What are breast cancer metastatic mouse models?

Breast cancer metastatic mouse models are experimental systems where mice are genetically modified to develop mammary tumors that lead to distant lesions of mammary epithelium through metastasis. These models can be created based on genetic mutations identified in human cancers, allowing for the study of molecular lesions consistent with the human disease.

How is metastasis defined in the context of breast cancer research?

Metastasis is defined as the process by which tumor cells migrate from the primary cancer site to a distant location, where they form secondary tumors. It is considered an advanced-stage event in cancer and is the most devastating attribute of the disease.

What are the common distant organs to which human breast cancer metastasizes?

Human breast cancer commonly metastasizes to distant organs such as the brain, lungs, bones, and liver.

What was the classical theory regarding the cause of metastasis, developed in the early 1970s?

The classical theory, developed in the early 1970s, proposed that metastasis arises from genetically determined subpopulations within primary tumors.

How does tumor heterogeneity relate to genetic variance in metastatic tumors?

Tumor heterogeneity implies that genetic variance between metastatic foci is significant for only particular genetic loci and within specific cell populations. This means that some loci might diverge in only one cell subpopulation, contributing to the overall genetic diversity observed.

What is the concept of tumor evolution in relation to genetic events?

Tumor evolution refers to the order in which genetic events occur, leading to the development and progression of cancer, including its metastatic capabilities.

What is the relationship between genes driving primary tumor growth and dissemination/colonization?

Genes that drive growth at the primary tumor site can also determine the dissemination and colonization of cancer cells at an ectopic, or distant, site.

Why is breast cancer considered a genetically and clinically heterogeneous disease?

Breast cancer is considered heterogeneous because it reflects the diversity and variations present in the normal breast tissue from which it originates. This heterogeneity is observed both genetically and clinically.

What is required for individual tumor cells to grow at an ectopic site?

For individual tumor cells to grow at an ectopic site, a number of discrete genetic events must occur, and the metastatic progression depends on the regulation of developmental programs and environmental events.

When is metastatic potential considered to occur in mouse mammary cells?

The metastatic potential of subpopulations within mouse mammary cells is now considered to be a relatively early event, with dissemination occurring concurrently with pre-invasive or micro-invasive lesions.

What do the genetic profiles of primary and metastatic breast carcinoma lesions reveal?

The genetic profiles of primary breast carcinomas and their metastases show a significant extent of clonal relatedness between the lesions, indicating a shared origin.

What do various patterns of genetic mutations in primary breast tumors and their metastases confirm?

The patterns of prevalence of genetic mutations in primary breast tumors and their metastases confirm the genetic heterogeneity that exists between the primary neoplasm and its corresponding metastases.

How do breast cancer phenotypes express genes related to metastasis?

Breast cancer phenotypes periodically express genes that are indispensable for the metastatic process, with metastatic diversity being mediated by the activation of genes that couple to organ-specific growth.

What factors influence the growth of lesions at ectopic sites?

The growth of lesions at ectopic sites depends on complex interactions between the metastatic cells and the host's homeostatic mechanisms. Lethal protein-protein interactions at the metastatic site can aid the survival of adapted cells.

What are two primary methods for generating mouse models of human breast cancer?

Two primary methods for generating mouse models of human breast cancer involve the targeted expression of oncogenes in mouse mammary epithelial cells, or the targeted inhibition of a tumor suppressor gene.

How does targeted expression of oncogenes contribute to modeling human breast cancer?

Targeted expression of oncogenes allows researchers to control their expression within a specific cellular context, rather than throughout the entire organism, thereby modeling human breast cancer more accurately.

Who developed the first inbred mouse strain, and what was it called?

Clarence C. Little developed the first inbred mouse strain in 1909, which was named the DBA (Dilute, brown non-Agouti) mouse.

What significant genetic discovery was made by N.M. Haldane in 1915 regarding mice?

In 1915, N.M. Haldane identified the first genetic linkage in mice between Albino mice and pink eye dilution on chromosome seven.

Which mouse strain became widely used in genetics and was the first to have its genome sequenced?

The C57BL mouse strain became one of the most widely used in genetics and was the first strain to have its genome sequenced.

What groundbreaking achievement in genetic engineering of mice occurred in 1982?

In 1982, Palmiter and Brinster generated the first transgenic mice by implanting a foreign gene into a fertilized egg, engineering them to express dominant oncogenes.

