Peritoneal Milky Spots Serve as a Hypoxic Niche and Favor Gastric Cancer Stem/Progenitor Cell Peritoneal Dissemination Through Hypoxia-Inducible Factor 1α

被引:42
作者
Miao, Zhi-Feng [1 ]
Wang, Zhen-Ning [1 ]
Zhao, Ting-Ting [2 ]
Xu, Ying-Ying [2 ]
Gao, Jian [3 ]
Miao, Feng [4 ]
Xu, Hui-Mian [1 ]
机构
[1] China Med Univ, Dept Surg Oncol, Affiliated Hosp 1, Shenyang 110001, Liaoning Provin, Peoples R China
[2] China Med Univ, Dept Breast Surg, Affiliated Hosp 1, Shenyang 110001, Liaoning Provin, Peoples R China
[3] China Med Univ, Ctr Lab Technol & Expt Med, Shenyang 110001, Liaoning Provin, Peoples R China
[4] China Med Univ, Affiliated Hosp 4, Dept Digest, Shenyang 110001, Liaoning Provin, Peoples R China
基金
美国国家科学基金会;
关键词
Stomach cancer; Peritoneal dissemination; Peritoneal milky spots; Hypoxia; Cancer stem cell; Cancer stem cell niche; EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; PROGENITOR CELLS; SIDE POPULATION; PRIMARY TUMORS; BREAST-CANCER; EXPRESSION; HIF-1-ALPHA; GROWTH; GLIOBLASTOMA;
D O I
10.1002/stem.1816
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Peritoneal dissemination is the most common cause of death in gastric cancer patients. The hypoxic microenvironment plays a major role in controlling the tumor stem cell phenotype and is associated with patients' prognosis through hypoxia-inducible factor-1 (HIF-1), a key transcriptional factor that responds to hypoxic stimuli. During the peritoneal dissemination process, gastric cancer stem/progenitor cells (GCSPCs) are thought to enter into and maintained in peritoneal milky spots (PMSs), which have hypoxic microenvironments. However, the mechanism through which the hypoxic environment of PMSs regulated GCSPC maintenance is still poorly understood. Here, we investigated whether hypoxic PMSs were an ideal cancer stem cell niche suitable for GCSPC engraftment. We also evaluated the mechanisms through which the HIF-1-mediated hypoxic microenvironment regulated GCSPC fate. We observed a positive correlation between HIF-1 expression and gastric cancer peritoneal dissemination (GCPD) in gastric cancer patients. Furthermore, the GCSPC population expanded in primary gastric cancer cells under hypoxic condition in vitro, and hypoxic GCSPCs showed enhanced self-renewal ability, but reduced differentiation capacity, mediated by HIF-1. In an animal model, GCSPCs preferentially resided in the hypoxic zone of PMSs; moreover, when the hypoxic microenvironment in PMSs was destroyed, GCPD was significantly alleviated. In conclusion, our results demonstrated that PMSs served as a hypoxic niche and favored GCSPCs peritoneal dissemination through HIF-1 both in vitro and in vivo. These results provided new insights into the GCPD process and may lead to advancements in the clinical treatment of gastric cancer. Stem Cells2014;32:3062-3074
引用
收藏
页码:3062 / 3074
页数:13
相关论文
共 49 条
[1]   Expression of a candidate marker for progenitor cells, Musashi-1, in the proliferative regions of human antrum and its decreased expression in intestinal metaplasia [J].
Akasaka, Y ;
Saikawa, Y ;
Fujita, K ;
Kubota, T ;
Ishikawa, Y ;
Fujimoto, A ;
Ishii, T ;
Okano, H ;
Kitajima, M .
HISTOPATHOLOGY, 2005, 47 (04) :348-356
[2]   Stem Cell Differentiation and Lumen Formation in Colorectal Cancer Cell Lines and Primary Tumors [J].
Ashley, Neil ;
Yeung, Trevor M. ;
Bodmer, Walter F. .
CANCER RESEARCH, 2013, 73 (18) :5798-5809
[3]   Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro [J].
Barker, Nick ;
Huch, Meritxell ;
Kujala, Pekka ;
van de Wetering, Marc ;
Snippert, Hugo J. ;
van Es, Johan H. ;
Sato, Toshiro ;
Stange, Daniel E. ;
Begthel, Harry ;
van den Born, Maaike ;
Danenberg, Esther ;
van den Brink, Stieneke ;
Korving, Jeroen ;
Abo, Arie ;
Peters, Peter J. ;
Wright, Nick ;
Poulsom, Richard ;
Clevers, Hans .
CELL STEM CELL, 2010, 6 (01) :25-36
[4]   The cancer stem cell niche-there goes the neighborhood? [J].
Cabarcas, Stephanie M. ;
Mathews, Lesley A. ;
Farrar, William L. .
INTERNATIONAL JOURNAL OF CANCER, 2011, 129 (10) :2315-2327
[5]   Omental milky spots in screening gastric cancer stem cells [J].
Cao, L. ;
Hu, X. ;
Zhang, Y. ;
Sun, X. T. .
NEOPLASMA, 2011, 58 (01) :20-26
[6]   Omental milky spots - highly efficient "natural filter" for screening gastric cancer stem cells [J].
Cao, Liang ;
Hu, Xiang ;
Zhang, Yi .
MEDICAL HYPOTHESES, 2009, 73 (06) :1017-1018
[7]   Lymphocytes in the Peritoneum Home to the Omentum and Are Activated by Resident Dendritic Cells [J].
Carlow, Douglas A. ;
Gold, Michael R. ;
Ziltener, Hermann J. .
JOURNAL OF IMMUNOLOGY, 2009, 183 (02) :1155-1165
[8]   TRRAP and the Maintenance of Stemness in Gliomas [J].
Charles, Nikki A. ;
Holland, Eric C. .
CELL STEM CELL, 2010, 6 (01) :6-7
[9]   Milky Spots Promote Ovarian Cancer Metastatic Colonization of Peritoneal Adipose in Experimental Models [J].
Clark, Robert ;
Krishnan, Venkatesh ;
Schoof, Michael ;
Rodriguez, Irving ;
Theriault, Betty ;
Chekmareva, Marina ;
Rinker-Schaeffert, Carrie .
AMERICAN JOURNAL OF PATHOLOGY, 2013, 183 (02) :576-591
[10]  
Comen EA, 2012, DISCOV MED, V14, P97