1. Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
2. Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing, 100050, China.
Background: Angiogenesis is important for tumor proliferation and distant metastasis. However, the role of drug-resistant tumor cells in angiogenesis remains largely unknown. Current anti-angiogenic strategies also have limitations and it would be useful to develop novel targets and treatment strategies.
Methods: Differential ultracentrifugation was used to isolate conditioned medium-derived exosomes from 5-flurouracil (5-FU)-sensitive or -resistant colon cancer cells. Exosome endocytosis into human umbilical vein endothelial cells was observed via immunofluorescence. Differentially expressed proteins in the exosomes were confirmed via qRT-PCR and Western blotting. The angiogenic capacity of endothelial cells was evaluated using cell function assays and a rat model of abdominal aortic neovascularization. The underlying mechanisms were verified using qRT-PCR and Western blotting assays. Immunohistochemistry was used to evaluate in vivo angiogenesis.
Results: We observed that the conditioned medium and exosomes from 5-FU-resistant colon cancer cells could promote angiogenesis. Exosomal growth/differentiation factor 15 (GDF15) was a potent inducer of this angiogenesis in vitro by inhibiting the Smad signaling pathway, thus increasing periostin (POSTN) levels. Moreover, 5-FU-resistant colon cancer cells showed high microvascular density in vivo. TGF-β1, an activator of the Smad signaling pathway, could partly eliminate those effects.
Conclusions: Our study reveals the molecular regulation of angiogenesis in 5-FU-resistant colon cancer and suggests that the GDF15-POSTN axis may be a novel target for anti-angiogenic therapies in colon cancer.
Keywords: Colon cancer, 5-FU resistance, Exosomes, GDF15, Angiogenesis