How was the relevance of the proto-oncogene c-myc evaluated in mice in 1982?

In 1982, the stimulation of expression from the MMTV-LTR (Mouse mammary tumor virus-Long terminal repeat) was evaluated through multiple rounds of pregnancy and lactation to assess the relevance of the proto-oncogene c-myc.

What are the key similarities between human and mouse genomes that make mice useful models for studying human diseases?

Mice are useful models for human diseases due to close similarities in physiology, development, and cell biology. Both species have approximately 30,000 protein-coding genes with less than 1% of mouse genes lacking human homologs, and 90% of their genomes are syntenic, with 40% alignable at the nucleotide level.

What are some of the limitations of using mouse models for breast cancer research, particularly concerning metastasis?

Mouse models can have limitations in breast cancer research, such as a lack of precision in determining the exact location and frequency of metastasis. Additionally, it can be challenging to specifically target epithelial subtypes when introducing mutations.

What issue arises when studying tumorgenesis in K14-Cre BRCA2 mice if p53 is also mutated?

In K14-Cre BRCA2 mice, if p53 is mutated and inactivated, tumorgenesis will occur, but this extra mutation in p53 makes it difficult to definitively determine the origin of the tumor.

What are some examples of metastatic mouse mammary carcinoma cell lines used in research?

Examples of metastatic mouse mammary carcinoma cell lines used to identify genes and pathways involved in metastasis include 4T1 and TS/A. These cell lines are metastatic in syngeneic immunocompetent mice.

How are tumor cells transplanted into immunodeficient mice to study metastasis?

Tumor cells are transplanted into immunodeficient mice as either allotransplants or xenographic transplants. Commonly, human cells are inoculated into an immunocompromised murine recipient.

What are the different routes of inoculation for studying breast cancer metastasis in mice, and what organs do they seed?

Common inoculation routes include intraductal transplantation, injections into the cleared mammary fat pad, or transplantation into the tail vein. Different routes can seed different organs: cardiac injection targets the bone, tail vein injection targets the lung, splenic injection targets the liver, and carotid artery injection targets the brain.

What type of immunodeficient mice are used for xenograft tissue integration in breast cancer metastasis studies?

NOD/SCID mice (non-obese diabetic/severe conditional immunodeficient) are used for xenograft tissue integration because their mutations allow for the integration of new xenograft tissue.

What is the process of 'humanizing' the mammary fat pads in NOD/SCID mice for tumor transplantation?

Mammary fat pads are humanized by injecting human telomerase-immortalized human mammary stromal fibroblasts (RMF/EG fibroblasts). This step is crucial because, without it, human mammary epithelial cells grafted onto the pad are unable to colonize and grow. The fibroblasts are then irradiated to allow the expression of key proteins and growth factors.

What are some methods used to construct genetically engineered mice for studying metastasis?

Genetically engineered mice can be constructed using various methods, including introducing transgenes via tetracycline-inducible systems (Tet-On/Tet-Off), targeted mutations through knock-in/knock-out gene strategies using the Cre-Lox recombination system, introducing retroviral mutations, or introducing chemically induced mutations.

What are the basic components of a transgene used in transgenic mice?

A basic transgene typically consists of a promoter region, a protein-coding sequence, an intron, and a stop codon.

How does the Mouse Mammary Tumor Virus (MMTV) contribute to breast cancer models?

The Mouse Mammary Tumor Virus (MMTV) acts as a promoter that can induce breast tumors when activated. It contains a regulatory DNA sequence called the long terminal repeat (LTR), which facilitates steroid-hormone-inducible transcription. Tumors can also be induced by the integration of the viral genome into critical cellular regulation genes.

What is another common promoter used in generating mouse mammary cancer models besides MMTV?

Besides MMTV, the Whey acidic protein (WAP) promoter is another commonly used promoter for generating mouse mammary cancer models.

What is the MMTV-PyMT model and why is it significant?

The MMTV-PyMT model uses the MMTV-LTR to drive the expression of the polyomavirus middle T-antigen in mammary glands, leading to rapid development of highly metastatic tumors. It is the most commonly used model for studying mammary tumor progression and metastasis.

What are some examples of how MMTV-PyMT mice are crossed with other genetically modified mice to create specific breast cancer models?

