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Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
Markus Loeffler, … , Andreas G. Niethammer, Ralph A. Reisfeld
Markus Loeffler, … , Andreas G. Niethammer, Ralph A. Reisfeld
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1955-1962. https://doi.org/10.1172/JCI26532.
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Research Article Oncology

Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake

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Abstract

Tumor-associated fibroblasts are key regulators of tumorigenesis. In contrast to tumor cells, which are genetically unstable and mutate frequently, the presence of genetically more stable fibroblasts in the tumor-stromal compartment makes them an optimal target for cancer immunotherapy. These cells are also the primary source of collagen type I, which contributes to decreased chemotherapeutic drug uptake in tumors and plays a significant role in regulating tumor sensitivity to a variety of chemotherapies. To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma. Through CD8+ T cell–mediated killing of tumor-associated fibroblasts, our vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma. Furthermore, tumor tissue of FAP-vaccinated mice revealed markedly decreased collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. Most importantly, pFap-vaccinated mice treated with chemotherapy showed a 3-fold prolongation in lifespan and marked suppression of tumor growth, with 50% of the animals completely rejecting a tumor cell challenge. This strategy opens a new venue for the combination of immuno- and chemotherapies.

Authors

Markus Loeffler, Jörg A. Krüger, Andreas G. Niethammer, Ralph A. Reisfeld

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Figure 1

Characterization of the FAP construct and chemoresistant tumor cell lines.

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Characterization of the FAP construct and chemoresistant tumor cell line...
(A) The cDNA encoding the entire murine FAP, verified by nucleotide sequencing, was inserted into the EcoRI site of the pFap vector. (B) Protein expression was demonstrated by Western blotting after transient transfection of CT26 and D2F2 cells. (C) CT26 colon and D2F2 breast carcinoma cells were treated with various chemotherapeutic agents at the concentrations indicated. After 48 hours of incubation, nuclear apoptosis was assessed by staining with Hoechst 33342 dye. Staurosporine was used as a positive control. PCMV, human cytomegalovirus immediate-early promoter/enhancer; BGHpA, bovine growth hormone polyadenylation signal; f1 ori, f1 origin; SV40 ori, SV40 early promoter and origin; neomycin, neomycin (G418) resistance gene; SV40pa, SV40 polyadenylation signal; pUC, pUC-derived origin; ampicillin, ampicillin resistance gene (β-lactamase).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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