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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Zebrafish Model

Key regulators of bone formation are highly conserved between mammals and teleosts. The corresponding orthologs share significant sequence similarities and an overlap in expression patterns when compared to mammals.

Cranial cartilage is the first skeletal structure to be detected as early as 3 days post-fertilization, while first calcified intramembranous bone structures start to form at about the same time.

Due to its rapid generation time, large offspring numbers, external development, transparency and the availability of genetic maps, the zebrafish is a very attractive model system to study the function of genes involved in bone formation.

Transgenic zebrafish lines represent unique tools to follow osteoblasts in vivo and to analyze their function in wild type or mutant backgrounds.

This animal model can be used to evaluate drug or treatment effects on cartilage and bone formation by measuring:

  • The intensity and progression of bone formation
  • Their level of ossification
  • The level of calcification
  • Morphometric analysis

Using this model, researchers from GIGA have evaluated the physiological consequences of altered gravity on bone formation and more generally on whole genome gene expression.

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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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pilocarpine mouse model

The main features of temporal lobe epilepsy (TLE) are:

  • Epileptic foci in the limbic system
  • An “initial precipitating injury”
  • The so-called “latent period”
  • The presence of hippocampal sclerosis leading to reorganization of neuronal networks

Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine.

In this animal model, status epilepticus is followed by a latent period and later by the appearance of spontaneous recurrent seizures.

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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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Model of Dicer depletion in the otocyst

Previous studies have demonstrated the importance of Dicer during early cochlear development.

To extend this investigation to the establishment and differentiation of the prosensory domain, researchers at GIGA crossed Dicerflox/flox mice with FoxG1Cre/+ mice to generate embryos (i.e., FoxG1:Dicer-cKO) with an early (E8.5) depletion of Dicer in the otocyst.

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