MMTV-PyMT mice are crossed with other genetically modified mice to study various aspects of breast cancer, such as: PI3K/Akt signaling in metastasis (using Akt1-/- mice), chemoattractive paracrine loops involving CSF-1 and EGF (using Csf-1-/- mice), the role of innate and adaptive immune responses (using Rag1-/- mice for T cell loss or IL4-/- mice), the function of the adhesion molecule CD44 in lung metastasis, pro-metastatic actions of angiogenic factors like VEGF-A (using conditional ablation), the role of autocrine TGF-β1 signaling on motility and survival, and the involvement of urokinase (uPA-/-) and MEKK1 (MEKK1-/-).

How does the MMTV-HER2/neu model contribute to breast cancer research?

The MMTV-HER2/neu model uses the MMTV-LTR to promote the expression of the receptor tyrosine-protein kinase ErbB2, which is an oncogene amplified and overexpressed in about 20% of human breast cancers. Mice with this oncogene develop multifocal adenocarcinomas with lung metastases.

What modification was made to the MMTV-HER2/neu model to improve its accuracy in representing HER2 gene mutations?

To better model HER2 gene amplification, researchers fused the mouse gene containing neu with a rat gene containing neu. This fusion improved the model's accuracy compared to the non-fused mouse, where the mammary gland would revert to a near-virgin state, whereas the fused version maintained the developed function.

What defines a bi-transgenic mouse model, and what was an early example of their use?

Bi-transgenic mouse models contain two transgenes. An early example, created in 1987 by Tim Stewart's group, involved crossing MMTV-Myc and MMTV-Ras mice to study the cooperation of these two oncogenes, which resulted in accelerated tumorigenesis.

How can the expression of TGF-β be studied in relation to HER2 in bi-transgenic mice?

The expression of TGF-β in breast cancer cells of MMTV-ErbB2; MMTV-TGF-β double-transgenic mice can lead to higher levels of circulating tumor cells and lung metastasis, allowing for the study of their interaction.

How can inducible bi-transgenic mouse models be generated using tetracycline-controlled transcriptional activation?

Inducible bi-transgenic models can be generated by combining the Ras gene with rtTA (reverse tetracycline transactivator). For example, mice carrying TetO-KrasG12D (TOR) and MMTV-rtTA (MTB) can be used, where the transgene expresses rtTA in mammary epithelial cells, allowing for tetracycline-controlled gene expression.

What characterizes tri-transgenic mouse models, and how can gene expression be controlled?

Tri-transgenic mouse models involve more than two genes, with multiple combinations and genetic modifications. Gene expression can be controlled to be continuously expressed or activated at different time points, for instance, by using tetracycline operators for genes like Myc and Ras, which can be activated or deactivated by adding doxycycline.

How can genetically modified mice be used to study the metastatic cascade?

The metastatic cascade can be studied by controlling gene activation or by incorporating reporter genes, such as Beta-actin GFP (Green fluorescent protein) or RFP (Red fluorescent protein), into the mouse models.

How can gene knockin/knockout be used to identify genes that regulate metastasis?

By knocking in or knocking out specific genes using homologous recombination, researchers can measure the extent of metastasis and identify new target genes. For example, acute ablation of TGF-β signaling in MMTV-PyMT mammary tumor cells led to a five-fold increase in lung metastasis, identifying TGF-β1 as a gene that consistently regulates metastatic behavior.

How can enhancer regions associated with cancer genes be analyzed?

Enhancer regions associated with cancer-critical genes, such as p53, can be analyzed and determined to be crucial for cell proliferation using techniques like CRISPR-Cas9.

What is lineage tracing in metastasis models, and what are its key components?

Lineage tracing in metastasis models is a quantitative strategy used to resolve cell fates. It requires two engineered components in the mouse genome: a switch, typically a drug-regulated Cre-recombinase enzyme that recognizes LoxP sites, and a reporter transgene that encodes proteins enhancing the identification of labeled cells.

How are cells traced in metastasis studies using lineage tracing?

After harvesting mammary glands from transgenic mice, single-cell suspensions are transplanted into recipient mice. These cells can then be followed in various organs like the bloodstream, lungs, bone marrow, and liver to observe metastasis. The transgenic cells can be traced by their fluorescence or by inducing them with doxycycline.

How are circulating tumor cells (CTCs) studied in breast cancer metastasis models?

Circulating tumor cells are studied by detecting them in the blood or bone marrow of transgenic mice, such as MMTV-PyMT mice, which can respond to therapies by shedding tumor cells. For instance, cytokeratin-positive cells were identified in the bone marrow of MMTV-pyMT and MMTV-Neu transgenic mice but not in wild-type controls.

