Tumor–stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition

Abstract

To test the effects of hedgehog (Hh) pathway inhibition on the stroma of orthotopically grown primary pancreatic cancer xenografts, and investigate the potential to monitor these effects non-invasively using magnetic resonance imaging (MRI), mice bearing orthotopically grown primary pancreatic cancer xenografts were treated with the Hh neutralizing antibody 5E1. Pathway inhibition was determined by RT-PCR using primer sets for human and mouse Hh pathway genes, and effects on stroma assessed by automated image analysis of tissue sections stained for collagen and a-smooth muscle actin (aSMA). MRI provided quantitative biomarkers of stromal density based on magnetization transfer (MT-MRI) and dynamic contrast enhancement (DCE-MRI). Modest growth inhibition was seen in both models tested using 5E1, but was greater in OCIP19, which showed high expression of mouse Hh pathway genes and an extensive fibrous stroma. However, despite profound inhibition of both mouse and human Hh pathway genes, in neither model did we observe depletion of the stroma. Alignment of MT-MRI ratio images to histological sections showed co-registration with areas of fibrosis, although this was confounded by the presence of tumor necrosis. Due to the lack of stromal depletion by 5E1 it was not possible to determine the utility of MT-MRI for monitoring this effect. Cancer-and stromal cell-derived Hh signaling elements are expressed in orthotopic primary pancreatic cancer xenografts, and selective targeting is growth-inhibitory. In contrast to some recent reports, growth inhibition does not involve attenuation of the tumor stroma, pointing to additional effects of Hh signaling in pancreatic cancer.

Novel Aspects of the Liver Microenvironment in Hepatocellular Carcinoma Pathogenesis and Development

“…Hh expression from the primary tumour has been found to induce dense fibrous stroma formation in primary pancreatic cancer xenografts [245] and to break down bone stroma prior to breast cancer bone metastasis [246]. In the context of HCC, the Hh pathway has been shown to up-regulate glycolysis in surrounding myofibroblasts [247].…”

Cyclopamine-Loaded Core-Cross-Linked Polymeric Micelles Enhance Radiation Response in Pancreatic Cancer and Pancreatic Stellate Cells

“…Both stellate cells and stroma tissue contribute to the resilience of PDAC. Stellate cells may protect tumor cells against radiation and chemotherapy 24 . They also enhance the stemness of cancer cells that may cause tumor regrowth 25 .…”

Deciphering the role of stroma in pancreatic cancer

“…In contrast to these studies, another study found that inhibition of Hh signaling using the anti-Shh 5E1 antibody in primary patient derived pancreatic cancer xenografts at orthotopic sites did not result in attenuation of the stroma (40). These differences may be due to different levels of SHH production in the different models used, or alternatively it is possible that targeting different components of the Hh pathway may account for different effects of the tumor and its associated stroma (40). Recently an elegant study detailed the role of Gli1 in Kras induced carcinogenesis (41).…”