Authors thank Jeffrey Sellers to assist orthotopic pancreatic cancer mouse modeling. This work was supported by Research Initiative Pilot Awards from the Department of Radiology at UAB and NIH grants 2P30CA013148 and P50CA101955.

Todos os procedimentos foram aprovados pelo Comitê de Uso e Cuidado Animal Institucional da Universidade do Alabama, em Birmingham. 1. Orthotopic pâncreas Tumor Rato Modeling <ol><li> Linhas de padrão de cultura de células humanas do pâncreas-cancro em meio de Eagle modificado por Dulbecco (DMEM) suplementado com 10% de soro fetal bovino. Mantenha todas as culturas a 37 ° C em atmosfera humidificada com 5% de CO 2. </li><li> Use 8-10 semanas de idade, do sexo feminino graves ratos imunodeficientes combinados. Coloque as gaiolas dos animais em 12 horas de luz e escuridão ciclo de 12 horas à temperatura ambiente (21 ± 2 ° C) e 60% de humidade. </li><li> Anestesiar todos os animais utilizando ventilação com 2% de isoflurano misturado com oxigénio (2 L / min) durante toda a cirurgia. Confirme a profundidade da anestesia por toe pitada reflexo. Colocar os animais de uma almofada de aquecimento (37 ° C) para manter a temperatura corporal. Aplicar pomada oftálmica veterinária nos olhos para evitar a secura e sob anestesia. &amp;# 160; </li><li> Remover o cabelo no quadrante superior esquerdo do abdómen de cada rato, e dar um medicamento analgésico (carpofen, 5 mg / kg de peso corporal por via subcutânea) na área. Aplique uma solução de betadine para a pele exposta. Prepare instrumentos cirúrgicos autoclavada. </li><li> Faça uma incisão de 1 cm na pele e peritônio usando iris tesoura reta. Remova cuidadosamente o pâncreas do abdome utilizando pinças cirúrgicas. </li><li> Insira 28 L agulha de uma seringa de 0,5 mL de insulina na cauda do pâncreas e, em seguida, lentamente, uma solução de infusão de 2,5 milhões de células de cancro pancreático humano em 30 ul de DMEM. Confirme se uma pequena bolha é criado na cabeça do pâncreas pela solução. </li><li> Delicadamente, coloque o pâncreas volta para o abdômen utilizando pinças cirúrgicas. Feche o peritônio e da pele em uma camada com 2 interrompido 5-0 Prolene, e, em seguida, terminar a anestesia. Não devolva um animal que passou por uma cirurgia para a companhia de outros animais até que esteja totalmente recuperado.60; Remover suturas em 7 ~ 10 dias após a cirurgia. </li><li> Dê outra dose do medicamento analgésico (carpofen, 5 mg / kg de peso corporal por via subcutânea) a 24 h após a cirurgia. </li><li> Verifique o tamanho do tumor através da palpação da área de cirurgia usando dois dedos. Os tumores normalmente se sentir mais denso e mais instável do que os tecidos e órgãos adjacentes. Normalmente demora ~ 1-2 semanas para começar a sentir um tumor. </li><li> Monitorar os animais diariamente para sinais de doença. Quando os animais aparecem doentes (comportamentos de higiene e de prevenção de falta normais), encerramos-los usando deslocamento cervical sob anestesia. </li></ol> 2. Imagem por Ressonância Magnética <ol><li> Aplicar ressonância magnética quando o tamanho do tumor é de cerca de 5-7 mm de diâmetro a normalmente 2 a 4 semanas após a implantação da célula. Use um scanner de ressonância magnética dedicada a pequena imagem de animal ou um scanner MR clínica equipado com uma bobina especializado para pequena imagem animal. NOTA: Foi utilizado um animal pequeno scanner de ressonância magnética 9.4T com uma combinação de um volume de ressonância 1 H/ Transmissor e um receptor de superfície da bobina (30 mm de diâmetro) (Bruker BioSpin Corporation, Billerica, MA). A bobina de superfície proporciona melhor relação sinal-ruído (SNR) 14. </li><li> Prepara-se uma agente de contraste à base de gadolínio para MRI injectar ~ 0,1-0,2 mmol / kg a cada animal em ~ 0,1-0,2 ml de PBS (tampão fosfato salino). NOTA: Foi utilizado gadoteridol, e injectado 0,2 mmol / kg em 0,15 ml de PBS durante um período de 15 segundos (0,1 ml / seg). </li><li> Prepara-se uma micro-tubo de polietileno (comprimento: 7,62 milímetros, o diâmetro interno forma: 0,28 mm, diâmetro externo = 0,64 mm). Inserir uma agulha G 30 (comprimento de 12,7 mm) em uma das