What is a limitation in studying circulating tumor cells in live animals?

A limitation in studying circulating tumor cells is the low volume of peripheral blood that can be obtained from live animals, which restricts the application of this technique, especially when specific markers for mammary cells are absent.

What are the general categories of non-invasive techniques used for imaging metastatic mouse models?

Genetically modified mouse models can be imaged using various non-invasive techniques, including bioluminescence imaging, fluorescent imaging, radioisotopic imaging (PET, SPECT, CT), and MRI imaging.

How does bioluminescence imaging work for studying metastasis?

Bioluminescence imaging detects light produced by the enzymatic oxidation of a substrate, typically luciferin, in the presence of luciferase. This light can be detected using systems like IVIS. For example, in the MMTV-PyMT:IRES:Luc model, bioluminescence is observed in the lungs only after doxycycline exposure, indicating tumor cell presence.

What role does fluorescent imaging play in studying metastasis?

Fluorescent imaging, particularly intravital microscopy with multi-photon excitation, allows for the visualization of genetically engineered cells directly within a living organism. Multi-step metastatic cascades can be observed by labeling cells with unique fluorescent colors under a fluorescence microscope.

Mouse Models Of Breast Cancer Metastasis Wiki: Metastasis Unveiled: The Precision of Mouse Models in Cancer Research

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Introduction to Metastasis Models

Defining Metastasis Models

Breast cancer metastatic mouse models are sophisticated experimental systems where mice are genetically manipulated to develop mammary tumors that subsequently lead to the formation of distant focal lesions. These models are crucial for understanding the complex process of metastasis, which is the migration of tumor cells from the primary site to secondary locations, representing the most formidable aspect of advanced-stage breast cancer.

Mimicking Human Pathology

These models are designed to replicate key genetic mutations identified in human breast cancer. By mirroring the molecular lesions found in human disease, researchers can study the progression of mammary tumors and the subsequent metastatic cascade, including the dissemination of tumor cells to organs such as the brain, lungs, bones, and liver, mirroring human clinical presentations.

Research Significance

The study of metastasis is paramount because it is the primary cause of cancer-related mortality. Mouse models provide an invaluable platform to investigate the biological mechanisms underlying tumor cell migration, invasion, survival in foreign microenvironments, and the establishment of secondary tumors, thereby facilitating the development of novel therapeutic strategies.

The Metastatic Cascade

Process of Dissemination

Metastasis is a multi-step process involving the migration of tumor cells from the primary tumor site to distant locations, where they establish secondary tumors. This phenomenon is considered an advanced-stage event in cancer progression and is responsible for the majority of cancer-related deaths.

Organ Tropism

Breast cancer commonly metastasizes to specific organs, including the brain, lungs, bones, and liver. The precise mechanisms dictating this organ-specific tropism are complex and involve intricate interactions between tumor cells and the microenvironment of the target organ.

Tumor Heterogeneity

Breast cancer is inherently a heterogeneous disease, reflecting the diverse cellular origins and the accumulation of genetic and epigenetic alterations. This heterogeneity extends to metastatic lesions, where significant genetic variance can exist between primary tumors and their disseminated foci, influencing treatment response and prognosis.

Tumor heterogeneity refers to the presence of distinct cell populations within a single tumor, differing in their genetic makeup, phenotype, and behavior. This diversity can arise from:

Clonal Evolution: The accumulation of genetic mutations over time, leading to the selection and proliferation of subpopulations with advantageous traits, including metastatic potential.
Somatic Evolution: The continuous adaptation and diversification of tumor cells through genetic and epigenetic changes, influencing their ability to disseminate and colonize ectopic sites.
Order of Genetic Events: The sequence in which genetic alterations occur can significantly impact the metastatic phenotype, with some genes driving primary tumor growth and others facilitating dissemination and colonization.

Studies indicate that metastatic potential can be an early event, with dissemination occurring even at pre-invasive or micro-invasive stages of tumor development.

Genetic Underpinnings of Metastasis

Key Genes and Pathways

The metastatic process is driven by the activation of specific genes that are indispensable for tumor cell migration, invasion, and adaptation to distant microenvironments. These genes often interact with host homeostatic mechanisms, facilitating the survival and growth of adapted metastatic cells.

