PMID- 29458390 OWN - NLM STAT- MEDLINE DCOM- 20190509 LR - 20190509 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 37 IP - 1 DP - 2018 Feb 20 TI - FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer. PG - 32 LID - 10.1186/s13046-018-0696-4 [doi] LID - 32 AB - BACKGROUND: Extracellular matrix (ECM) is a mediator of tumor progression. However, whether the alterations of the intraperitoneal ECM prior to tumor establishment affects the malignant progression of ovarian cancer remains elusive. METHODS: Apolipoprotein (ApoE) knock-out mice was used to analyze the intraperitoneal ECM alterations by quantification of the major components of ECM. ID8 cells were implanted in vivo to generate allografts and human ovarian cancer cell lines were characterized in vitro to assess the effects of ECM alterations on the malignant progression of ovarian cancer. Adhesion assay, immunochemistry, cytokines profile, proliferation assay, transwell invasion assay and western blot were used to determine the malignant phenotype of ovarian cancer cells. RESULTS: ApoE loss induced increased ECM deposition, which stimulated the adhesions of ovarian cancer cells. The adhesion-mediated focal adhesion kinase (FAK) signaling enhanced the invasive behaviors of ovarian cancer cells through activation of a ERK-MMP linkage. This ECM-induced signaling cascade was further confirmed in human ovarian cancer cell lines in vitro. Furthermore, reversal of the ECM accumulation with BAPN or abrogation of adhesion-induced ERK activation in ovarian cancer cells with MEK inhibitors (MEKi) was found to effectively delay ovarian cancer progression. CONCLUSIONS: These findings identify the FAK-ERK activation in cell/matrix adhesion in the malignant progression of ovarian cancer and the efficiency of BAPN or MEKi for tumor suppression, providing an impetus for further studies to explore the possibility of new anticancer therapeutic combinations. FAU - Lai, Huiling AU - Lai H AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Zhao, Xuejiao AU - Zhao X AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Qin, Yu AU - Qin Y AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Ding, Yi AU - Ding Y AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Chen, Ruqi AU - Chen R AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Li, Guannan AU - Li G AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Labrie, Marilyne AU - Labrie M AD - Department of Systems Biology, University of Texas MD Anderson Cancer Center, TX77030, Houston, USA. FAU - Ding, Zhiyong AU - Ding Z AD - Department of Systems Biology, University of Texas MD Anderson Cancer Center, TX77030, Houston, USA. FAU - Zhou, Jianfeng AU - Zhou J AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Hu, Junbo AU - Hu J AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Ma, Ding AU - Ma D AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. FAU - Fang, Yong AU - Fang Y AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. yongfang@tjh.tjmu.edu.cn. FAU - Gao, Qinglei AU - Gao Q AD - Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan, 430030, People's Republic of China. qlgao@tjh.tjmu.edu.cn. LA - eng GR - 81572565/National Natural Science Foundation of China/ GR - 81602291/National Natural Science Foundation of China/ GR - 81572570/National Natural Science Foundation of China/ GR - 81472783/National Natural Science Foundation of China/ GR - 81630060/National Natural Science Foundation of China/ GR - 81372801/National Natural Science Foundation of China/ GR - 81230038/National Natural Science Foundation of China/ GR - 2015CB553903/National Development Program (973) For Key Basic Research of China/ GR - 2016YFC0902901/National Key Research & Development Program of China/ PT - Journal Article DEP - 20180220 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (Apolipoproteins E) RN - 151-18-8 (Aminopropionitrile) RN - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM EIN - J Exp Clin Cancer Res. 2019 Oct 15;38(1):415. PMID: 31615580 MH - Aminopropionitrile/pharmacology MH - Animals MH - Apolipoproteins E/*deficiency MH - Cell Adhesion MH - Cell Line, Tumor MH - Cell Transformation, Neoplastic/genetics/metabolism MH - Disease Models, Animal MH - Disease Progression MH - Extracellular Matrix/*metabolism MH - Extracellular Signal-Regulated MAP Kinases/*metabolism MH - Female MH - Focal Adhesion Protein-Tyrosine Kinases/*metabolism MH - Humans MH - Mice MH - Mice, Knockout MH - Ovarian Neoplasms/*genetics/*metabolism/pathology MH - Signal Transduction/drug effects MH - Tumor Microenvironment PMC - PMC5819228 OTO - NOTNLM OT - Adhesion OT - Apolipoprotein E OT - Extracellular matrix OT - Ovarian cancer OT - Tumor progression COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All mouse experiments were carried out in accordance with a protocol approved by the Ethics Committee of Tongji Hospital, Tongji Medical College. Human tissues were donated for research purposes by patients undergoing oophorectomy surgery at Tongji Hospital (Wuhan, China). Ethical approval was granted by the Ethics Committee of Tongji Hospital. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors have no competing interest to disclose. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/02/21 06:00 MHDA- 2019/05/10 06:00 PMCR- 2018/02/20 CRDT- 2018/02/21 06:00 PHST- 2017/11/12 00:00 [received] PHST- 2018/02/02 00:00 [accepted] PHST- 2018/02/21 06:00 [entrez] PHST- 2018/02/21 06:00 [pubmed] PHST- 2019/05/10 06:00 [medline] PHST- 2018/02/20 00:00 [pmc-release] AID - 10.1186/s13046-018-0696-4 [pii] AID - 696 [pii] AID - 10.1186/s13046-018-0696-4 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2018 Feb 20;37(1):32. doi: 10.1186/s13046-018-0696-4.