Tumor growth

After irradiation, the tumor is daily measured to determine the mean diameter, or volume. Unirradiated tumors will grow continuously whereas irradiated tumors show some shrinkage or delayed growth, then regrow. The measured score is growth delay or time to grow to a specified size in function of the received dose.

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Tumor control (TCD50 assay) provides data of most obvious relevance to radiotherapy. In experiments, animals with tumors of uniform size are irradiated locally with graded doses. The tumors subsequently are observed regularly for recurrence or local control. The proportion of tumors that are locally controlled can be plotted as a function of dose, and data of this kind are amenable to a statistical analysis to determine the TCD50, the dose at which 50% of the tumors are locally controlled.

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Angiogenesis

ear sponge assayIn this model, a polymer matrix (in the form of a sponge or a Matrigel gel/plug) containing cells and/or an angiogenic factor is implanted between the two skin layers of mice ear.

The test substance is directly injected into the sponge.

Neovascularization can then be assessed by a variety of methods including immunohistological staining or by evaluation of the blood/hemoglobin content of the sponge.

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choroidal neovascularization modelThe Choroidal neovascularization model relies on laser injury to perforate Bruch’s membrane, resulting in subretinal blood vessel recruitment from the choroid.

By recapitulating the main features of the exudative form of human age-related macular degeneration, this assay serves for the backbone for testing antiangiogenic therapies.

The protocol is outlined in the published article Lambert V. et al., Nature protocols (2013), 8.

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Lung colony assay

Lung colony assay is a technique to assay the clonogenicity of the cells of a solid tumor irradiated in situ by injecting them into recipient animals and counting the number of lung colonies produced.

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GVM Mouse model

Researchers at GIGA have developed a murine graft-versus-myeloma (GVM) model by combining an immunocompetent myeloma model and a chronic graft-versus-host (GVH) disease model. This model is currently used for further studies aiming at dissociating GVM and GVH effect.

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Transgenic mice

To determine in vivo actual functions of ADAMTS-3, researchers at GIGA have created an ADAMTS-3 knockout mouse (Adamts-3-/3) model.

Heterozygous Adamts-3-/- mice were viable and fertile but their intercrosses demonstrated lethality of Adamts-3-/- embryos after 15 days of gestation.

Procollagens I, II and III processing was unaffected in these embryos. However, a massive lymphedema caused by the lack of lymphatics development, an abnormal blood vessel structure in the placenta and a progressive liver destruction were observed. These phenotypes are most probably linked to dysregulation of the VEGF-C pathways. This study is the first demonstration that an aminoprocollagen peptidase is crucial for developmental processes independently of its primary role in collagen biology and has physiological functions potentially involved in several human diseases related to angiogenesis and lymphangiogenesis.

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The mutant mice Adamts-12-/- had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, matrigel plug and aortic ring assays) to Adamts-12-/- mice, researchers provide evidence for a protective effect of this host enzyme towards angiogenesis and cancer progression.

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The mutant mice Adamts-14-/- did not display a specific phenotype. However, Adamts-2-/-/Adamts-14-/- double knockout mice are more severely affected than Adamts-2 single knockout, illustrating some level of functional redundancy between the two enzymes.

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Mammary gland-specific expression of polyoma middle T antigen (PyMT) under the control of the Mouse Mammary Tumor Virus (MMTV) promoter/enhancer in transgenic mice (MMTV-PyMT) results in widespread transformation of the mammary epithelium and in the development of multifocal mammary adenocarcinomas and metastatic lesions in the lymph nodes and in the lungs.

Tumor formation and progression in these mice is characterized by four stages: hyperplasia, adenoma/mammary intra-epithelial neoplasia, and early and late carcinoma. The close similarity of this model to human breast cancer is also exemplified by the fact that in these mice a gradual loss of steroid hormone receptors (estrogen and progesterone) and β1-integrin is associated with overexpression of ErbB2 and cyclin D1 in late-stage metastatic cancer.

The MMTV-PyMT mouse model of breast cancer is furthermore characterized by short latency, high penetrance, and a high incidence of lung metastasis occurring independently of pregnancy and with a reproducible kinetics of progression.

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In this model,  basal cells of the squamous epithelium are targeted using a fragment of the human keratin 14 (K14) promoter/enhancer to drive the expression of human papillomavirus type 16 (HPV16).

In these mice, hyperplasia, papillomatosis and dysplasia appear at multiple epidermal and squamous mucosal sites, including ear and truncal skin, face, snout and eyelids and anus.

