Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancer.
Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancer.
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DOI：
10.1186/1471-2407-14-660
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发表时间：
2014-09-10
期刊：
影响因子：
3.8
通讯作者：
Gallick G
中科院分区：
文献类型：
--
作者：
Kopetz S;Morris VK;Parikh N;Overman MJ;Jiang ZQ;Maru D;Elvin P;Gallick G
非受体酪氨酸激酶Src调控多种对肿瘤增殖、化疗耐药和上皮向间充质转化至关重要的通路。急性奥沙利铂暴露后，在体内外获得奥沙利铂耐药的情况下，它被强烈激活，但单独使用5-氟尿嘧啶(5-FU)后则不能。然而，在奥沙利铂治疗的转移性结直肠癌中，Src及其底物粘着斑激酶(FAK)的激活还没有被研究。我们回顾评估了Src和FAK在结直肠癌肝转移中的激活情况，并将这些结果与奥沙利铂治疗的患者的临床结果相关联。采用免疫组织化学方法检测两组170例转移性结直肠癌患者肝组织中Src、激活的Src(PSRC)、FAK和激活的FAK(PFAK)的表达。对第一组患者(120例)的免疫组织化学蛋白表达和生存结果进行了分析。在第二个队列中，组织收集自25名接受连续肝转移切除术的患者(n = 50)。在第一个队列中，Src的激活与pFAK的表达呈正相关(P = 0.44，P <； 0.001)。奥沙利铂联合5-FU组较单用5-FU组和伊立替康/5-FU组pFAK表达增加(P = 0.017)。总的src表达与奥沙利铂新辅助周期数有关(P = 0.047)。在第二个队列中，暴露于奥沙利铂后pFAK的表达更高。根据pFAK和pSRC的表达进行分层后，无复发生存率与pFAK的水平呈负相关(低、中、高水平的pFAK分别为21.1月、16.5月和7.4月；P = 0.026)和pRC(分别为19.6、13.6和8.2月；P = 0.013)。在总体存活率方面没有发现差异。接受新辅助奥沙利铂治疗的患者在肝转移瘤中表现出更高水平的Src通路信号，这一发现与较差的无复发生存率有关。这些结果与之前的体外研究一致，并支持将抑制Src与铂化疗相结合值得进一步研究转移性结直肠癌的观点。本文的在线版本(DOI：10.1186/1471-2407-14-660)包含补充材料，可供授权用户使用。
The nonreceptor tyrosine kinase Src regulates multiple pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. It is robustly activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance in vitro and in vivo, but not after 5-fluorouracil (5-FU) alone. However, activation of Src and its substrate focal adhesion kinase (FAK) in metastatic colorectal cancer treated with oxaliplatin has not been investigated. We retrospectively evaluated the activation of Src and FAK in hepatic metastases of colorectal cancer and correlated these findings with the clinical outcomes of patients treated with oxaliplatin. Samples from 170 hepatic resections from patients with metastatic colorectal cancer from two cohorts were examined by IHC for expression of Src, activated Src (pSrc), FAK, and activated FAK (pFAK). Patients in the first cohort (120 patients) were analyzed for immunohistochemical protein expression and for survival outcomes. In the second cohort, tissue was collected from 25 patients undergoing sequential hepatic metastasectomies (n = 50). In the first cohort, Src activation was positively correlated with pFAK expression (P = 0.44, P < 0.001). Patients pretreated with oxaliplatin and 5-FU demonstrated increased expression of pFAK (P = 0.017) compared with patients treated with 5-FU alone or irinotecan/5-FU. Total Src expression was associated with the number of neoadjuvant cycles of oxaliplatin (P = 0.047). In the second cohort, pFAK expression was higher following exposure to oxaliplatin. When patients were stratified by expression of pFAK and pSrc, an inverse relationship was observed between relapse-free survival rates and levels of both pFAK (21.1 months, 16.5 months, and 7.4 months for low, medium, and high levels of pFAK, respectively; P = 0.026) and pSrc (19.6 months, 13.6 months, and 8.2 months, respectively; P = 0.013). No differences in overall survival were detected. Patients administered neoadjuvant oxaliplatin demonstrated higher levels of Src pathway signaling in hepatic metastases, a finding associated with poorer relapse-free survival. These results are consistent with prior in vitro studies and support the idea that combining Src inhibition with platinum chemotherapy warrants further investigation in metastatic colorectal cancer. The online version of this article (doi:10.1186/1471-2407-14-660) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Griffiths, GJ;Koh, MY;Dive, C
通讯作者：
Dive, C
DOI：
10.1016/j.bbrc.2005.03.012
发表时间：
2005-05-27
影响因子：
3.1
作者：
Roskoski, R
通讯作者：
Roskoski, R
影响因子：
2.7
作者：
Avizienyte, E;Brunton, VG;Frame, MC
通讯作者：
Frame, MC
对结直肠癌的可切除肝转移的FOLFOX4和手术的围手术性化疗（EORTC组间试验40983）：一项随机对照试验。
影响因子：
168.9
作者：
Nordlinger, Bernard;Sorbye, Halfdan;Glimelius, Bengt;Poston, Graeme J.;Schlag, Peter M.;Rougier, Philippe;Bechstein, Wolf O.;Primrose, John N.;Euan, T. Walpole;Finch-Jones, Meg;Jaeck, Daniel;Mirza, Darius;Parks, Rowan W.;Collette, Laurence;Praet, Michel;Bethe, Ullrich;Van Cutsem, Eric;Scheithauer, Werner;Gruenberger, Thomas
通讯作者：
Gruenberger, Thomas
影响因子：
6.2
作者：
Allgayer, H;Boyd, DD;Gallick, GE
通讯作者：
Gallick, GE