Download Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma

Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and
Progression
Akihisa Fukuda, Sam C. Wang, John P. Morris, IV, Alexandra E. Folias, Angela Liou, Grace E. Kim, Shizuo Akira, Kenneth M.
Boucher, Matthew A. Firpo, Sean J. Mulvihill, and Matthias Hebrok
Cancer Cell 19, 441–455, April 12, 2011
Presenter : Peng-Ming Chen               
Commentator : Dr. Wu Chou Su           
  
Date/Time : 2011/09/22  16:10 -17:00
Location : Room 601,Med College Building
Background :
It has been shown that pancreatitis is a risk factor for pancreatic ductal adenocarcinoma (PDA)
development because pancreatitis has been shown to promote the development of pancreatic intraepithelial
neoplasia (PanIN) and PDA in Kras-driven mouse models of PDA. However, the molecular mechanisms
involved in the PDA enhancing effect of pancreatitis are largely unknown. Stat3 is known to be involved in
inflammation-associated tumorigenesis in many cancer types. Stat3 is aberrantly activated in human PDA
and controls proliferation in PDA cell lines, but the role of Stat3 in Kras-dependent initiation of the
PanIN/PDA lineage is unknown. MMP7 is overexpressed in PanIN and PDA, and associated with advanced
tumor stage (tumor size, lymph node involvement, and distant metastasis), and poor clinical outcomes.
Interestingly, MMP7 is induced through a Stat3-dependent mechanism in prostate and breast cancer cell
lines.
Objective:
In this study, the investigators want to identify the role of STAT3 in the linkage of PanIN and PDA
initiation and pancreatitis. Furthermore, the effect of STAT3-MMP7 signaling in pancreas is investigated,
and they also want to know the role of MMP7 in PDA initiation and progression.
Result:
The investigators firstly examine the expression of activated Stat3 in the caerulin-induced acute
pancreatitis in wild-type and KRASG12D mice model, which showed caerulin treatment would induce the
expression of activated Stat3 in the pancreas and persistent Stat3 activation in Kras-driven ductal metaplatic
cells. Mouse model with expressing KrasG12D and conditional Stat3 knockout (Ptf1a-Cre; KrasG12D; Stat3f/f)
was established to study whether the presence of Stat3 would affect PanIN/PDA formation in
caerulin-treated KRASG12D mice. Spontaneous and caerulin-induced PanIN formation was inhibited with
pancreatic Stat3 deletion. Further study suggested that Stat3 is required to support persistent ductal cell
proliferation of Kras-driven metaplastic ductal cells and PanIN of caerulin-treated KRASG12D mice. The
expression level of inflammation-associated cytokine is also noted to be lower Kras-driven ductal
metaplasia of Stat3 depleted mice. In addition, Stat3 supports MMP7 expression during Kras-driven PanIN
development following caerulin-induced pancreatitis. Using MMP7 knockout mice, the investigator further
demonstrated that MMP7 was not the direct effector of Stat3 for ductal metaplasia and PanIN development,
but MMP7 signaling was important for tumor growth and metastasis. Clinically, the investigators found that
the median survival of patients with metastatic PDA whose serum MMP7 level above and equal or below
20.2 ng/mL was 114.5 days and 329days, respectively.
Conclusion:
In this study, Fukuda et al. demonstrate that Stat3 contributes to pancreatic neoplasm Initiation, and MMP7
contributes to PDA progression and metastasis. Both Stat3 and MMP7 may be potentially novel targets to
development future therapies for PDA.
References :
1. Yamamoto, H., et al. (2001). Expression of matrix metalloproteinases and tissue inhibitors of
metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance
of matrilysin expression. J. Clin. Oncol. 19, 1118–1127.
2. Morris, J.P., et al. (2010). beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic
cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520.