期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 30, 页码 12325-12330出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1300415110
关键词
chemoresistance; pancreatic tumor stroma; genetically engineered mouse models
资金
- University of Cambridge
- Cancer Research UK
- Li Ka Shing Foundation
- Hutchison Whampoa Limited
- National Institute for Health Research Cambridge Biomedical Research Centre
- Lustgarten Foundation for Pancreatic Cancer Research
- Cold Spring Harbor Laboratory Association
- European Community [EPC-TM-Net 256974]
- Deutsche Krebshilfe Mildred Scheel postdoctoral fellowship
- University Medical Center Giessen and Marburg
- Cancer Research UK [15678] Funding Source: researchfish
Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients.
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