Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling.
Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling.
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DOI：
10.1002/hep.28755
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发表时间：
2016-11
期刊：
影响因子：
13.5
通讯作者：
Wells, Alan
中科院分区：
文献类型：
--
作者：
Ma, Bo;Wheeler, Sarah E.;Clark, Amanda M.;Whaley, Diana L.;Yang, Min;Wells, Alan
肝脏是癌症转移的最常见部位之一。一旦扩散，预后很差，因为这些肿瘤通常表现出广泛的化疗耐药性，特别是对于非呼吸消化道来源的癌。当这些癌症在肝脏中播种时，侵袭性细胞通常经历间充质到上皮的回复转变（MErT），这既有助于定植又使肿瘤细胞具有化学抗性。体外研究表明，肝细胞驱动这种表型转变。然而，体内证据和保护这些细胞免于诱导死亡的分子信号尚未确定。在此，我们报告，膜表面的E-cadherin表达的前列腺癌（PCa）细胞耐化疗药物的细胞死亡，但E-cadherin空或那些只在细胞质中表达E-cadherin的细胞在体外和体内的死亡信号和化疗敏感。虽然细胞-细胞E-钙粘蛋白配体减少有丝分裂，但这种化学保护是增殖无关的，因为EdU+（或Ki 67+）和EdU-（Ki 67-）细胞的杀伤与膜结合的E-钙粘蛋白呈负相关。细胞外信号调节蛋白激酶（ERK）、蛋白激酶B（PKB/AKT）和janus激酶（JAK）是典型的存活激酶，它们在上皮转化的PCa中被化疗剂激活，抑制它们在细胞培养物和转移癌动物模型中消除了化学抗性。对于播散性肿瘤，AKT破坏本身对肿瘤存活没有影响，但与化疗协同作用，导致杀伤增加。结论：肝微环境驱动的癌细胞表型转换和随后的存活信号传导导致典型存活途径的激活，其以增殖非依赖性方式保护播散性PCa肝微转移，并且这些途径可以作为辅助治疗的靶向，以提高传统化疗药物的功效。
Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition (MErT) that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence, and the molecular signals that protect these cells from induced death, are yet to be defined. Herein, we report that membrane surface E-cadherin-expressing prostate cancer (PCa) cells were resistant to cell death by chemotherapeutic drugs, but E-cadherin null or those expressing E-cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo. While cell-cell E-cadherin ligandation reduced mitogenesis, this chemo-protection was proliferation-independent as killing of both EdU+ (or Ki67+) and EdU− (Ki67−) cells was inversely related to membrane-bound E-cadherin. Inhibiting the canonical survival kinases extracellular signal-regulated protein kinases (ERK), protein kinase B (PKB/AKT) and janus kinase (JAK), which are activated by chemotherapeutics in epithelial transitioned PCa, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, AKT disruption in itself had no effect on tumor survival but was synergistic with chemotherapy leading to increased killing. Conclusion: liver microenvironment-driven phenotypic switching of carcinoma cells and subsequent survival signaling results in activation of canonical survival pathways that protect the disseminated PCa liver micrometastases in a proliferation-independent manner, and that these pathways can be targeted as an adjuvant treatment to improve the efficacy of traditional chemotherapeutics.
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DOI：
10.1111/j.1440-1746.1996.tb00006.x
发表时间：
1996-01-01
影响因子：
4.1
作者：
Kuruppu, D;Christophi, C;OBrien, PE
通讯作者：
OBrien, PE
影响因子：
64.8
作者：
Fischer KR;Durrans A;Lee S;Sheng J;Li F;Wong ST;Choi H;El Rayes T;Ryu S;Troeger J;Schwabe RF;Vahdat LT;Altorki NK;Mittal V;Gao D
通讯作者：
Gao D
影响因子：
37.3
作者：
Chao YL;Shepard CR;Wells A
通讯作者：
Wells A
DOI：
10.1186/bcr651
发表时间：
2003
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kowalski PJ;Rubin MA;Kleer CG
通讯作者：
Kleer CG
影响因子：
4.8
作者：
Pece, S;Chiariello, M;Gutkind, JS
通讯作者：
Gutkind, JS