extremidades do tubo, e uma agulha 30 G romba ponta (9,5 mm de comprimento) na outra extremidade. Conectar uma seringa de 1 ml, contendo agente de contraste MR à agulha de ponta romba, e empurrar lentamente a seringa para encher todo o tubo com o agente de contraste de MR. </li><li> Anestesiar os animais utilizando ventilação com ~ 1 - 2% de isoflurano misturado com oxigénio (2 L / min) durante toda a preparação e imagiologia. Confirme a profundidade de Anesthesia por toe pitada reflexo. Aplicar pomada oftálmica veterinária nos olhos para evitar a secura e sob anestesia. Dilatar a veia da cauda usando uma lâmpada de calor antes da inserção da agulha. Pegue o meio da agulha de 30 G com a pinça Kelly, e inseri-lo na veia da cauda. Fita ambos a cauda e o tubo sobre uma folha de plástico ou de papel de cartão (10 mm de largura x 100 mm de comprimento) para manter a linha reta cauda. </li><li> Colocar o animal em decúbito dorsal em uma cama de animais equipado com circulação de água quente (ou ar quente) para regular a temperatura corporal durante o exame. Ajuste da temperatura no leito de 37 ° C. Insira uma sonda de temperatura rectal para monitorizar a temperatura do corpo durante o exame. </li><li> Aplicar uma placa de plástico orthogonally dobrada na área abdominal. Verifique se o tumor está localizado atrás da extremidade superior do tabuleiro, e, em seguida, puxe para baixo a placa ligeiramente (~ 2 mm) para garantir o tumor é capturado pela diretoria. Tape o tabuleiro para a cama dos animais com firmeza. </li><li> Tape um transduce pad respiraçãor (SA Instrument, Inc., Stony Brook, NY) na região do peito para monitorar a respiração animal durante o exame. Inserir uma bobina de superfície no topo da região do tumor, e fita-lo para a cama de animais com firmeza. Empurrar a cama dos animais no scanner MR para colocar a região do tumor no centro da bobina de volume (diâmetro interno: 72 milímetros). </li><li> Executar a correspondência e afinação tanto para o receptor e transmissor, seguido por calços. </li><li> Comece com uma sequência MR anatômica para localizar o tumor. Use uma sequência spin-echo (T2W) turbo T2 para obter imagens axiais com os seguintes parâmetros de aquisição. Tempo de repetição (TR) / tempo de eco (TE) = 3.000 / 34 ms, 128 x matriz de 128, 30 x 30 mm campo de visão, número de médias = 1, comprimento do comboio echo = 4 e 20 contíguas de 1 mm de espessura em um modo entrelaçado para cobrir toda a região do tumor (tempo total de digitalização: 1,6 min). Observação: Uma vez que os tumores pancreáticos ortotópicos são mais difíceis de ser localizado do que as subcutâneas, locali convencionalzer imagens com resolução mais baixa pode não ser útil. </li><li> Adquirir imagens ponderadas em T1 (T1W) com vários ângulos de aleta para recuperar T1 mapa. Para esta finalidade, utilizar um gradiente de eco abordagem ângulo multiflip com os seguintes parâmetros: tempo de repetição (TR) / tempo de eco (TE) = 115/3 mseg, de 128 x 128 de matriz, um campo de 30 x 30 mm de vista, o número de médias = 4, ~ 5-7 contíguas de 1 mm de espessura em um modo entrelaçado para cobrir a região do tumor, e sete ângulos de aleta de 10, 20, 30, 40, 50, 60 e 70 (tempo total de digitalização por flip angle: 1 min). NOTA: No entanto, a abordagem ângulo multiflip é eficiente somente quando o campo B1 homogeneidade é alta. Se não, mapas T1 pode ser obtido com a abordagem TR múltipla, em vez de 15. </li><li> Adquira imagens T1W antes e após a injeção de contraste gadolínio baseado MR. Use os mesmos parâmetros de aquisição e da geometria para o mapeamento T1 mas com o ângulo da aleta fixa de 30. Use codificação linear para garantir estado estacionário quando o centro de k-espaço é obtido, especially quando um curto TR e um ângulo de baixo grau de aleta são usados. Adquirir 5 imagens de base antes de injeção de contraste. Em seguida, adquirir 40 imagens após a injeção de contraste (tempo total de digitalização: 45 min). Usar uma bomba de seringa para injectar agente de contraste a uma taxa constante (0,01 ml / seg). </li><li> Controlar a respiração dos animais de forma contínua, e ajustar concentração de isoflurano