In�vivo acquired sorafenib‑resistant patient‑derived tumor model displays alternative angiogenic pathways, multi‑drug resistance and chromosome instability
| العنوان: | In�vivo acquired sorafenib‑resistant patient‑derived tumor model displays alternative angiogenic pathways, multi‑drug resistance and chromosome instability |
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| المؤلفون: | Xueyang Yang, Kunyan Liu, Luyong Zhang, Gang Hu, He Zhou, Weikang Tao, Wang Zongyu, Fubo Xie, Kedong Ouyang, Lei Yang, Xuzhen Tang, Yixin Zhang, Jibin Liu, Fang Houshun, Zhenzhou Jiang |
| المصدر: | Oncology Letters |
| بيانات النشر: | Spandidos Publications, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Sorafenib, Cancer Research, patient-derived xenograft, Angiogenesis, Cell, Drug resistance, 03 medical and health sciences, 0302 clinical medicine, In vivo, fibroblast growth factor, Medicine, Protein kinase B, business.industry, acquired resistance, Articles, hepatocellular carcinoma, Cell cycle, digestive system diseases, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, sorafenib, 030211 gastroenterology & hepatology, Human umbilical vein endothelial cell, business, medicine.drug |
| الوصف: | Acquired resistance to targeted therapies is an important clinical challenge. Research focusing on acquired resistance is hindered by the lack of relevant model systems. In the present study, the generation and characterization of an in vivo acquired sorafenib-resistant hepatocellular carcinoma (HCC) xenograft model derived from a patient tumor is reported. A cancer cell line (LIXC-004SR) was generated from a tumor that had developed following ~100 days of sorafenib treatment of a HCC patient-derived xenograft (PDX) model (LIX004). The xenograft tumors derived from this cell line demonstrated sorafenib-resistance in vivo. By contrast, a cell line (LIXC-004NA) generated from a vehicle-treated LIX004 PDX model remained sensitive to sorafenib in vivo. Following treatment with sorafenib in vivo, angiogenesis was significantly elevated in the LIXC-004SR tumors when compared with that in the LIXC-004NA tumors. The LIXC-004SR cell culture supernatant stimulated human umbilical vein endothelial cell proliferation and extracellular-signal-regulated kinase and protein kinase B phosphorylation, which can only be inhibited by the combination of sorafenib and a fibroblast growth factor receptor 1 (FGFR1) inhibitor, AZD4547. The tumor growth of the sorafenib-resistant LIXC-004SR xenograft was inhibited by the FGFR1 inhibitor in vivo, suggesting that one of the underlying mechanisms of the acquired resistance is likely due to activation of alternative angiogenic pathways. The LIXC-004SR cell line also exhibited signs of multi-drug resistance and genetic instability. Taken together, these data suggest that this in vivo model of acquired resistance from a PDX model may reflect sorafenib-resistance in certain patients and may facilitate drug resistance research, as well as contributing to the clinical prevention and management of drug resistance. |
| تدمد: | 1792-1082 1792-1074 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13395f3a375e925a2d1d06dbe8265d83Test https://doi.org/10.3892/ol.2018.9078Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....13395f3a375e925a2d1d06dbe8265d83 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17921082 17921074 |
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