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Reshaping Prostate Tumor Microenvironment To Suppress Metastasis via Cancer-Associated Fibroblast Inactivation with
Jiayan Lang1,2,3, Xiao Zhao1,2, Yingqiu Qi1,4
1CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology , Beijing 100190 , China.
Abstract:
Prostate cancer is one of the most common malignant tumors in men, and inhibiting metastasis is a key event but still a major challenge in prostate cancer treatment. Cancer-associated fibroblasts (CAFs) play an important role in prostate tumor metastasis by shaping the malignant tumor microenvironment. Herein, we constructed a CAF-targeting siRNA delivery system by loading the fibroblast activation protein-α (FAP-α) antibody onto the cell-penetrating peptide (CPP)-based nanoparticles, which specifically downregulated C-X-C motif chemokine ligand 12 (CXCL12) expression in CAFs. This regulation generated a series of changes through inactivating CAFs so that the malignant prostate tumor microenvironment was reshaped. The tumor cell invasion, migration, and tumor angiogenesis were significantly inhibited, which all contributed to the suppression of the metastasis of an orthotopic prostate tumor. This tumor microenvironment reshaping strategy via CAF targeting and inactivation provides an alternative approach for malignant prostate tumor metastasis inhibition.
Insights
This study developed nanoparticles targeting cancer-associated fibroblasts (CAFs) to inhibit prostate cancer metastasis. By downregulating CXCL12 in CAFs, the treatment reshaped the tumor microenvironment, reducing tumor spread.
Area of Science:
- Oncology
- Biotechnology
- Nanomedicine
Background:
- Prostate cancer metastasis remains a significant challenge in treatment.
- Cancer-associated fibroblasts (CAFs) are key players in promoting prostate tumor metastasis by altering the tumor microenvironment.
Purpose of the Study:
- To develop a targeted siRNA delivery system to inhibit prostate cancer metastasis.
- To investigate the potential of targeting CAFs to reshape the tumor microenvironment and suppress metastasis.
Main Methods:
- Constructed CAF-targeting nanoparticles by conjugating a fibroblast activation protein-α (FAP-α) antibody to cell-penetrating peptide (CPP)-based nanoparticles.
- Loaded siRNA to specifically downregulate C-X-C motif chemokine ligand 12 (CXCL12) expression in CAFs.
- Evaluated the effect of CAF inactivation on prostate tumor cell invasion, migration, angiogenesis, and metastasis in an orthotopic model.
Main Results:
- The FAP-α antibody-conjugated nanoparticles effectively targeted CAFs.
- Downregulation of CXCL12 in CAFs led to their inactivation and reshaping of the tumor microenvironment.
- Significant inhibition of tumor cell invasion, migration, and angiogenesis was observed.
- Suppression of orthotopic prostate tumor metastasis was achieved.
Conclusions:
- Targeting CAFs via a FAP-α antibody-loaded CPP-nanoparticle siRNA delivery system is a viable strategy to inhibit prostate cancer metastasis.
- Reshaping the tumor microenvironment through CAF inactivation offers a novel therapeutic approach for prostate cancer.
- This strategy holds promise for improving treatment outcomes for advanced prostate cancer.