para manter a freqüência respiratória para 50 - 100 respirações por minuto. Monitore a temperatura do corpo do animal durante exames de imagem. </li><li> Depois de completar DCE-MRI, retirar a agulha e outras sondas, e colocar o animal em uma gaiola vazia camas com toalhas de papel. Massageie suavemente a área abdominal inferior. A gaiola deve ser colocado metade sob uma lâmpada de calor para que os animais possam entrar e sair do gradiente de calor como ele se recupera. Não deixe um animal sem supervisão até que ele recuperou a consciência suficiente para manter decúbito esternal. </li></ol> 3. Processamento de Imagem e Análise <ol><li> Regi tumorais Segmento<html> em em imagens em T2. Em imagens em T2, a intensidade do sinal na região do tumor é mais brilhante do que a dos tecidos circundantes, de modo que o limite do tumor pode ser delineada manualmente. NOTA: técnicas semi-automáticas de segmentação, como limiar global ou contorno ativo pode ser usado 16,17, mas a intensidade de fundo irregular deve ser corrigido especialmente quando uma bobina de superfície é usado. </li><li> Criar mapas T1 e densidade de prótons. Em imagens T1W adquiridos com uma sequcia de eco de gradiente, assumindo que o tempo de eco (TE) é muito menor do que em T2 * valor, o valor de pixel é determinada pela <img alt="Equação 1" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq1.jpg" /> onde S 0 é a densidade de prótons, T 1 T 1 é tempo de relaxamento constante, TR é tempo de repetição, e θ é um ângulo de flip. A equação (1) pode ser reescrito para 641eq2.jpg &quot;/&gt; quando S (θ) / sinθ é substituído com Y, e S (θ) / tanθ é substituído com X. A equação (2) é uma equação linear, e a sua inclinação e intersecção pode ser utilizado para recuperar e T1 S valores 0, respectivamente. </li><li> Calcule concentração contraste MR em imagens DCE-MR. Quando agente de contraste MR base de gadolínio é injetado, T 1 relaxamento constante de tempo é alterada ao longo do tempo. Então, a equação (1) pode ser reescrito para <img alt="Equação 3" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq3.jpg" /> T 1 (t) está relacionada com a concentração de contraste MR, C (t), como se segue, <img alt="Equação 4" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq4.jpg" /> em que r é 1 a relaxação longitudinal do agente de contraste de MR. Assim, combinando as equações (3) e (4), a concentração de contraste MR é determinada pela <img alt = &quot;Equação 5&quot; fo: content-width = src &quot;3in&quot; = &quot;/ files / ftp_upload / 52641 / 52641eq5.jpg&quot; /&gt; </li><li> Quantificar os parâmetros farmacocinéticos do MR contraste agente. C p (t) apresenta concentração contraste MR no plasma sanguíneo no tempo t após o início da injeção de contraste. C p (t) é chamada função de entrada arterial (AIF). Se FIA ​​está disponível, os parâmetros farmacocinéticos do agente de contraste MR pode ser calculado <img alt="Equação 6" fo:content-width="4in" src="/files/ftp_upload/52641/52641eq6.jpg" /> em que C t (t) é a concentração de contraste na RM de um tecido alvo, p v é o volume do plasma sanguíneo fraccionada, e v é o volume extracelular extravascular fraccionada, e K é uma constante trans transferência de volume. Taxa de fluxo constante, k ep é igual a K trans divididos por v e. Se FIA não está disponível, então o modelo da região de referência pode ser utilizado em vez 18,19. O modelo da região de referência é baseado no modelo de fluxo Kety-20 e limitada usa concentração de contraste em uma região de referência para eliminar a necessidade de AIF como se segue, <img alt="Equação 7" fo:content-width="5in" src="/files/ftp_upload/52641/52641eq7.jpg" /> em que C t, ROI (t), K trans, ROI, e v e, ROI são concentração contraste, a transferência de volume constante, e volume extracelular extravascular-fraccionada, respectivamente, na região de interesse (ROI), enquanto a C t, RR (t), K trans, RR, e v e, RR são os da região de referência. Músculo paravertebral é frequentemente seleccionada como a região de referência e v e, em pa murino RRravertebral músculo é assumido ser constante a 0,08 21. Usamos o modelo região de referência. </li></ol>

