Abstract
Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.
Highlights
The oncogenic c-herpesvirus known as the Kaposi’s sarcomaassociated herpesvirus (KSHV) is a principal causative agent of cancers arising in patients with compromised immune systems [1]
Intraperitoneal injection of KSHV+ BCBL-1 cells into the peritoneal cavity of 6–8 week-old male NOD/SCID mice resulted in rapid tumor growth, massive ascites and splenic enlargement within 3–4 weeks when compared with the PBS-injected control group (Fig. 1A-C)
These markers are expressed on surface for most KSHV+ primary effusion lymphoma (PEL) cell lines isolated from patients, including BCBL-1 [6,15]
Summary
The oncogenic c-herpesvirus known as the Kaposi’s sarcomaassociated herpesvirus (KSHV) is a principal causative agent of cancers arising in patients with compromised immune systems [1] One of these cancers, primary effusion lymphoma (PEL), is composed of transformed B cells harboring KSHV episomes and arises preferentially within the pleural or peritoneal cavities of patients infected with HIV [2]. Use of combination cytotoxic chemotherapies represents the standard approach for PEL [4,5], but the toxicity of systemic chemotherapy synergizes with those caused by antiretroviral therapy or immune suppression, further limiting treatment efficacy [3,4,6]. Several novel approaches for PEL therapy that increase the survival for some patients have been reported in recent studies, but a lack of sufficient safety and efficacy data have precluded their routine use. Here we used a KSHV+ PEL xenograft model, employing body cavity-based lymphoma cells (BCBL-1) and non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, to characterize PEL cells from effusions and solid tumors in the model, and compared these cells with their counterparts passed in cell culture
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