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.
Takashi MurakamiYukihiko HiroshimaKentaro MiyakeHo Kyoung HwangTasuku KiyunaJonathan C DeLongThinzar M LwinRyusei MatsuyamaRyutaro MoriTakafumi KumamotoTakashi ChishimaKuniya TanakaYasushi IchikawaMichael BouvetItraru EndoRobert M HoffmanPublished in: Cell cycle (Georgetown, Tex.) (2017)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- mouse model
- high resolution
- drug delivery
- endothelial cells
- bone marrow
- quantum dots
- binding protein
- signaling pathway
- stem cells
- cancer therapy
- single molecule
- open label
- induced pluripotent stem cells
- randomized controlled trial
- cell therapy
- wild type
- clinical trial
- metabolic syndrome
- photodynamic therapy
- mass spectrometry
- long non coding rna
- combination therapy
- study protocol