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Authors do not have any conflicts of interest to declare.

Nós introduzimos os métodos detalhados de modelagem de tumor pancreático orthotopic usando ratos imunodeficientes, DCE-MRI de tumores abdominais em ratos, e quantificação de seus parâmetros cinéticos. Na modelagem de tumor pancreático orthotopic, é preciso ter cuidado ao inserir uma agulha na cauda do pâncreas. Se for bem sucedido, as células serão transferidos para a cabeça do pâncreas criando uma pequena bolha. Ao aplicar-se uma placa de plástico orthogonally dobrado, é fundamental para confirmar que o...

O objetivo geral deste método é a aplicação de contraste dinâmico aprimorado ressonância magnética (DCE-MRI) para ortotópicos xenografts tumor pancreático em camundongos. DCE-MRI é um método não-invasivo de avaliação da microvasculatura num tecido alvo por monitorização da alteração de contraste MR ao longo de um certo período de tempo após a injecção. DCE-MRI tem sido utilizada para diagnóstico de tumores malignos e para avaliar a resposta do tumor a várias terapias 1-4. Quantitative DCE-MRI apresentou alta reprodutibilidade 5. Para quantificar os parâmetros farmacocinéticos de um agente de contraste MR em um tecido alvo, todas as imagens DCE-MR adquiridas em diferentes momentos e mapa T1 obtidos antes da injeção de contraste devem ser georeferenciados 6. No entanto, devido aos movimentos respiratórios e peristálticas na área abdominal, quantitativa DCE-MRI teve aplicação limitada para tumores gastrointestinais. Modelos ortotópicos de tumor pancreático foram utilizados para avaliarresposta de pâncreas-tumor seguinte terapias biológicas e quimioterapias 7,8. Modelos ortotópicos de tumor são considerados superiores aos modelos subcutâneos convencionais, uma vez que o microambiente no local do tumor original é reflectida e, assim, a resposta do tumor à terapia humana podem ser previstos com mais precisão. No entanto, o pâncreas do mouse está localizado no quadrante superior esquerdo do abdome, de modo quantitativo DCE-MRI de ortotópicos xenotransplantes de tumor do pâncreas em ratos não foi prontamente implementadas. Nós estabelecemos um protocolo de DCE-MRI de tumores abdominais em camundongos, fixando os tumores usando uma placa de plástico orthogonally dobrado para evitar a transferência de movimento da região do tórax 9. A pressão aplicada por este fórum foi localizada na área abdominal, e não resultou em dificuldade respiratória. Uma técnica automatizada imagem coregistration foi validado para DCE-MRI de órgãos abdominais em um modo livre de respiração, mas ele executa effectively apenas quando as regiões alvo mover-se lentamente e regularmente 10. A freqüência respiratória dos animais é variável durante o exame, moderação, de modo físico na área abdominal será necessário para recuperar os parâmetros farmacocinéticos de confiança em modelos de ratos tumor pancreático ortotópicos. Temos quantificada com sucesso os parâmetros farmacocinéticos de um agente de contraste MR em ortotópicos xenografts tumor pancreático usando a placa de plástico orthogonally dobrado em DCE-MRI 11-13. Aqui apresentamos o procedimento detalhado de modelagem tumor pancreático orthotopic, DCE-MRI dos xenotransplantes de tumor em ratos, e quantificação dos parâmetros farmacocinéticos.

