Injection of human primary effusion lymphoma cells or associated macrophages into severe combined immunodeficient mice causes murine lymphomas.
ABSTRACT The pathogenesis of immunodeficiency-associated lymphoma is poorly understood. During the past several years, numerous lines of evidence implicating a multistep process of malignant transformation, also known as sequential pathogenesis, have emerged. Tumor-associated macrophage production of specific lymphostimulatory products has been demonstrated and hypothesized to be central to this process. While attempting to establish primary effusion lymphoma in severe combined immunodeficient (SCID) mice, we discovered a potential model of murine lymphomagenesis consistent with the sequential pathogenesis model. This pathogenesis-based model of lymphoma could significantly impact the current thinking about posttransplantation and other immunodeficiency-related lymphoproliferative disorders. Human primary effusion lymphoma-derived CD14+ cell-injected SCID mice developed aggressive murine large cell lymphomas. Tumor cell preparations containing CD14 cells or isolated CD14 cells induced lymphoma/lymphoproliferative diseases in 74% (20 of 27) of injected SCID mice. No tumors were induced by tumor-associated CD3 cells (0 of 4), normal human macrophages (0 of 13), or a murine macrophage cell line (0 of 10). Human macrophages were detected in tumor-bearing animals up to 6 months postinjection in association with the murine T-cell tumors but were not detected in controls or unaffected animals. These observations are consistent with the macrophage-initiated sequential pathogenesis model of disease (M. S. McGrath et al., Acquir. Immune Defic. Syndr., 8: 379-385, 1995; M. S. McGrath et al., Infectious Causes of Cancer: Targets for Intervention, pp. 231-242, Totowa, NJ: Humana Press, 2000).
[show abstract] [hide abstract]
ABSTRACT: HIV-infected individuals are at risk for developing certain types of cancers. While there are data to show that non-random HIV integration may occur, our goal was to identify preferential genomic sites where HIV integration might be targeted leading to oncogenesis. Initially, a linker-primer PCR strategy was used to identify HIV integration in isolated macrophages. Inverse-PCR was then used to analyze specimens from patients diagnosed with HIV-associated malignancies. From isolated macrophages, integration near a toll-like receptor on chromosome 4 was found. Necropsy tissues from 11 cases were analyzed with 1 tumor specimen found to have HIV integrated in chromosome 22q13.2 and within 300 kb of HSCBCIP1 (CAP-binding protein complex interacting homologue). Tumor-specific primers were then used to screen uninvolved tissue from the same patient, which did not amplify the site-specific region. This report demonstrates that in both an in vitro system and human malignant tissue, specific viral integration can be identified.Cellular and molecular biology 02/2004; 50 Online Pub:OL581-9. · 0.98 Impact Factor