Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of metastatic
cancer cells in blood, lymphatic circulation and distant organs. Compared to ordinary
cancer cells, anoikis resistant
cancer cells undergo various cellular and molecular alterations, probably characterizing the cells with unique features not limited to anoikis resistance. However, the molecular mechanisms connecting anoikis resistance to other metastatic properties are still poorly understood. Here, the
biological interaction between anoikis resistance and angiogenesis as well as their involvement into peritoneal
metastasis of
gastric cancer (GC) were investigated in vitro and in vivo. The prognostic value of key components involved in this interaction was evaluated in the GC cohort. Compared to ordinary GC cells, GCAR cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated
PDGFB secretion. Mechanistically,
transcription factor C/EBPβ facilitated
PDGFB transcription by directly binding to and interacting with
PDGFB promoter elements, subsequently increasing
PDGFB secretion. Secreted
PDGFB promoted the survival of detached GC cells through a C/EBPβ-dependent self-feedback loop. Moreover, secreted
PDGFB promoted angiogenesis in
metastases via activation of the MAPK/ERK signaling pathway in vascular endothelial cells. Both C/EBPβ activation level and
PDGFB expression were significantly elevated in GC and correlated with metastatic progression and poor prognosis of patients with GC. Overall, interaction between GCAR cells and vascular endothelial cells promotes angiogenesis and peritoneal
metastasis of GC based on C/EBPβ-mediated
PDGFB autocrine and paracrine signaling. C/EBPβ-
PDGFB-PDGFRβ-MAPK axis promises to be potential prognostic
biomarkers and therapeutic targets for peritoneal
metastasis of GC.