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			<td height="21" style="height:21px;">DMEM</td>
			<td>Invitrogen</td>
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			<td height="21" style="height:21px;">Fetal bovine serum</td>
			<td>Harlan Laboratories</td>
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			<td height="21" style="height:21px;">Betadine</td>
			<td style="width:199px;">Purdue products</td>
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			<td height="21" style="height:21px;">5-0 Prolene sutures</td>
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			<td height="42" style="height:42px;">9.4T MR scanner</td>
			<td>Bruker Biospin Corporation</td>
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			<td>Bracco Diagnostics Inc</td>
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			<td height="21" style="height:21px;">Micro-polyethelene tube</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
			<td style="width:119px;">#PE-10-25</td>
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			<td height="21" style="height:21px;">30G blunt tip needle</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
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			<td height="21" style="height:21px;">Monitoring and gating system</td>
			<td style="width:199px;">SA instruments, Inc</td>
			<td style="width:119px;">Model 1030</td>
			<td>This is an MR compatiable system to measure resiratory rating and body temperature of small animals at the same time.</td>
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			<td height="21" style="height:21px;">Syringe pump</td>
			<td>New Era Pump Systems, Inc.</td>
			<td>NE-1600</td>
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dynamic contrast enhanced magnetic resonance imaging of an orthotopic pancreatic cancer mouse model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

As células tumorais pancreáticas humanas crescer com sucesso em pâncreas de rato criando um tumor sólido. A Figura 1 apresenta fotografias de (A) um pâncreas normal onde a solução da célula de tumor é injectada, e (B) um ratinho representativo tendo um xenoenxerto de tumor pancreático ortotópico (MIA PaCa-2 ). Tumor está localizado no quadrante superior esquerdo do abdómen, ao lado do baço. Ele normalmente leva 2-4 semanas para que os tumores a crescer até 5-7 mm de diâmetro após o impl...

Watch this Scientific Journal Video about Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model at JoVE.com

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy.

Contraste Dinâmico aprimorada Ressonância Magnética de um Modelo de câncer de pâncreas Orthotopic Rato

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

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Research

JoVE Journal

Medicine

15.0K visualizações.  University of Alabama at Birmingham. The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy. 

Vídeo: Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Contrast Enhanced Vessel Imaging using MicroCT

Microscopic computed tomography (microCT) offers high-resolution volumetric imaging of the anatomy of living small animals. However, the contrast between different soft tissues and body fluids is inherently poor in micro-CT images 1. Under these circumstances, visualization of blood vessels becomes a nearly impossible task. To overcome this and to improve the visualization of blood vessels exogenous contrast agents can be used. Herein, we present a methodology for visualizing the vascular network in a rodent model. By using a long-acting aqueous colloidal polydisperse iodinated blood-pool contrast agent, eXIA 160XL, we optimized image acquisition parameters and volume-rendering techniques for finding blood vessels in live animals. Our findings suggest that, to achieve a superior contrast between bone and soft tissue from vessel, multiple-frames (at least 5-8/ frames per view), and 360-720 views (for a full 360&deg; rotation) acquisitions were mandatory. We have also demonstrated the use of a two-dimensional transfer function (where voxel color and opacity was assigned in proportion to CT value and gradient magnitude), in visualizing the anatomy and highlighting the structure of interest, the blood vessel network. This promising work lays a foundation for the qualitative and quantitative assessment of anti-angiogenesis preclinical studies using transgenic or xenograft tumor-bearing mice.

Contrast enhanced small animal vessel imaging by microCT is a rapid, cost-effective and high-throughput technique for serial in situ examination for tumor development, for analyzing the network of blood vessels that nourish them, and for following the response of tumors to preclinical therapeutic intervention(s).

Contraste de imagem aprimorada navio usando MicroCT

Microscopic computed tomography (microCT) offers high-resolution volumetric imaging of the anatomy of living small animals. However, the contrast between ...

Medicina

An Orthotopic Model of Murine Bladder Cancer

In this straightforward procedure, bladder tumors are established in female C57 mice through the use of catheterization, local cauterization, and subsequent cell adhesion. After their bladders are transurethrally catheterized and drained, animals are again catheterized to permit insertion of a platinum wire into bladders without damaging the urethra or bladder. The catheters are made of Teflon to serve as an insulator for the wire, which will conduct electrical current into the bladder to create a burn injury. An electrocautery unit is used to deliver 2.5W to the exposed end of the wire, burning away extracellular layers and providing attachment sites for carcinoma cells that are delivered in suspension to the bladder through a subsequent catheterization. Cells remain in the bladder for 90 minutes, after which the catheters are removed and the bladders allowed to drain naturally. The development of tumor is monitored via ultrasound. Specific attention is paid to the catheterization technique in the accompanying video.

