Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.tumor stroma | cancer therapy | Sonic hedgehog | hedgehog agonist | cerulein P ancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer-related death in the United States and is the most lethal of common human malignancies, with a 5-y survival rate of ∼7% (1, 2). The most effective chemotherapy regimens for metastatic or locally advanced inoperable disease are largely palliative and are capable of extending overall survival by only several months (3, 4). Even localized disease, treatable with surgery followed by adjuvant chemotherapy, has a dismal 5-y survival rate of 24% (1). Among gastrointestinal malignancies, PDA is unique in that it is predominantly driven by oncogenic Kras activity. In addition, PDA pathogenesis is marked by a striking desmoplastic reaction to invading tumor cells. This desmoplasia includes a dense extracellular matrix with abundant stromal fibroblasts and influences the cellular biology of the tumor as well as its response to chemotherapeutic agents.Hedgehog (Hh) signaling has been thought to play a role in PDA desmoplasia and tumor progression but is notable during embryonic development of the pancreas for its absence in the region of embryonic endoderm from which the pancreas forms (5-7). This absence of activity is required for normal specification of early pancreatic progenitor fate, and pharmacologic or antibody treatments that inhibit Hh ...
BACKGROUND & AIMS
Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.
METHODS
Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.
RESULTS
Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.
CONCLUSION
We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.
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