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Published on: April 29, 2014
Transformable Dual-Inhibition System Effectively Suppresses Renal Cancer Metastasis through Blocking Endothelial
Lu Wang1,2, Yulin Lv1,2, Cong Li1,2
1Department of Urology (Heilongjiang Key Laboratory of Scientific Research in Urology), The Fourth Hospital of Harbin Medical University, Harbin, 150001, China.
Abstract:
Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual-inhibition system (TDS) based on a self-assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand-receptor interaction-induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human-derived CSCs, TDS inhibits stemness by reducing endogenic miR-19b and its transportation via CSCs-derived exosomes, which increases PTEN expression and consequently suppresses CSCs-mediated metastasis. In patient-derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0-fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer.
Insights
A novel dual-inhibition system effectively targets both tumor blood vessels and cancer stem cells (CSCs) to combat renal cancer metastasis. This peptide-based system reduces vascularization and inhibits CSCs, offering a promising new therapeutic strategy.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- Renal cancer metastasis is accelerated by tumor vasculature and cancer stem cells (CSCs).
- Simultaneously targeting both endothelial cells and CSCs presents a significant therapeutic challenge due to distinct pathological features.
- CD105 receptor is overexpressed in both tumor endothelium and CSCs, presenting a potential dual-targeting strategy.
Purpose of the Study:
- To develop a transformable dual-inhibition system (TDS) for simultaneously targeting tumor vasculature and CSCs in renal cancer.
- To investigate the efficacy of TDS in reducing endothelial permeability, angiogenesis, and inhibiting CSC stemness and metastasis.
- To evaluate the therapeutic potential of TDS in preclinical models of renal cancer.
Main Methods:
- A self-assembly peptide-based TDS was designed to form nanofibrous barriers on cell membranes.
- TDS was engineered to specifically target the CD105 receptor.
- The effects of TDS on vascular permeability, angiogenesis, CSC stemness (miR-19b, PTEN expression), and metastasis were assessed in vitro and in vivo.
- Therapeutic efficacy was evaluated in patient-derived xenograft mouse models.
Main Results:
- TDS reduced vascular permeability by 67.0% ± 4.7% and angiogenesis by 62.0% ± 4.0%, inhibiting renal cancer metastasis.
- TDS suppressed CSC stemness by downregulating miR-19b and its exosomal transport, leading to increased PTEN expression and reduced CSC-mediated metastasis.
- In vivo studies showed significant inhibition of tumorigenesis and angiogenesis, with a 5.0-fold reduction in lung metastatic nodules.
Conclusions:
- The TDS effectively establishes nanofibrous barriers on cell membranes, enabling dual inhibition of tumor vasculature and CSCs.
- TDS demonstrates significant potential in suppressing renal cancer progression and metastasis by targeting both endothelial cells and CSCs.
- This approach offers a promising new strategy for the treatment of metastatic renal cancer.
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