α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study

Abstract

Background:Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods:CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results:High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions:Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

“…5F; Supplemental Fig. 5D,E ;Fujita et al 2010;Sinn et al 2014). No dramatic differences were found in cleaved caspase 3-positive cells undergoing apoptosis between the control and Brg1 "put back" tumors ( Fig.…”

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…There is emerging interest to stratify patients on the basis on stromal characteristics. 61,62 Stromal collagen topology has already been shown to correlate with breast tumors that have a greater propensity to metastasize and negatively impact prognosis. 16 It is likely that a diversity of collagen topology profiles exist in pancreatic ductal adenocarcinoma tumors, which may prove useful as an ancillary disease marker to subtype patients during histological evaluation.…”

Impact of SPARC expression on outcome in patients with advanced pancreatic cancer not receiving nab-paclitaxel: a pooled analysis from prospective clinical and translational trials

“…On the other hand, recent preclinical data showed a deleterious effect of myofibroblast depletion in genetically engineered mouse models of PDAC, resulting in poor tumour differentiation, increased aggressiveness, proliferation, vascularisation and immunosuppression, finally leading to inferior OS (Özdemir et al , 2014; Rhim et al , 2014). Moreover, as the data on the prognostic role of the peritumoral stroma in humans (as measured by α -SMA expression) are still conflicting (Özdemir et al , 2014; Sinn et al , 2014a) and clinical trials for stromal depletion in PDAC have failed (Bramhall et al , 2002; Moore et al , 2003) clear conclusions on this subject cannot be drawn yet. Especially, the exact functions and interactions of each stromal component, such as myofibroblasts, extracellular matrix, pancreatic stellate cells and immune cells in tumour promotion or inhibition are contradictory, context dependent and still poorly understood in its complexity (Neesse et al , 2015).…”