Oncogenes and Tumor Suppressors: Alterations in genes controlling cell growth and differentiation, such as oncogenes (promoting growth) and tumor suppressor genes (inhibiting growth), are fundamental to cancer development and progression.
Organ-Specific Genes: Certain genes are activated during metastasis, mediating interactions that are crucial for growth at specific ectopic sites, highlighting the role of gene regulation in metastatic diversity.

Clonal Pertinence

Genetic analyses of primary breast tumors and their metastases reveal a significant degree of clonal pertinence, suggesting that metastatic lesions often originate from specific subpopulations within the primary tumor. However, variations in the prevalence of genetic mutations across different lesions confirm the inherent genetic heterogeneity of breast cancer and its metastases.

Generating Metastatic Mouse Models

Historical Context

The development of mouse models for cancer research has a rich history, beginning with the establishment of the first inbred strain (DBA) in 1909. Key milestones include the identification of gene linkage in mice, the sequencing of the C57BL/6 genome, and the groundbreaking generation of the first transgenic mice in 1982 by implanting foreign genes into fertilized eggs, enabling the study of oncogene expression.

Engineering Approaches

Mouse models are engineered to mimic human breast cancer through various genetic manipulation techniques:

Targeted Oncogene Expression: Introducing oncogenes into mouse mammary epithelial cells to study their role in tumor initiation and progression.
Tumor Suppressor Inhibition: Targeting tumor suppressor genes to observe their impact on cancer development.
Transgenesis: Incorporating specific genes (transgenes) using methods like retroviral vectors or Cre-Lox recombination systems to control gene expression and study specific pathways.

Genetic Modifications

Advanced genetic engineering techniques are employed:

Tet-On/Tet-Off Systems: Allowing inducible control over transgene expression using tetracycline.
Cre-Lox Recombination: Facilitating targeted gene knock-in or knock-out for precise genetic modifications.
Retroviral Mutagenesis: Introducing mutations via retroviral vectors.
Chemical Induction: Using chemical agents to induce mutations.

Human vs. Mouse Genomics

Comparative Genomics

Mice serve as valuable models for human diseases due to significant biological similarities:

Physiological Parallels: Close similarities in physiology, development, and cell biology between humans and mice.
Gene Homology: Approximately 90% of the human and mouse genomes are syntenic, with over 30,000 protein-coding genes shared between species, and less than 1% of mouse genes lacking a human homologue.
Genome Alignment: About 40% of both genomes can be aligned at the nucleotide level.

Model Limitations

Despite these similarities, mouse models have limitations:

Precision Issues: Difficulty in precisely determining the location and frequency of metastasis in some models.
Epithelial Subtype Targeting: Challenges in specifically targeting epithelial subtypes when introducing mutations.
Complex Interactions: The influence of additional mutations (e.g., p53 inactivation) can complicate the interpretation of tumor origins and progression.

Types of Metastasis Models

Genetically Engineered Models (GEMs)

GEMs are created by introducing specific genetic modifications to mimic human cancer mutations. Key examples include:

MMTV-PyMT: A widely used model where the Mouse Mammary Tumor Virus (MMTV) long terminal repeat (LTR) drives the expression of the polyomavirus middle T-antigen, leading to highly metastatic tumors. This model is instrumental for studying tumor progression and metastasis.
MMTV-HER2/neu: Utilizes MMTV-LTR to promote the expression of the HER2/neu oncogene, which is amplified in about 20% of human breast cancers. These mice develop adenocarcinomas with lung metastases.

These models can be further refined by crossing them with other genetically modified mice to investigate specific signaling pathways (e.g., PI3K/Akt) or the role of immune responses and specific molecules (e.g., CSF-1, CD44).

Cell Line and Tissue Transplantation

These models involve the introduction of cancer cells or tissue into mice:

Cell Lines: Metastatic mouse mammary carcinoma cell lines like 4T1 and TS/A are used in syngeneic immunocompetent mice to identify genes and pathways involved in metastasis.
Tumor Transplantation: Human cancer cells are inoculated into immunodeficient mice (e.g., NOD/SCID) to study xenografts. Different injection routes (e.g., cardiac, tail vein, splenic, carotid artery) can seed cancer cells to specific organs (bone, lung, liver, brain, respectively), allowing targeted study of organ-specific metastasis.
Humanized Fat Pads: For more accurate modeling, mouse mammary fat pads can be "humanized" by injecting human stromal fibroblasts before engrafting human mammary epithelial cells.

