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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors
Open accessPublished version of a preprint
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.
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“Thus the use of NP to modify CAFs can be an effective strategy to treat desmoplastic cancers (Fig. 2b) [83].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [83]
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Cites
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Turning foes to friends: targeting cancer-associated fibroblasts
Chen, X., & Song, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0004-1 · Cited by 1,929
Tumor microenvironment complexity and therapeutic implications at a glance
Baghban, R., Roshangar, L., Jahanban-Esfahlan, R., Seidi, K., Ebrahimi-Kalan, A., Jaymand, M., Kolahian, S., Javaheri, T., & Zare, P. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-0530-4 · Cited by 1,784
“2b) [83] .”
Chehelgerdi, M., Chehelgerdi, M., Allela, O. Q. B., Pecho, R. D. C., Narayanan, J., Rao, D. P., Thamaraikani, T., Vasanthan, M., Viktor, P., Lakshmaiya, N., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01865-0 · Cited by 1,132
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer
Wu, F., Yang, J., Liu, J., Wang, Y., Mu, J., Zeng, Q., Deng, S., & Zhou, H. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00641-0 · Cited by 773
Self-citationFibrosis and cancer: A strained relationship
Piersma, B., Hayward, M.-K., & Weaver, V. M. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188356 · Cited by 715
Metadata
- Authors
- Miao, L., Liu, Q., Lin, C. M., Luo, C., Wang, Y., Liu, L., Yin, W., Hu, S., Kim, W. Y., & Huang, L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Shenyang Pharmaceutical University (CN)
- China Pharmaceutical University (CN)
- Corresponding author
- Huang, Leaf
- ORCID
- Venue
- Cancer Research
- Published
- 2017-01-31
- Volume
- 77
- Issue
- 3
- Pages
- 719-731
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5290135
- OpenAlex
- W2555883270
- Cited by
- 215
- References
- 50
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 16 · 2023: 16 · 2022: 26 · 2021: 29 · 2020: 31 · 2019: 31 · 2018: 21 · 2017: 16
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- NIH (CA149363, CA151652, and CA149387)
- North Carolina Biotech Center Institutional (2005-IDG-1016)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Keywords
- cancer-associated fibroblasts, desmoplastic tumors, tumor microenvironment, lipid-coated nanoparticles, pancreatic cancer, nanoparticle delivery
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Urinary Bladder Neoplasms, Carcinoma, Transitional Cell, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Neoplasms, Experimental, Pancreatic Neoplasms, Blotting, Western, Polymerase Chain Reaction, Apoptosis, Xenograft Model Antitumor Assays, NIH 3T3 Cells, Cell Line, Tumor, Mice, TNF-Related Apoptosis-Inducing Ligand, Nanoconjugates, Tumor Microenvironment
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