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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors
Lei Miao1, Qi Liu1,2, C Michael Lin1
1Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Abstract:
The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719-31. ©2016 AACR.
Insights
Nanoparticles can reprogram tumor-associated fibroblasts (TAFs) to secrete cytotoxic proteins, overcoming the barrier of desmoplastic tumors and enhancing cancer treatment efficacy.
Area of Science:
- Oncology
- Nanomedicine
- Cancer Biology
Background:
- Desmoplastic tumors present a significant challenge for nanoparticle-based cancer therapies due to off-target distribution in fibroblasts.
- Tumor-associated fibroblasts (TAFs) contribute to the tumor microenvironment and can impede treatment efficacy.
Purpose of the Study:
- To investigate the potential of exploiting nanoparticle-fibroblast interactions to target TAFs for cancer therapy.
- To develop a novel strategy for treating desmoplastic cancers by reprogramming TAFs.
Main Methods:
- Lipid-coated protamine DNA complexes encoding secretable TNF-related factor sTRAIL were developed.
- These complexes were administered to murine xenograft models of human desmoplastic bladder and pancreatic carcinoma.
- The study assessed TAF reprogramming, sTRAIL production, tumor cell apoptosis, and microenvironment modulation.
Main Results:
- Three doses of nanoparticles successfully induced approximately 70% of TAFs to produce sTRAIL.
- sTRAIL triggered apoptosis in adjacent tumor cells and reverted TAFs to a quiescent state.
- This approach remodeled the tumor microenvironment, favoring subsequent nanotherapy and inhibiting tumor growth.
Conclusions:
- Reprogramming TAFs using nanoparticles to secrete cytotoxic proteins is a viable strategy for treating desmoplastic cancers.
- This proof-of-concept study demonstrates a novel approach to overcome therapeutic barriers in challenging tumor types.
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