Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition.
Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition.
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DOI：
10.1007/s10549-014-2875-0
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发表时间：
2014-04
影响因子：
3.8
通讯作者：
Wells, Alan
中科院分区：
文献类型：
--
作者：
Taylor, Donald P.;Clark, Amanda;Wheeler, Sarah;Wells, Alan
关键词：
近一半的乳腺癌转移在原发肿瘤消融后5年或更长时间才会出现临床症状。这意味着转移性癌细胞存活了很长一段时间而没有出现可检测的结节。肝脏是一个常见的转移目的地，其实质肝细胞已被证明对转移癌细胞具有较小的侵袭性，休眠表型。我们研究了肝非实质细胞（NPCs）是否有助于转移性乳腺癌细胞的生长和指示出现的间充质表型转移。对人原代肝细胞、内皮细胞（TMNK-1或hmec -1）和乳腺癌细胞系（MCF-7或MDA-MB-231）进行共培养实验。将癌细胞暴露于npc条件培养基中，分离出有助于生长的可溶性因子。为了阐明其生长机制，进行了表皮生长因子受体（EGFR）抑制共培养实验。流式细胞术分析和免疫荧光染色分别量化乳腺癌细胞生长和表型。MDA-MB-231细胞在原代鼻咽癌共培养中的生长明显大于仅肝细胞或肝细胞+鼻咽癌共培养。MCF-7细胞与人NPC以及内皮型NPC亚型共培养时的生长明显高于对照组。在HMEC-1共培养中，MCF-7细胞的纺锤体形态、E-cadherin的膜清除和p38核易位表明MCF-7细胞发生了间质转移。hmec -1条件培养基诱导了类似的结果，表明分泌因子负责这种转变，而阻断EGFR会减弱theMCF-7的生长。我们得出结论，转移性肝生态位中的NPCs分泌因子可以诱导上皮性乳腺癌细胞的部分间质转移，从而启动生长，这部分是由EGFR激活介导的。这些数据表明，肝转移微环境中实质细胞和NPC比例（或激活状态）的变化可能有助于转移性休眠的出现。
Nearly half of breast carcinoma metastases will become clinically evident five or more years after primary tumor ablation. This implies that metastatic cancer cells survived over an extended timeframe without emerging as detectable nodules. The liver is a common metastatic destination, whose parenchymal hepatocytes have been shown to impart a less invasive, dormant phenotype on metastatic cancer cells. We investigated whether hepatic nonparenchymal cells (NPCs) contributed to metastatic breast cancer cell outgrowth and a mesenchymal phenotypic shift indicative of emergence. Co-culture experiments of primary human hepatocytes, NPCs or endothelial cell lines (TMNK-1 orHMEC-1) and breast cancer cell lines (MCF-7 or MDA-MB-231) were conducted. Exposure of carcinoma cells to NPC-conditioned medium isolated soluble factors contributing to outgrowth. To elucidate outgrowth mechanism, epidermal growth factor receptor (EGFR) inhibition co-culture experiments were performed. Flow cytometry analyses and immunofluorescence staining were conducted to quantify breast cancer cell outgrowth and phenotype, respectively. Outgrowth of the MDA-MB-231 cells within primary NPC co-cultures was substantially greater than in hepatocyte-only or hepatocyte+NPC co-cultures. MCF-7 cells co-cultured with human NPCs as well as with the endothelial NPC subtypes grew out significantly more than controls. MCF-7 cells underwent a mesenchymal shift as indicated by spindle morphology, membrane clearance of E-cadherin, and p38 nuclear translocation when in HMEC-1 co-culture. HMEC-1-conditioned medium induced similar results suggesting that secretory factors are responsible for this transition while blocking EGFR blunted theMCF-7 outgrowth. We conclude that NPCs in the metastatic hepatic niche secrete factors that can induce a partial mesenchymal shift in epithelial breast cancer cells thus initiating outgrowth, and that this is in part mediated by EGFR activation. These data suggest that changes in the parenchymal cell and NPC ratios (or activation status) in the liver metastatic microenvironment may contribute to emergence from metastatic dormancy.
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影响因子：
8
作者：
Shepard, C. R.;Kassis, J.;Wells, A.
通讯作者：
Wells, A.
DOI：
10.1158/1078-0432.ccr-12-3180
发表时间：
2013-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Taylor DP;Wells JZ;Savol A;Chennubhotla C;Wells A
通讯作者：
Wells A
需要上皮钙粘着蛋白的下调以引发乳腺癌的转移性生长。
影响因子：
3.3
作者：
Wendt MK;Taylor MA;Schiemann BJ;Schiemann WP
通讯作者：
Schiemann WP
影响因子：
37.3
作者：
Chao YL;Shepard CR;Wells A
通讯作者：
Wells A
影响因子：
14.5
作者：
Demicheli, R
通讯作者：
Demicheli, R