Anoikis resistant gastric cancer cells promote angiogenesis and peritoneal metastasis through C/EBPβ-mediated PDGFB autocrine and paracrine signaling

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, GC(AR) cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated PDGFB secretion. Mechanistically, transcription factor C/EBP beta 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/EBP beta-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/EBP beta 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 GC(AR) cells and vascular endothelial cells promotes angiogenesis and peritoneal metastasis of GC based on C/EBP beta-mediated PDGFB autocrine and paracrine signaling. C/EBP beta-PDGFB-PDGFR beta-MAPK axis promises to be potential prognostic biomarkers and therapeutic targets for peritoneal metastasis of GC.

Automated summary

Anoikis resistance is crucial for the survival of metastatic cancer cells, but the molecular mechanisms are poorly understood. Study found that GC(AR) cells exhibit stronger metastatic and pro-angiogenic traits, promoting GC cell survival and angiogenesis through elevated PDGFB secretion.