Abstract 4315: Transgenic expression of human Thymidylate Synthase cooperates with an Ink4a/Arf mutation to enhance tumor progression
Authors: Chen Min , Nawab Akbar , Hoffmann Vickie , Zajac-Kaye Maria 
Published: July 2012

While thymidylate synthase (TS) is an established tumor prognostic biomarker and therapeutic target, it was only recently shown to exhibit an unexpected direct role in tumorgenesis. Overexpression of catalytically active human TS (hTS) transformed rodent cells in vitro and in vivo, while TS missence mutants with loss of enzymatic function were non-transforming (Cancer Cell v5, p341, 2004). In addition, transgenic hTS mice developed hyperplasia and tumors of the endocrine pancreas (Oncogene v26, p4817, 2007). These mice showed high levels of hTS expression in pancreatic tissue and lower levels in most other organs. Since hTS transgenic animals developed islet cell adenomas after long latency, we asked whether deregulated hTS would cooperate with other genetic lesions in the initiation and progression of tumor development. To address this, we have crossed hTS transgenic animals with Ink4a/Arf null mice and evaluated tumor spectra, incidence, latency and tumor burden. The Ink4a/Arf null control mice developed predominantly lymphomas and fibrosarcomas while the hTS/Ink4a/Arf -/- mice develop liposarcoma, rabdomyosarcoma, teratoma, hystiocytic neoplasms as well as fibrosarcoma and lymphoma. Soft tissue sarcomas (excluding fibrosarcoma) were large and developed only in hTS/Ink4a/Arf -/- mice ranging from 2.8 to 10 grams. In addition, tumors isolated from hTS/Ink4a/Arf -/- mice contained blood filled cyst-like structures in the lymph nodes, liver, lung, spleen and pancreas as well as on the surface of teratoma and liposarcoma suggesting increased or dysplastic angiogenesis. The frequency of histiocytic neoplasms in hTS/Ink4a/Arf -/- mice was significantly enhanced (42%) as compared to control mice (8%) and these tumors spread to multiple sites (as many as 9 different organs) as compared to the control mice where tumors were localized predominantly in lymph nodes and spleen. Similarly, lymphomas spread to many extranodal organs, while the control tumors were localized predominantly to lymph nodes or spleen. In summary, we observed that transgenic expression of hTS in Ink4a/Arf null mice accelerated tumor growth leading to more aggressive disease with higher tumor burden. Understanding the mechanism of TS-mediated tumor progression may lead to development of new agents that may act synergistically with known TS inhibitors. The observation that TS promotes tumor growth and it is not just a passive biomarker for cell proliferation will have an important impact for the prevention and treatment of human cancers given the widespread over-expression of TS in the common adult tumors including lymphomas, colorectal, breast, pancreatic, sarcomas and lung cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4315. doi:10.1158/1538-7445.AM2011-4315