Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors

Lei Miao, Qi Liu, C. Michael Lin, Cong Luo, Yuhua Wang, Lina Liu, Weiyan Yin, Shihao Hu, William Y. Kim, Leaf Huang

Research output: Contribution to journalArticle

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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. Ó2016 AACR.

LanguageEnglish (US)
Pages719-731
Number of pages13
JournalCancer Research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2017

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Nanoparticles
Neoplasms
Heterografts
Fibroblasts
Therapeutics
Protamines
Pancreatic Neoplasms
Urinary Bladder
Plasmids
Cancer-Associated Fibroblasts
Apoptosis
Carcinoma
Lipids
DNA
Growth
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. / Miao, Lei; Liu, Qi; Lin, C. Michael; Luo, Cong; Wang, Yuhua; Liu, Lina; Yin, Weiyan; Hu, Shihao; Kim, William Y.; Huang, Leaf.

In: Cancer Research, Vol. 77, No. 3, 01.02.2017, p. 719-731.

Research output: Contribution to journalArticle

Miao, L, Liu, Q, Lin, CM, Luo, C, Wang, Y, Liu, L, Yin, W, Hu, S, Kim, WY & Huang, L 2017, 'Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors' Cancer Research, vol. 77, no. 3, pp. 719-731. DOI: 10.1158/0008-5472.CAN-16-0866
Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L et al. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Research. 2017 Feb 1;77(3):719-731. Available from, DOI: 10.1158/0008-5472.CAN-16-0866
Miao, Lei ; Liu, Qi ; Lin, C. Michael ; Luo, Cong ; Wang, Yuhua ; Liu, Lina ; Yin, Weiyan ; Hu, Shihao ; Kim, William Y. ; Huang, Leaf. / Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. In: Cancer Research. 2017 ; Vol. 77, No. 3. pp. 719-731
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