These K14-HPV16 transgenic mice present an opportunity to study the role of the HPV16 oncogenes in the neoplastic progression of squamous epithelium and provide a model to identify genetic and epigenetic factors necessary for carcinogenesis. It also allows to test drugs as well as the adaptation of tumor to drugs.

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Dual specificity protein phosphatase 3 (DUSP3) is a member of the dual specificity protein phosphatase subfamily which inactivates their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues.

To analyze the actual function of DUSP3, researchers at GIGA have generated a dual-specificity phosphatase 3 deficient mice.

These mice develop normally and do not exhibit any spontaneous phenotype.

However, researchers have observed that DUSP3 is an important player in angiogenesis. Indeed, they have observed that DUSP3 deficiency prevents net-vascularization and is required for basic fibroblast growth factor (b-EGF)-induced microvessel outgrowth.

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PDX mouse model

“Tumor graft models” (also known as Patient-Derived Xenografts or PDXs) are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse.

To accomplish this, patient tumors must be obtained fresh from surgery. Tumors can be engrafted heterotopically or orthotopically.

PDX models may be superior to traditional cell line – xenograft models of cancer because they maintain more similarities to the parental tumors. Detailed examination of PDX mice indicate that histology and gene expression profiles are retained, along with SNPs and copy number variants.

PDX models are maintained by passaging cells directly from mouse to mouse once the tumor burden becomes too high.

PDX models offer a powerful tool for studying tumor biology and for evaluating anticancer drugs.

The in vivo imaging system (Xenogen®) can be used to better follow tumor progression. For more information, click here.

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Tumor xenograft models

In this model, human cancer cells are transplanted either heterotopically (into the subcutaneous flank) or orthotopically (direct implantation to the mouse organ from which the tumor is originated) into immunocompromised mice.

The response to appropriate therapeutic regimes (such as anti-angiogenic drugs) on tumor size (diameter, area or volume) and animal survival (determined at regular intervals) can be pursued.

The in vivo imaging system (Xenogen®) can be used to better follow tumor progression. For more information, click here.

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Orthotopic xenograft mouse model

Orthotopic xenografts of human glioblastoma cells (e.g. by the intracranial transplantation into nude or NOD-SCID mice) provide new in vivo models for the evaluation of tumorigenicity, cancer cell migration, identification of tumor initiating cells and in vivo analyses of therapeutic efficacy of drugs on primary human tumors.

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GVHD mouse models

Most mouse models of graft-versus-host disease (GvHD) involve the transplantation of T-cell-depleted bone marrow supplemented with varying numbers and phenotypic classes of donor lymphocytes (either splenocytes or lymph node T-cells) into lethally irradiated recipients. The bone marrow provides donor stem cells that allow hematopoietic reconstitution after transplant. T-cell depletion is carried out to control the dose and type of immune cells that are delivered.

GvHD mouse models are used to mimic the clinical disorders of acute and chronic GvHD that occur after allogeneic bone marrow transplantation. They can also be used to study T-cell regulation, tolerance induction, autoimmune diseases and drugs or cell therapy products.

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Cancer zebrafish models

The zebrafish is emerging as a powerful system for human cancer modeling. Its greatest asset resides in the combination of genetic versatility and the possibility to perform high throughput screenings of chemical libraries enabling fast identification of anti-tumoral drugs in a whole organism cancer model.

Such large-scale assays require the generation of fish in which protein of interest is inactivated using the CRISPR technology.

For more information on the zebrafish platform, please click here.

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In vivo matrix-inserted surface transplantation model

The matrix-inserted surface transplantation model is an in vivo assay used to analyze the kinetics of tumor-vessel interactions during different stages of tumor progression. This system allows the study of host-tumor interface, i.e. penetration of tumor cells into normal host tissue as well as infiltration of normal host cells into the tumor and tissue remodeling events associated to tumor progression.

Researchers at GIGA have developed image analysis algorithms for processing and quantifying the extent of such migratory and tissue remodeling events. The proposed method is non-parametric and its originality lies in its particularity to take into account the specific geometry of tumor-host interface.

This methodology was validated by evaluating the contribution of matrix metalloproteases (MMPs) in skin carcinoma invasion and vascularization through pharmacological and genetic approaches.

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Preclinical imaging

Logo_Logo-autres_GIGAOur GIGA platforms offer advanced preclinical functional and anatomical imaging solutions for a broad spectrum of application fields.

