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Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic
Young Sun Choi1,2,3, Hyeonha Jang1,2, Biki Gupta4,5
1BK21 Plus KNU Multi-Omics Creative Drug Research Team, Daegu, Republic of Korea.
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 Gα13-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.
Insights
Novel protein C nanoparticles (PCNs) target tumor vasculature, reducing hypoxia and enhancing anti-cancer immunity. This approach inhibits tumor growth and metastasis, improving survival and chemotherapy efficacy.
Area of Science:
- Nanotechnology in oncology
- Tumor microenvironment modulation
- Vascular targeting agents
Background:
- Conventional anti-angiogenesis therapies targeting VEGF worsen tumor hypoxia and metastasis.
- Targeting tumor vascular abnormalities offers a promising alternative strategy.
- Protein C nanoparticles (PCNs) were developed with antiseptic properties to address these limitations.
Purpose of the Study:
- To investigate the efficacy of novel ferritin-based protein C nanoparticles (PCNs) in inhibiting tumor growth and metastasis.
- To elucidate the underlying mechanisms of PCNs' antitumor effects, including vascular normalization and immune modulation.
- To evaluate the synergistic potential of PCNs with chemotherapy.
Main Methods:
- PCNs (TFG and TFMG) were generated and tested in Lewis lung carcinoma (LLC) and MMTV-PyMT breast cancer models.
- Tumor vasculature was assessed via immunohistochemistry; Western blot and permeability assays explored PCN mechanisms.
- siRNAs were used for gene knockdown in endothelial cells; statistical analysis included ANOVA.
Main Results:
- PCNs significantly reduced tumor hypoxia, increased pericyte coverage, and inhibited tumor growth and metastasis in both models.
- Combination therapy with PCNs and cisplatin demonstrated synergistic tumor suppression, enhanced drug delivery, and improved survival.
- PCNs modulated the tumor immune microenvironment, increasing cytotoxic T cells and M1-like macrophages, and stabilized vascular tight junctions via specific signaling pathways.
Conclusions:
- PCNs represent a novel therapeutic strategy for cancer by targeting tumor vasculature.
- This approach normalizes tumor vasculature, enhances chemotherapy delivery, and stimulates antitumor immune responses, leading to tumor regression.
- PCNs hold potential for effective cancer treatment by overcoming limitations of conventional therapies.
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