title: 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 α-smooth muscle actin (αSMA). 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.
authors.affiliation: Ontario Cancer Institute/Princess Margaret Hospital, ON, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000072079:Patched Receptors; D012334:RNA, Neoplasm / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C509246:IHH protein, human; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C514061:ihh protein, mouse