Abstract
Abstract Acquired drug resistance represents a major obstacle to effective cancer treatment. Sorafenib is an oral multikinase inhibitor with proven efficacy for various types of advanced solid tumors, including non-small cell lung carcinomas (NSCLC). However, its clinical response is often short lived due to the emergence of acquired resistance. The objective of our ongoing project is to identify potential mechanisms underlying the acquisition of sorafenib resistance using in vivo models of A549 human NSCLC xenograft in athymic nude mice. The in vivo sorafenib-resistant tumor model was established by exposing A549 xenografts to once daily treatment with 40 mg/kg of sorafenib for 4 months. Cells isolated from fresh sorafenib-resistant A549 tumors were propagated in vitro and then reimplanted into the same strain of mice. Tumor tissues obtained from the primary and secondary A549 xenografts were subjected to Western blot and immunohistrochemistry analyses. The in vitro study demonstrated that there was no statistically significant difference in the sensitivity to sorafenib treatment between A549 parental cells and tumor cells derived from sorafenib-resistant A549 xenografts. In the in vivo study, relatively accelerated tumor growth rate was observed in 4 out of 10 sorafenib-treated animals bearing the primary A549 xenografts. Re-implantation of tumor cells derived from the sorafenib-resistant A549 xenografts into the secondary mice showed relatively rapid tumor growth in 6 out of 7 sorafenib-treated tumor bearing animals. Preliminary results from the immunofluorescence analysis of frozen tumor sections revealed that the expression of CD31 and α-smooth muscle actin (α-SMA) in sorafenib-resistant primary A549 tumors was significantly reduced compared with the untreated A549 tumors. In contrast, the expression of α-SMA in the secondary sorafenib-resistant A549 tumors was upregulated as compared with that in the primary A549 tumors, while the CD31 expression in the secondary tumors was similar to that in the primary control tumors. Moreover, in the primary A549 tumors, α-SMA immunofluorescence was often observed immediately adjacent to tumor microvessels; whereas in the secondary sorafenib-resistant tumors, α-SMA immunofluorescence mainly appeared in the stromal cells that were involved in the fibrous sheaths surrounding tumor cell nests. Overall, observations from the preliminary study suggest that the secondary sorafenib-resistant tumors have an increased ability to recruit stromal cells, which in turn promote resistance to sorafenib treatment. Further studies are currently underway to explore the potential mechanism associated with the enhanced recruitment of stromal cells in secondary sorafenib-resistant tumors. Citation Format: Qingyu Stephanie Zhou, Xiaofang Guo. Enhanced recruitment of tumor microenvironment components in A549 xenografts with acquired resistance to sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1387. doi:10.1158/1538-7445.AM2015-1387
Published Version
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