Abstract
Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.
Highlights
Activated hepatic stellate cell-mediated liver fibrosis is essential to the development of liver metastasis
The nanoparticles are surface modified with aminoethyl anisamide (AEAA), a potent ligand for sigma-1 receptor (Sig-1R)[21], which is overexpressed by both Activated hepatic stellate cell (aHSC) and metastatic tumors
We first compared HSCassociated gene expression profiles (data extracted from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) database under the accession number GSE68468) between liver metastasis lesions and matched normal liver samples from 40 CRC liver metastasis patients (Fig. 1a)
Summary
Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. Clinical studies demonstrated the association of liver metastasis with reduced response and shortened progression-free survival of PD-L1 checkpoint blockade therapy even for those originally well responding tumor types such as melanoma and non-small-cell lung cancer[13,14]. We evaluated the RLN gene therapy on experimental murine CRC, pancreatic cancer, and breast cancer liver metastasis models via hemi-splenic inoculation of CT26-FL3, KPC, and 4T1 cells, respectively. The further combination of the RLN gene therapy with locally expressed PDL1 trap fusion protein produced a synergistic antimetastatic efficacy in the CRC and pancreatic cancer liver metastasis models
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
