Cancer and Metastasis Reviews

, Volume 34, Issue 1, pp 97–114

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
Clinical

DOI: 10.1007/s10555-014-9541-1

Cite this article as:
Bijlsma, M.F. & van Laarhoven, H.W.M. Cancer Metastasis Rev (2015) 34: 97. doi:10.1007/s10555-014-9541-1

Abstract

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.

Keywords

Pancreatic cancer Stroma Desmoplasia Smooth muscle actin Hedgehog 

Abbreviations

aSMA

Alpha smooth muscle actin

CAF

Cancer-associated fibroblast

CCL5

Chemokine (C-C motif) ligand 5

CTGF

Connective tissue growth factor

CTLA4

Cytotoxic T lymphocyte-associated protein 4

ECM

Extracellular matrix

EMT

Epithelial-to-mesenchymal transition

FAP

Fibroblast activation protein

ICG

Ink4a/Arf−/−Pdx1-Cre;Gli1nLacZ/+

KC

Ptf1a-Cre; KrasLSL.G12D/+

KCS

Ptf1a-Cre; KrasLSL.G12D/+;Shhfl/fl

KICG

KrasLSL.G12D/+;Ink4a/Arf−/−;Pdx1-Cre;Gli1nLacZ/+

KPC

KrasLSL.G12D/+;p53LSL-R172H/+;Pdx1-Cre (Rhim et al.) or Ptf1a-Cre;p53fl/+;KrasLSL.G12D/+ (Lee et al.)

KPC

αSMA-tk KrasLSL.G12D/+;p53LSL-R172H/+;Pdx1-Cre;aSMA-tk

KRAS

Kirsten rat sarcoma

OS

Overall survival

PanIN

Pancreatic intraepithelial neoplasm

PDGF

Platelet derived growth factor

PKT

αSMA-tk Ptf1a-Cre;KrasLSL-G12D/+;Tgfbr2fl/fl;aSMA-tk

PKT

αSMA-tk;YFP Ptf1a-Cre;KrasLSL-G12D/+;Tgfbr2fl/fl;RosaLSL-YFP

PKT

αSMA-tk; αSMA-RFP Ptf1a-Cre; KrasLSL-G12D/+;Tgfbr2fl/fl;aSMA-tk;aSMA-RFP

PDAC

Pancreatic ductal adenocarcinoma

PKCY

p53fl/+;KrasLSL.G12D/+;Pdx1-Cre;RosaLSL-YFP

PSC

Pancreatic stellate cell

SHH

Sonic Hedgehog

ShhKPCY

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

SMO

Smoothened

SPARC

Secreted protein acidic and rich in cysteine

TGFb

Tissue growth factor beta

VEGFR2

Vascular endothelial growth factor receptor 2

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