期刊论文详细信息
Clinical Epigenetics
Decreased efficacy of drugs targeting the vascular endothelial growth factor pathway by the epigenetic silencing of FLT1 in renal cancer cells
Jei Kim6  Sukhoon Lee1  Byung Hoon Kim3  Kyu Sang Song4  Jin Man Kim4  Jae Sung Lim7  Hyeseon Jeong2  Jaroslav Jelinek5  Hyo Jin Lee8  Seo Hyun Lee1  Junha Hwang2  Jee Yeon Kim2 
[1] Department of Information and Statistics, College of Natural Science, Chungnam National University, Daejeon, South Korea;Neuroepigenetics Laboratory and Department of Neurology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Department of Urology, Hospital and School of Medicine, Keimyung University, Daegu, South Korea;Department of Pathology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA;Department of Neurology, Chungnam National University Hospital, 282 Moonhwa-ro, Daejeon, Joong-gu, South Korea;Department of Urology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Department of Internal Medicine, Cancer Research Institute, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea
关键词: Renal cancer;    Axitinib;    Sunitinib;    Tyrosine kinase inhibitor;    Anti-vascular endothelial growth factor antibody;    Vascular endothelial growth factor receptor;    Vascular endothelial growth factor;   
Others  :  1225840
DOI  :  10.1186/s13148-015-0134-9
 received in 2015-04-04, accepted in 2015-09-07,  发布年份 2015
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【 摘 要 】

Background

The vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling pathway is involved in cancer-related biological functions and is a therapeutic target in cancer. However, the influence of epigenetic regulation of VEGF-VEGFR signaling-related genes remains unclear. Here, we evaluated the effects of FLT1 and KDR promoter hypermethylation combined with drugs targeting VEGF-VEGFR signaling on cancer-related phenotypes in renal cancer cells (RCCs) and examined changes in FLT1 and KDR promoter hypermethylation in tissues from patients with renal cancer.

Results

In vitro experiments were performed to evaluate the effects of beavacizumab (an anti-VEGF antibody), an anti-FLT1 peptide, an anti-KDR antibody, and the VEGFR tyrosine kinase inhibitors (TKIs) sunitinib and axitinib in 13 RCC lines with different levels of FLT1 and/or KDR promoter methylation and in 2 FLT1 or KDR in vitro knockdown models. The synergistic effects of sunitinib and axitinib treatment were also evaluated in four RCC lines having different levels of FLT1 and/or KDR methylation. In our in vitro experiments, bevacizumab and an anti-KDR antibody did not affect the proliferation of RCCs having FLT1 and/or KDR hypermethylation. In contrast, in RCCs with FLT1 hypermethylation, proliferation inhibition was counteracted by treatment with an anti-FLT1 peptide and both VEGF-TKIs (sunitinib and axitinib). Demethylation with sunitinib or axitinib synergistically increased proliferation inhibition in the RCCs exhibiting FLT1 hypermethylation. Using in vitro FLT1 or KDR knockdown models, decreased proliferation inhibition following anti-FLT1 peptide, sunitinib, and axitinib treatment was observed only in FLT1-knockdown cells. In patients with renal cancer who received sunitinib, FLT1 promoter methylation was higher in renal cancer tissues from eight nonresponders (stable or progressive disease assessed by the Response Evaluation Criteria in Solid Tumors) than in cancer tissues from five responders (complete response or partial response).

Conclusions

The present data showed that hypermethylated FLT1 was important for the efficacy of anti-VEGF/VEGFR drugs targeting FLT1 or intracellular VEGFR signaling. FLT1 hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in FLT1 status in RCCs.

【 授权许可】

   
2015 Kim et al.

【 预 览 】
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【 参考文献 】
  • [1]Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005, 23:1011-27.
  • [2]Sitohy B, Nagy JA, Dvorak HF: Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 2012, 72:1909-04.
  • [3]Sherwood LM, Parris EE: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182-6.
  • [4]Kim J, Hwang J, Jeong H, Song HJ, Shin J, Hur G, et al.: Promoter methylation status of VEGF receptor genes: a possible epigenetic biomarker to anticipate the efficacy of intracellular-acting VEGF-targeted drugs in cancer cells. Epigenetics 2012, 7:191-200.
  • [5]Kim JY, Hwang JH, Zhou W, Shin J, Noh SM, Song IS, et al.: The expression of VEGF receptor genes is concurrently influenced by epigenetic gene silencing of the genes and VEGF activation. Epigenetics 2009, 4:313-21.
  • [6]Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92(3):205-16.
  • [7]Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al.: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997, 57(20):4593-9.
  • [8]Bae DG, Kim TD, Li G, Yoon WH, Chae CB: Anti-FLT1 peptide, a vascular endothelial growth factor receptor 1-specific hexapeptide, inhibits tumor growth and metastasis. Clin Cancer Res 2005, 11:2651-61.
  • [9]Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, et al.: Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev 1998, 17(2):155-61.
  • [10]Gotink KJ, Verheul HM: Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010, 13:1-14.
  • [11]Jones PA, Baylin SB: The epigenomics of cancer. Cell 2007, 128(4):683-92.
  • [12]Dawson MA, Kouzarides T: Cancer epigenetics: from mechanism to therapy. Cell 2012, 150:12-27.
  • [13]Sato K, Terada K, Sugiyama T, Takahashi S, Saito M, Moriyama M, et al.: Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J Exp Med 1994, 173(3):355-60.
  • [14]Hervé MA, Buteau-Lozano H, Vassy R, Bieche I, Velasco G, Pla M, et al.: Overexpression of vascular endothelial growth factor 189 in breast cancer cells leads to delayed tumor uptake with dilated intratumoral vessels. Am J Pathol 2008, 172:167-78.
  • [15]Duncan TJ, Al-Attar A, Rolland P, Scott IV, Deen S, Liu DT, et al.: Vascular endothelial growth factor expression in ovarian cancer: a model for targeted use of novel therapies? Clin Cancer Res 2008, 14:3030-5.
  • [16]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350(23):2335-42.
  • [17]Sobrero AF, Bruzzi P: Vatalanib in advanced colorectal cancer: two studies with identical results. J Clin Oncol 2011, 29:1938-40.
  • [18]Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. doi:. 10.1126/scisignal.2004088 webcite
  • [19]Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al.: The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012, 2:401-4.
  • [20]Kawamoto K, Hirata H, Kikuno N, Tanaka Y, Nakagawa M, Dahiya R: DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines. Int J Cancer 2008, 123:535-42.
  • [21]Hwang E, Lee HJ, Sul CK, Lim JS: Efficacy and safety of sunitinib on metastatic renal cell carcinoma: a single-institution experience. Korean J Urol 2010, 51:450-5.
  • [22]Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5:649-55.
  • [23]Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999, 17:2530-40.
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