Our range of techniques includes:

Magnetic resonance imaging (MRI) scanners use strong magnetic fields and radio-waves to visualize detailed internal structures. Images are obtained in vivo with very high spatial and temporal resolution, good contrast for brain and soft tissues. MRI can be used in a wide variety of applications including anatomical, functional (fMRI) and molecular imaging for medical diagnosis, staging of disease and for follow-up without exposure to ionizing radiation.

Our system, Agilent MicroMRI 9,4T 310 ASR, is equipped with a technical imaging unit (MINERVE). It ensures the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Computed Tomography (CT) is a non-destructive technique that yields structural and anatomical high-resolution 3D images with limited or no sample preparation required. This imaging modality complements the metabolic or functional images obtained with PET.

Being equipped with two beds for mice (25 mm) and rats (75 mm), our system, the TriFoil Imaging eXplore CT 120 micro-CT, is designed to visualize, quantify and characterize anatomical parameters in small animals. The system is also equipped with a technical imaging unit (MINERVE), ensuring the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Positron Emission Tomography (PET) has the sensitivity at picomolar level to visualize molecular processes in 3D. In vivo PET imaging with labelled lead compounds will help to select the best one for clinical trials.

 

The technique allows:

  • The collection of quantitative and dynamic biodistribution data (e.g. micro-dosing studies) at an early stage of the clinical development: dynamic data for in-depth kinetic modeling, online blood measurements and in-brain positron-emission measurements
  • Detailed drug occupancy studies (proof of targets, mechanism, efficacy, pharmacokinetics, biodistribution)
  • Concentration analysis of targeted analytes after having developed and validated a dedicated method using microdialysis, a technique used for continuous measurement of free, bound analyte concentrations in the extracellular fluid. Analytes may include endogenous molecules (e.g. neurotransmitter, hormones, glucose, etc.) to assess their biochemical functions in the body, or exogenous compounds (e.g. pharmaceuticals) to determine their distribution within the body)

We are authorized to conduct research programs with classical (18F-FDG) and original radiotracers. Furthermore, we have developed expertise in experimental design, data collection, correction and modeling for kinetic analysis.

Being equipped with two beds for mice (25 mm) and rats (75 mm), our system, the Siemens Concorde FOCUS 120 micro-PET, is designed to visualize, quantify and characterize anatomical parameters in small animals. The system is also equipped with a technical imaging unit (MINERVE), ensuring the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Our equipment includes the high-resolution, high-frequency ultrasound imaging system Vevo 2100 (Visualsonics). This is a non-invasive, in vivo micro imaging system, enabling visualization, assessment and measurement of anatomical structures and hemodynamic function in longitudinal studies for small animal phenotyping.

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The Xenogen IVIS 200 system is a highly sensitive and flexible system to trace bioluminescent reporter genes both in vivo and in vitro. It allows non-invasive longitudinal monitoring of disease progression, cell trafficking and gene expression patterns in living animals. By performing spectral fluorescence imaging, it allows the simultaneous use of bioluminescence and fluorescence imaging.

Bioluminescence imaging uses the enzyme, luciferase, that can be inserted into the genome of cancer cells or the cells you wish to track. Once these cells are implanted within mice, a tail vein or intra-peritoneal injection of luciferin (luciferase substrate) allows to follow their distribution ex vivo without euthanasia.

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Intravital microscopy is an extremely powerful tool that enables imaging several biological processes in living animals. In particular, to analyze:

 

 

  • Recruitment processes of leukocytes and platelets on microvessel endothelia
  • Bacterial adhesion on the microvessel endothelia
  • Thrombi and vascular occlusion formation
  • Lymphocytes migration to lymph nodes and lymphocytes adhesion to endothelia

Our equipment includes a motorized Olympus Cell R (Upright) microscope with EMCCD camera, controlled via the Slidebook software.

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PXI X-RAD SmART Image Guided Irradiator combines 3D imaging with highly accurate radiotherapy for Small Animals: mice, rats and rabbits. It combines a user friendly interface with state-of-the-art Monte Carlo calculation algorithms to rapidly devise treatment plans.

The system is fully integrated, with automated CT-CT registration, allowing, Image Guided Radiotherapy for precise tumor/organ localization. The integrated treatment planning enables rapid and highly conformal radiotherapy treatments, with collimator from 1 mm to 10 cm in round and non-round shapes, to be delivered in any scenario, ranging from simple subcutaneous xenografts to complex metastatic models or to develop non tumoral model as radiation-induced injury for a specific purpose.

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