ACVP > 2004 ACVP Christopher T. Starost Memorial Oncology Scholarship

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2004 ACVP Christopher T. Starost Memorial Oncology Scholarship

2004 Christopher T. Starost Memorial Oncology Scholarship Abstracts

First Place

AN INTRATIBIAL METASTASIS MODEL OF HUMAN LUNG CANCER: THE ROLE OF THE OSTEOCLAST, AND THE USE OF SERIAL IN VIVO BIOLUMINESCENT IMAGING IN DETERMINING RESPONSE TO THERAPY. S.H. Tannehill-Gregg, A.L. Levine, H. Iguchi*, and T.J. Rosol. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH and *National Kyushu Cancer Center, Fukuoka, Japan.

Certain tumor types have a propensity to metastasize to bone. The pathogenesis of bone metastases often involves, and may require, the activation of osteoclasts by tumor secreted factors, which promote important interactions with the bone microenvironment. Current methods of assessment of effective therapies to combat bone metastases are labor intensive and result in the euthanasia of large numbers of animals. We utilized an intratibial injection model of bone metastasis with serial bioluminescent imaging to monitor the effect of osteoclast inhibition on the interaction of the neoplastic cells with bone, and on overall growth of the tumor. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma), and divided into three groups: (1) untreated, (2) biweekly treatment with a bisphosphonate, or (3) a proprietary anti-osteoclast agent. Mice were euthanized one month after tumor cell injection. Histomorphometry and serial imaging were used to evaluate tumor burden, and parameters of bone resorption and osteoclast activity. Mice in the treated groups demonstrated increased bone density and decreased osteoclast activity. In the bisphosphonate-treated group, tumor growth over time was decreased, as assessed by bioluminescent imaging. The use of serial in vivo bioluminescent imaging to monitor tumor growth over time resulted in the ability to quantify tumor growth and response to therapy using a relatively small number of animals, and was less labor intensive than evaluation by histomorphometry. Bisphosphonates may be useful as inhibitors of bone metastases both by decreasing osteoclast activity and slowing tumor growth.

Second Place:

HUMAN T-LYMPHOTROPIC VIRUS TYPE-1 p30II INTERACTS WITH p300 AND MODULATES VIRAL GENE EXPRESSION. B. Michael, A. Datta, A. Nair, H. Hiraragi, and M. Lairmore. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH.

Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma, and is implicated in a variety of lymphocyte-mediated inflammatory disorders. HTLV-1 provirus has regulatory and accessory genes in four pX open reading frames. HTLV-1 pX ORF-II encodes two proteins, p13II and p30II, which are incompletely defined in virus replication or pathogenesis. We have demonstrated that pX ORF-II mutations diminish the ability of the virus to maintain high viral loads in vivo and that p30II, a nuclear-localizing protein interacts with CREB-binding protein (CBP)/p300, disrupts CREB-Tax-CBP/p300 complexes bound to the viral Tax-Responsive Element repeats (TRE) and differentially modulates CREB and TRE-mediated transcription. Herein, we further characterized the role of p30II in regulation of viral gene expression, by identifying its motifs critical in binding p300 and regulating TRE-mediated transcription. Additionally, we demonstrate that p30II-mediated LTR repression can be rescued by p300 and that lysine 106 (K3) of p30II is critical in LTR repression. We have further characterized the interaction between p30II and p300 and demonstrate that p300 histone acetyl transferase (HAT) mutants do not rescue p30II-mediated LTR repression, unlike wildtype p300. In addition, we also show that p30II is acetylated and that deacetylation by HDAC-1 enhances while inhibition of deacetylation by trichostatin A decreases p30II-mediated HTLV-1 LTR repression. We are the first to demonstrate that HAT activity of p300 is crucial in modulating viral gene expression from the LTR by p30II. Collectively, our data indicates that HTLV-1, a complex retrovirus associated with lymphoproliferative disorders, uses accessory genes to promote cell-to-cell transmission of the virus, clonal expansion of infected cells and maintenance of proviral loads in vivo.

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