Sir,
We read with great interest the recent study by Sinn et al (2014) that demonstrated significantly increased α-smooth muscle actin (α-SMA) expression in pancreatic cancer stroma, which was correlated with worse survival outcomes in patients who underwent tumour resection and did not receive any adjuvant treatment. The authors also showed that dense stroma in the tumour microenvironment is associated with better outcomes in pancreatic cancer patients. We would like to discuss further points about the relationship between increased α-SMA expression and worse outcomes in pancreatic cancer patients.
Increased Sonic Hedgehog signalling in both tumour cell and tumour stroma has been found to be related to increased α-SMA expression (Bailey et al, 2008). Sonic Hedgehog signalling has also been demonstrated to be involved in pancreatic cancer stem cell development (Takebe et al, 2010), and the Sonic Hedgehog transcript was shown to be increased four-fold in the general pancreatic cancer cell population, but 46-fold in CD44+CD24+ESA+ pancreatic cancer stem cells (Lee et al, 2008). Moreover, pancreatic cancer stem cells have a 100-fold greater tumour-initiating capability compared with non-stem pancreatic cancer cells (Li et al, 2007). Therefore, increased α-SMA expression actually may indirectly indicate an increased pancreatic cancer stem cell population that is directly related to tumour growth and metastatic activity (Hermann et al, 2007), and the associated increased Sonic Hedgehog signalling in the tumour microenvironment.
A recent study showed that stromal elements that respond to tumour growth restrain the tumour growth, and that inhibition of the stromal response induces more aggressive tumour behaviour and disease progression via increased angiogenesis (Rhim et al, 2014). Similarly, increased cell proliferation in pancreatic intraepithelial neoplasia has been observed upon inhibition of hedgehog signalling in the tumour stroma (Lee et al, 2014). Moreover, a phase II clinical trial investigating the role of the Sonic Hedgehog signal inhibitor, saridegib combined with gemcitabine, was terminated early due to worse survival outcomes in the treatment arm compared with the placebo plus gemcitabine arm (Lou, 2014). A more recent clinical trial also failed to demonstrate any benefit of inhibiting the Sonic Hedgehog pathway; even more strikingly, there was no significant effect on pancreatic cancer stem cells either (Kim et al, 2014).
Altogether, elevated α-SMA expression in tumours may be indirectly related to survival outcomes and rather it may be a sign of increased cancer stem cell population, as studies have shown no benefit upon inhibition of desmoplasia. Further studies are required to enlighten the exact relationship between cancer stem cells and the tumour microenvironment.
The authors state no conflict of interest.
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