Bladder tumors are established in female mice in a minimally invasive fashion through catheterization, local cauterization, and subsequent adhesion of carcinoma cells to the burn sites.

Um modelo ortotópico de câncer de bexiga murino

In this straightforward procedure, bladder tumors are established in female C57 mice through the use of catheterization, local cauterization, and ...

Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient management strategies. Orthotopic mouse models of oral cancer have been developed to facilitate the study of factors that impact invasion and serve as model system for evaluating anti-tumor therapeutics. In these systems, visualization of disseminated tumor cells within oral cavity tissues has typically been conducted by either conventional histology or with in vivo bioluminescent methods. A primary drawback of these techniques is the inherent inability to accurately visualize and quantify early tumor cell invasion arising from the primary site in three dimensions. Here we describe a protocol that combines an established model for squamous cell carcinoma of the tongue (SCOT) with two-photon imaging to allow multi-vectorial visualization of lingual tumor spread. The OSC-19 head and neck tumor cell line was stably engineered to express the F-actin binding peptide LifeAct fused to the mCherry fluorescent protein (LifeAct-mCherry). Fox1nu/nu mice injected with these cells reliably form tumors that allow the tongue to be visualized by ex-vivo application of two-photon microscopy. This technique allows for the orthotopic visualization of the tumor mass and locally invading cells in excised tongues without disruption of the regional tumor microenvironment. In addition, this system allows for the quantification of tumor cell invasion by calculating distances that invaded cells move from the primary tumor site. Overall this procedure provides an enhanced model system for analyzing factors that contribute to SCOT invasion and therapeutic treatments tailored to prevent local invasion and distant metastatic spread. This method also has the potential to be ultimately combined with other imaging modalities in an in vivo setting.

A comprehensive overview of the techniques involved in generating a mouse model of oral cancer and quantitative monitoring of tumor invasion within the tongue through multi-photon microscopy of labeled cells is presented. This system can serve as a useful platform for the molecular assessment and drug efficacy of anti-invasive compounds.

Multi-fotão imagem de invasão das células tumorais em um modelo de camundongo ortotópico de carcinoma epidermóide oral

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient ...

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 &mu;l every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

The purpose of this article is to describe the use of an orthotopic glioblastoma model for chemoradiation studies. This article will go though cell processing, implanting, and radiotherapy of the mouse using an intracranial model.

Radioterapia em uma combinação ortotópico modelo de tumor de cérebro de camundongos

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the ...

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.
For this purpose, we injected 105 MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).
MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles7.
In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.

In the pathogenesis of bone metastasis, angiogenesis is a crucial process and therefore represents a target for imaging and therapy. Here, we present a rat model of site-specific breast cancer bone metastasis and describe strategies to non-invasively image angiogenesis in vivo using magnetic resonance imaging, volumetric computed tomography and ultrasound.

Multi-modal de imagem de angiogênese em um modelo de rato nu de Câncer de mama utilizando a ressonância magnética, tomografia computadorizada volumétrica e ultra-som

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell ...

