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<p>Free fatty acid receptor (FFAR)-mediated signaling plays a critical role in cancer pathogenesis. Within the tumor microenvironment (TME), stromal cells support cancer cell functions under hypoxic conditions, thereby promoting malignant progression. This study investigated whether FFAR1 contributes to stromal cell–induced malignancy in cancer cells under hypoxic conditions (1% O<sub>2</sub>), using highly invasive A549-M8 cells derived from lung cancer A549 cells. A549-M8 cells exhibit approximately eightfold higher invasiveness than A549 cells. Under 1% O<sub>2</sub>, <i>FFAR1</i> expression was upregulated in A549-M8 cells but downregulated in A549 cells. A549-M8 cell invasion was markedly promoted by culturing at 1% O<sub>2</sub>, whereas A549 cell invasion decreased. TUG-770 (FFAR1 agonist) stimulated A549-M8 cell invasion, whereas GW1100 (FFAR1 antagonist) suppressed it. In contrast, A549-M8 cell invasion was inhibited by TUG-891 (FFAR4 agonist). Co-culture with mouse-derived endothelial F2 cells, which lack <i>Ffar1</i> expression, further stimulated A549-M8 cell movement and motility relative to A549 cells. Under hypoxic co-culture conditions, A549-M8 cells exhibited significantly increased invasion, which was associated with elevated <i>FFAR1</i> expression. These results suggest that FFAR1-mediated signaling is a key driver of tumor progression in highly invasive lung cancer cells under hypoxic conditions, with stromal cell interactions promoting FFAR1 induction and enhancing malignancy, whereas FFAR4 activation exerts a suppressive effect on invasive activity.</p>

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Hypoxia and endothelial interaction cooperatively amplify free fatty acid receptor 1 (FFAR1)-mediated malignancy in highly invasive lung cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Shion Nagano,
  • Yuka Kusumoto,
  • Moemi Tamura,
  • Nanami Shimomura,
  • Hinata Amano,
  • Mahiro Yanome,
  • Nozomi Kano,
  • Mizuki Ishida,
  • Miwa Kawamoto,
  • Toshifumi Tsujiuchi

摘要

Free fatty acid receptor (FFAR)-mediated signaling plays a critical role in cancer pathogenesis. Within the tumor microenvironment (TME), stromal cells support cancer cell functions under hypoxic conditions, thereby promoting malignant progression. This study investigated whether FFAR1 contributes to stromal cell–induced malignancy in cancer cells under hypoxic conditions (1% O2), using highly invasive A549-M8 cells derived from lung cancer A549 cells. A549-M8 cells exhibit approximately eightfold higher invasiveness than A549 cells. Under 1% O2, FFAR1 expression was upregulated in A549-M8 cells but downregulated in A549 cells. A549-M8 cell invasion was markedly promoted by culturing at 1% O2, whereas A549 cell invasion decreased. TUG-770 (FFAR1 agonist) stimulated A549-M8 cell invasion, whereas GW1100 (FFAR1 antagonist) suppressed it. In contrast, A549-M8 cell invasion was inhibited by TUG-891 (FFAR4 agonist). Co-culture with mouse-derived endothelial F2 cells, which lack Ffar1 expression, further stimulated A549-M8 cell movement and motility relative to A549 cells. Under hypoxic co-culture conditions, A549-M8 cells exhibited significantly increased invasion, which was associated with elevated FFAR1 expression. These results suggest that FFAR1-mediated signaling is a key driver of tumor progression in highly invasive lung cancer cells under hypoxic conditions, with stromal cell interactions promoting FFAR1 induction and enhancing malignancy, whereas FFAR4 activation exerts a suppressive effect on invasive activity.