Citation Details

Journal Article

IVIS, Xen29, Xen 29, Staphylococcus aureus Xen29, Animals; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Pneumonectomy/*adverse effects; Postoperative Complications/*surgery; Stem Cell Transplantation/*methods; Thoracic Cavity/*surgery; Thoracoplasty/*methods; Tissue Engineering/*methods

BACKGROUND: Transfer of viable tissue flaps and thoracoplasty are effective against pleural space complications after pneumonectomy but highly disfiguring. The aim of this study was to explore the possibility of engineered tissue to treat space complications after pneumonectomy. METHODS: A left pneumonectomy was performed in mice, and the cavity immediately filled with the cellularized collagen matrices. First, bone marrow derived-mesenchymal stroma cells with luciferase expression were used as donor cells to evaluate cell viability and angiogenesis using bioluminescence imaging. Second, using bone marrow cells from GFP mice, histologic evaluation, immunohistochemistry for von Willebrand Factor, and flow cytometric analysis was performed compared with acellular matrix implants. The effect on bacterial clearance was examined using an empyema model with Staphylococcus aureus expressing luciferase. RESULTS: Embedded cells proliferated within the denatured collagen matrices ex vivo. In vivo, bioluminescent imaging activity could be detected till day 8, and the slope (suggesting rate of perfusion with luciferin) increased with time up to day 6 but decreased after day 7. Although GFP-positive donor cells decreased with time, total cellularity increased. Furthermore, vessels stained by von Willebrand factor were significantly increased. Both cellularized and acellularized matrices showed bacterial clearance in vivo. CONCLUSIONS: Cells within collagen matrices survive in the thoracic cavity at early time points. Cellularized matrices quickly lead to neovascularization and recipient cell infiltration. Both cellularized and acellularized matrices show bacterial clearance in vivo. This study indicates the potential feasibility of a novel tissue engineering approach to problems of the postpneumonectomy space.

Journal Article

angiogenesis imaging; in vivo imaging; Angiogenesis; Bioluminescence; Fluorescence; Molecular imaging; Optical imaging

In recent years, molecular imaging gained significant importance in biomedical research. Optical imaging developed into a modality which enables the visualization and quantification of all kinds of cellular processes and cancerous cell growth in small animals. Novel gene reporter mice and cell lines and the development of targeted and cleavable fluorescent “smart” probes form a powerful imaging toolbox. The development of systems collecting tomographic bioluminescence and fluorescence data enabled even more spatial accuracy and more quantitative measurements. Here we describe various bioluminescent and fluorescent gene reporter models and probes that can be used to specifically image and quantify neovascularization or the angiogenic process itself.

Journal Article

4T1-luc2, 4T1, Bioware, IVIS

Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.

Journal Article

Cancer; flank tumor; In vivo; MMPSense 750; ProSense 680; tomography; VisEn FMT

<AbstractText Label=“BACKGROUND” NlmCategory=“BACKGROUND”>The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models.</AbstractText> <AbstractText Label=“METHODS” NlmCategory=“METHODS”>We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis.</AbstractText> <AbstractText Label=“RESULTS” NlmCategory=“RESULTS”>We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ~5- to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and [d-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage-independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ~65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis.</AbstractText> <AbstractText Label=“CONCLUSIONS” NlmCategory=“CONCLUSIONS”>Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.</AbstractText>

Journal Article

Colorectal cancer; optical imaging; molecular imaging; cancer genetics

Colorectal cancer remains a major cause of morbidity and mortality in the United States. The advent of molecular therapies targeted against specific, stereotyped cellular mutations that occur in this disease has ushered in new hope for treatment options. However, key questions regarding the optimal dosing schedules, dosing duration, and patient selection remain unanswered. In this review, we describe how recent advances in molecular imaging, specifically optical molecular imaging with fluorescent probes, offer potential solutions to these questions and may play a key role in improving outcomes. We begin with an overview of optical molecular imaging, including a discussion on the various methods of design for fluorescent probes and the clinically relevant imaging systems that have been built to image them. We then focus on the relevance of optical molecular imaging to colorectal cancer. We review the most recent data on how this imaging modality has been applied to the measurement of treatment efficacy for currently available as well as some as-of-yet developmental molecularly targeted therapies in animal studies. We then conclude with a discussion on how this imaging approach has already begun to be translated clinically for human use.