC gene on chromosome 8 and immunoglobulin genes on chromosome 14, or, more rarely, chromosomes 2 or 22 , though alternative pathogenetic mechanisms leading to MYC activation have also been described [4, 5]. Burkitt’s Lymphoma is associated with the oncogenic Epstein-Barr virus , in particular, 98% of Burkitt’s Lymphoma cases in the Lymphoma belt show positivity to EBV . EBV is recognised as a Class 1 human carcinogen and is thought to play a pivotal role in lymphomagenesis in endemic Burkitt’s Lymphoma . Holoendemic malaria acts as an amplifier and has been shown to be able to activate the latent EBV in B-lymphocytes in children in the Equatorial Belt [9, 10]. The combination of malaria and early infection with the Epstein-Barr virus is thought to be responsible for boosting the incidence of Burkitt’s lymphoma a hundred-fold in Africa, compared with rates in the France, and the USA [11, 12]. Children who subsequently develop the endemic Burkitt’s Lymphoma have raised antibody levels to the EBV Viral Capsid Antigen (VCA) of EBV several years before they actually develop the tumour . Raised levels of this antibody are also found in the relatives of children with Burkitt’s Lymphoma  and in those who have used traditional herbal remedies , which have been shown to be capable of activating the EBV .
A potential transforming capability by E. tirucalli extracts has been suggested by a single publication in the last twenty years . No further studies have been performed since then to highlight through which molecular mechanisms it occurred. In this study, we report the results on cell proliferation and cell death, expression of EBV-antigens, and induction of chromosomal abnormalities in LCL and cord-blood-derived cell lines after treatment with E. tirucalli plant extracts. Results have been almost completely matching between the two cell lines, though the freshly established cord-blood-derived cell line is more likely to represent the in vivo situation in respect with an LCL, as a prolonged in vitro culture in the latter could determine the accumulation of preexisting genetic abnormalities.