Cancer and Metastasis Reviews

, Volume 34, Issue 1, pp 97–114 | Cite as

The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal

  • Maarten F. Bijlsma
  • Hanneke W. M. van Laarhoven


A nearly universal feature of pancreatic ductal adenocarcinoma (PDAC) is an extensive presence of activated stroma. This stroma is thought to aid in various tumor-promoting processes and hampers response to therapy. Here, we aim to evaluate the evidence that supports this role of the stroma in PDAC with functional experiments in relevant models, discuss the clinical trials that have aimed to target the stroma in this disease, and examine recent work that explains why these clinical trials based on stroma-targeting strategies have thus far not achieved the expected success. We systematically searched PubMed through August 2014 with no restrictions to identify published peer-reviewed research articles assessing the effect of targeting the stroma on tumor growth or metastases in preclinical animal models. Five hundred and thirty articles were extracted of which 31 were included in the analysis. Unfortunately, due to the large variety in models and outcome measures, we could not perform a meta-analysis of our data. We find that despite an abundance of positive outcomes reported in previous studies on stroma targeting, a strong discrepancy exists with the outcomes of clinical trials and the more recent preclinical work that is in line with these trials. We explain the incongruities by the duration of stroma targeting and propose that chronic stroma targeting treatment is possibly detrimental in the treatment of this disease.


Pancreatic cancer Stroma Desmoplasia Smooth muscle actin Hedgehog 



Alpha smooth muscle actin


Cancer-associated fibroblast


Chemokine (C-C motif) ligand 5


Connective tissue growth factor


Cytotoxic T lymphocyte-associated protein 4


Extracellular matrix


Epithelial-to-mesenchymal transition


Fibroblast activation protein


Ink4a/Arf −/− Pdx1-Cre;Gli1 nLacZ/+


Ptf1a-Cre; Kras LSL.G12D/+


Ptf1a-Cre; Kras LSL.G12D/+ ;Shh fl/fl


Kras LSL.G12D/+ ;Ink4a/Arf −/− ;Pdx1-Cre;Gli1 nLacZ/+


Kras LSL.G12D/+ ;p53 LSL-R172H/+ ;Pdx1-Cre (Rhim et al.) or Ptf1a-Cre;p53 fl/+ ;Kras LSL.G12D/+ (Lee et al.)


αSMA-tk Kras LSL.G12D/+ ;p53 LSL-R172H/+ ;Pdx1-Cre;aSMA-tk


Kirsten rat sarcoma


Overall survival


Pancreatic intraepithelial neoplasm


Platelet derived growth factor


αSMA-tk Ptf1a-Cre;Kras LSL-G12D/+ ;Tgfbr2 fl/fl ;aSMA-tk


αSMA-tk;YFP Ptf1a-Cre;Kras LSL-G12D/+ ;Tgfbr2 fl/fl ;Rosa LSL-YFP


αSMA-tk; αSMA-RFP Ptf1a-Cre; Kras LSL-G12D/+ ;Tgfbr2 fl/fl ;aSMA-tk;aSMA-RFP


Pancreatic ductal adenocarcinoma


p53 fl/+ ;Kras LSL.G12D/+ ;Pdx1-Cre;Rosa LSL- YFP


Pancreatic stellate cell


Sonic Hedgehog


Shh fl/fl ;KrasLSL.G12D/+;p53LSL-R172H/+;Pdx1-Cre;RosaLSL-YFP




Secreted protein acidic and rich in cysteine


Tissue growth factor beta


Vascular endothelial growth factor receptor 2



This work was supported by a KWF Dutch Cancer Society Research Grant (UVA 2012–5607) for MFB.

Author Contributions

Both MFB and HvL decided on inclusion of papers, analyzed the data, and wrote the manuscript.

Conflict of interest

HvL received research support from Celgene for a clinical study with nab-paclitaxel and participated in advisory boards of Lilly on ramucirumab.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Maarten F. Bijlsma
    • 1
  • Hanneke W. M. van Laarhoven
    • 2
  1. 1.Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  2. 2.Department of Medical Oncology, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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