Stromal response to Hedgehog signaling restrains pancreatic cancer progression

Abstract

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 ...

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

“…Hence, the beneficial effects of Hh-mediated suppression of inflammation also extend to its downstream sequelae, namely progression to adenocarcinoma. Such effects of stromal Hh pathway activity have also been seen in epithelial tumor progression in the pancreas and bladder (10,14,31).…”

“…2C). To further explore pathway activation, we tested the effect of a small-molecule Smoothened agonist, SAG21k (14,15), which generates a 2.8-fold maximal elevation of Gli1 transcript levels in the colon of uninjured FVB mice at a dose of 0.5 mg/kg twice per day (Fig. S2D).…”

Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice

“…1,3,16,18,19,22,26,32,34,38,40,43,46,50,60 The complex tissue architecture of ACPs, with a range of cell types (e.g., palisading epithelium, stellate reticulum, clusters, reactive glial tissue, and inflammatory cells), has posed a particular challenge. It is important to interpret the molecular data in the context of the appropriate cell types within the tumor and surrounding reactive tissue.…”

“…The experience of use of SHH pathway inhibitors in pancreatic cancer, or BRAF inhibitors in BRAF-fusion gene-positive low-grade gliomas highlights this best, as treatment was found to promote rather than inhibit tumor growth. 27,32,43 …”

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

“…Whereas, the current outcome of clinical trials targeting pancreatic stroma does not meet the high expectation. More importantly, recently published several studies provide new explanations for the failure of trials, suggesting ablation of the stroma may lead to poorly differentiated tumors and accelerate PDA progression (18)(19)(20)(21). These conflicting evidences prompt us to revisit the role of stromal cell.…”