UCSF team suggests proteins could represent therapeutic targets against PDA formation and progression.
Scientists have implicated the inflammatory mediator Stat3 in the process by which pancreatic cancer develops from chronic pancreatitis and matrix metalloproteinase 7 (MMP7; also known as matrilysin), in the triggering of subsequent metastases. The University of California, San Francisco (UCSF) team subsequently found that elevated serum MMP7 levels correlated with metastatic disease and poor survival in human pancreatic patients.
The research is published in Cancer Cell in a paper titled “Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression.”
Chronic pancreatitis is known to be a risk factor for pancreatic ductal carcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models, the authors write. However, the mechanistic link between inflammatory damage and PDA initiation has to date remained unclear.
To try and unravel the mechanisms behind pancreatic cancer development further, the UCSF team, led by Matthais Hebrok, Ph.D., and Akihisa Fukuda, Ph.D., used a variety of genetic models including a KRAS-driven mouse model of PDA, to investigate the roles of Stat3 and MMP7.
They found Stat3 signaling to be crucial for spontaneous and pancreatitis-induced KRAS-driven pancreatic intraepithelial neoplasia (PanIN) formation. Stat signaling was shown to support increased cell proliferation, activate an aberrant immune response, and upregulate MMP7 expression in PDA cells. Conversely, both spontaneous and pancreatitis-induced PanIN formation were inhibited by Stat3 deletion, the authors write.
They separately found what they claim is a previously unappreciated role for MMP7 in regulating PDA tumor size and metastasis, which was confirmed by showing that MMP7 deletion limited tumor size and metastasis in mice. Moreover, elevated levels of MMP7 in the serum of PDA patients was a significant predictor of survival even after stratifying for treatment type and tumor class in multivariate analysis. “The data suggests serum levels of MMP7 may be a useful clinical tool to predict survival in patients suffering from PDA”, the authors write.
“Our data suggest that Stat3 plays both a critical cell autonomous role in maintaining the proliferative, persistently de-differentiated epithelial state permissive for PDA precursor formation and also contributes to metaplasia associated inflammation,” the UCSF team concludes. “These findings demonstrate that Stat3 activation in pancreatic epithelial cells plays a significant role linking pancreatitis and PDA initiation in vivo. The involvement of Stat3 in PDA initiation highlights the potential of Stat3 as a therapeutic target for preventing inflammation-associated PDA formation at the earliest stage.”
They also suggest that the significant reduction of metastatic disease seen in MMP knockout mice could have major implications in a clinical setting, with MMP7 inhibition representing a potential adjuvant approach to blocking disease progression after resection. However, more studies are needed, the researchers stress. “As with many things, timing is critical,” admits Dr. Hebrok, Ph.D. “We will need to understand in more detail during which stage of the disease therapeutic targets are activated to efficiently inhibit their function and thus cancer formation and progression.”
Collaborators on the research with the UCSF team included scientists at Osaka University in Japan and the Huntsman Cancer Institute at the University of Utah in Salt Lake City.