An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma

Several types of animal models of human thyroid carcinomas have been established, including subcutaneous xenograft and orthotopic implantation of cancer cells into immunodeficient mice. Subcutaneous xenograft models have been valuable for preclinical screening and evaluation of new therapeutic treatments. There are a number of advantages to using a subcutaneous model; 1) rapid, 2) reproducible, and 3) tumor establishment, growth, and response to therapeutic agents may be monitored by visual inspection. However, substantial evidence has shed light on the short-comings of subcutaneous xenograft models1-3. For instance, medicinal treatments demonstrating curative properties in subcutaneous xenograft models often have no notable impact on the human disease. The microenvironment of the site of xenographic transplantation or injection lies at the heart of this dissimilarity.
Orthotopic tumor xenograft models provide a more biologically relevant context in which to study the disease. The advantages of implanting diseased cells or tissue into their anatomical origin equivalent within a host animal includes a suitable site for tumor-host interactions, development of disease-related metastases and the ability to examine site-specific influence on investigational therapeutic remedies. Therefore, orthotopic xenograft models harbor far more clinical value because they closely reproduce human disease. For these reasons, a number of groups have taken advantage of an orthotopic thyroid cancer model as a research tool4-7.
Here, we describe an approach that establishes an orthotopic model for the study of anaplastic thyroid carcinoma (ATC), which is highly invasive, resists treatment, and is virtually fatal in all diagnosed patients. Cultured ATC cells are prepared as a dissociated cellular suspension in a solution containing a basement membrane matrix. A small volume is slowly injected into the right thyroid gland. Overall appearance and health of the mice are monitored to ensure minimal post-operative complications and to gauge pathological penetrance of the cancer. Mice are sacrificed at 4 weeks, and tissue is collected for histological analysis. Animals may be taken at later time-points to examine more advance progression of the disease. Production of this orthotopic mouse model establishes a platform that accomplishes two objectives: 1) further our understanding of ATC pathology, and 2) screen current and future therapeutic agents for efficacy in combating ATC.

Generation of an orthotopic mouse model of anaplastic thyroid carcinoma is described here. This technique employs surgical placement of human anaplastic thyroid cancer cells into the thyroid of immunodeficient mice, thus creating a more clinically relevant setting to study disease progression as well as screen innovative therapeutic interventions.

Um modelo de camundongo ortotópico de Carcinoma anaplásico da tiróide

Several types of animal models of human thyroid carcinomas have been established, including subcutaneous xenograft and orthotopic implantation of cancer ...

An Orthotopic Bladder Cancer Model for Gene Delivery Studies

Bladder cancer is the second most common cancer of the urogenital tract and novel therapeutic approaches that can reduce recurrence and progression are needed. The tumor microenvironment can significantly influence tumor development and therapy response. It is therefore often desirable to grow tumor cells in the organ from which they originated. This protocol describes an orthotopic model of bladder cancer, in which MB49 murine bladder carcinoma cells are instilled into the bladder via catheterization. Successful tumor cell implantation in this model requires disruption of the protective glycosaminoglycan layer, which can be accomplished by physical or chemical means. In our protocol the bladder is treated with trypsin prior to cell instillation. Catheterization of the bladder can also be used to deliver therapeutics once the tumors are established. This protocol describes the delivery of an adenoviral construct that expresses a luciferase reporter gene. While our protocol has been optimized for short-term studies and focuses on gene delivery, the methodology of mouse bladder catheterization has broad applications.

Implantation of cancer cells into the organ of origin can serve as a useful preclinical model to evaluate novel therapies. MB49 bladder carcinoma cells can be grown within the bladder following intravesical instillation. This protocol demonstrates catheterization of the mouse bladder for the purpose of tumor implantation and adenoviral delivery.

Um modelo de cancro da bexiga para Ortotópico Gene Estudos de entrega

Bladder cancer is the second most common cancer of the urogenital tract and novel therapeutic approaches that can reduce recurrence and progression are ...

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

Improved understanding of pancreatic cancer biology is critically needed to enable the development of better therapeutic options to treat pancreatic cancer. To address this need, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression using in vivo bioluminescence imaging.

Modelo ortotópico bioluminescente de progressão do câncer de pâncreas

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%.  New therapeutic options are critically needed and depend on improved ...

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.

This orthotopic model of human prostate cancer allows for quantification of tumor size, circulating tumor cells, and formation of distinct metastasis to the lung. As cells must escape the primary organ, enter the blood stream, and implant into a secondary site, this model effectively recapitulates the scenario in humans.

Um Modelo murino de próstata humana Metástase Ortotópico

Our laboratory has developed a novel orthotopic implantation model of  human prostate cancer (PCa). As PCa death is not due to the primary tumor, but  ...

Simultaneous PET/MRI Imaging During Mouse Cerebral Hypoxia-ischemia

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-&#7429;-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes.

The method presented here uses simultaneous positron emission tomography and magnetic resonance imaging. In the cerebral hypoxia-ischemia model, dynamic changes in diffusion and glucose metabolism occur during and after injury. The evolving and irreproducible damage in this model necessitates simultaneous acquisition if meaningful multi-modal imaging data are to be acquired.

Simultânea de imagem PET / MRI Durante Rato isquemia-hipoxia cerebral

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics ...