title: Peritoneal milky spots serve as a hypoxic niche and favor gastric cancer stem/progenitor cell peritoneal dissemination through hypoxia-inducible factor 1α.
abstract: 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-1α (HIF-1α), 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-1α-mediated hypoxic microenvironment regulated GCSPC fate. We observed a positive correlation between HIF-1α 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-1α. 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-1α 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.
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Miao
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Wang
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhao
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Feng
authors.initials: F
authors.lastname: Miao
authors.forename: Hui-Mian
authors.initials: HM
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Cancer stem cell; Cancer stem cell niche; Hypoxia; Peritoneal dissemination; Peritoneal milky spots; Stomach cancer