Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model.

Abstract

Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-β (TGF-β) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor.

• Authors: Takashi Murakami, Yukihiko Hiroshima, Kentaro Miyake, Ho Kyoung Hwang, Tasuku Kiyuna, Jonathan C DeLong, Thinzar M Lwin, Ryusei Matsuyama, Ryutaro Mori, Takafumi Kumamoto, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M Hoffman
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 16 Issue 10 Pg. 1008-1014 (May 19 2017) ISSN: 1551-4005 [Electronic] United States
• PMID: 28441080 (Publication Type: Journal Article)

Chemical References

• 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
• Benzamides
• Dioxoles
• Luminescent Proteins
• Transforming Growth Factor beta
• red fluorescent protein
• Green Fluorescent Proteins

Topics

• Animals
• Benzamides (administration & dosage)
• Cell Tracking (methods)
• Dioxoles (administration & dosage)
• Disease Models, Animal
• Fluorescence
• Gene Expression Regulation, Neoplastic (genetics)
• Green Fluorescent Proteins (genetics)
• Humans
• Luminescent Proteins (genetics)
• Mice
• Mice, Transgenic
• Pancreatic Neoplasms (diagnostic imaging, drug therapy, genetics, pathology)
• Stromal Cells (drug effects, pathology)
• Transforming Growth Factor beta (antagonists & inhibitors, genetics)
• Tumor Microenvironment (drug effects)