Choi, Young Sun Jang, Hyeonha Gupta, Biki Jeong, Ji-Hak Ge, Yun Yong, Chul Soon Kim, Jong Oh Bae, Jong-Sup Song, Im-Sook Kim, In-San Lee, You Mie 2024-01-19T16:33:31Z 2024-01-19T16:33:31Z 2021-09-02 2020-09-14 1756-8722 https://pubs.kist.re.kr/handle/201004/118124 Background Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities. Methods Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett's multiple comparison test. Results PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in G alpha 13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway. Conclusions Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy. English BMC ENDOTHELIAL-BARRIER PROTECTION TIE2 ACTIVATION BLOOD-VESSELS THROMBIN CANCER NORMALIZATION ANGIOGENESIS PERMEABILITY MACROPHAGES INHIBITION Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities Article 10.1186/s13045-020-00952-9 1 JOURNAL OF HEMATOLOGY & ONCOLOGY, v.13, no.1 JOURNAL OF HEMATOLOGY & ONCOLOGY 13 1 scie scopus 000571957600001 2-s2.0-85091051988 Oncology Hematology Oncology Hematology Article ENDOTHELIAL-BARRIER PROTECTION TIE2 ACTIVATION BLOOD-VESSELS THROMBIN CANCER NORMALIZATION ANGIOGENESIS PERMEABILITY MACROPHAGES INHIBITION Antitumor immune response EPCR Ferritin-based protein C nanoparticles Tie2 Vascular normalization