Multi-Gene Models

Bi-transgenic and Tri-transgenic Models: These models incorporate two or three transgenes, respectively, to investigate the synergistic effects of multiple oncogenes or genetic alterations on tumor development and metastasis. For instance, combining MMTV-Myc and MMTV-Ras can accelerate tumorigenesis, while MMTV-ErbB2 and MMTV-TGFβ co-expression can enhance lung metastasis.

Applications in Research

Gene Discovery

By employing techniques like homologous recombination to knock in or knock out specific genes in mouse models, researchers can quantitatively measure the extent of metastasis and identify novel target genes. For example, acute ablation of TGF-β1 signaling has been shown to significantly increase lung metastasis, highlighting its pro-metastatic role.

Lineage Tracing

Inducible lineage-tracing strategies, utilizing a switch (e.g., Cre-recombinase) and a reporter (e.g., fluorescent protein), allow researchers to track the fate of specific cell populations during metastasis. By labeling tumor cells and monitoring their dissemination and colonization in various organs, these methods provide insights into the cellular dynamics of metastatic spread.

Circulating Tumor Cells (CTCs)

The detection and analysis of CTCs in the peripheral blood of transgenic mice offer a non-invasive method to study metastatic processes. Identifying cytokeratin-positive cells in the bone marrow of MMTV-PyMT and MMTV-Neu mice, for instance, indicates systemic dissemination, even in the absence of overt tumors.

In Vivo Imaging Techniques

Bioluminescence Imaging (BLI)

BLI relies on the detection of light emitted from cells expressing luciferase, an enzyme that oxidizes luciferin. In models like MMTV-PyMT:IRES:Luc, bioluminescence signals can be observed in the lungs after doxycycline induction, allowing real-time monitoring of tumor growth and response to therapies.

Fluorescent Imaging

Intravital microscopy with multi-photon excitation enables direct visualization of genetically engineered cells labeled with unique fluorescent colors. This technique allows for the real-time observation of multi-step metastatic cascades, providing detailed insights into cellular behavior during invasion and colonization.

Radioisotopic and MRI Imaging

Advanced imaging modalities such as Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Magnetic Resonance Imaging (MRI) are employed to detect metastatic lesions at early stages and evaluate treatment efficacy. MRI, for example, can utilize nanoparticle-loaded liposomes to accumulate in metastatic sites, rendering them visible in scans.

Model Limitations & Considerations

Precision and Specificity

While powerful, mouse models are not perfect replicas of human disease. Challenges include achieving precise targeting of specific cell populations and accurately modeling the complex interplay of genetic events that drive human cancer progression. The interpretation of results often requires careful consideration of these inherent limitations.

Technical Constraints

Techniques like lineage tracing, while informative, can be limited by the low volume of peripheral blood obtainable from live animals, potentially restricting the sensitivity of detecting disseminated cells. Furthermore, the complexity of genetic engineering can sometimes lead to unintended consequences or require extensive validation.

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References

Gupta, PB; Kuperwasser, C. (2004). Disease models of breast cancer. Drug Discovery Today: Disease Models 1(1), 9-16. doi: 10.1016/j.ddmod.2004.05.001

Wagner, KW. (2003). Models of Breast Cancer: quo vadis, animal modeling? Breast Cancer Research 6(31), 31-38.doi: 10.1186/bcr723

Pulaski BA, S Ostrand-Rosenberg. 2001. "Mouse 4T1 breast tumor model". Curr Protoc Immunol. Chapter 20:Unit 20.2. doi: 10.1002/0471142735.im2002s39

Kuperwasser, C; Chavarria, T; Wu, M; Magrane, G; Gray, JW; Carey, L; Richardson, A; Weinberg, RA. (2004). Reconstruction of functionally normal and malignant human breast tissue in mice. Pnas 101(14), 4966-4971. doi: 10.1073/pnas.0401064101

Ross, RS. (2010). Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2(9), 2000-2012. doi: 10.3390/v2092000

Fry, EA; Taneka, P; Inoue, K. (2016). Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu. International Journal of Cancer 140(3), 495-503. doi:10.1002/ijc.30399

A full list of references for this article are available at the Mouse models of breast cancer metastasis Wikipedia page

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Metastasis Unveiled

💡 Dive in with Flashcard Learning! 💡

Introduction to Metastasis Models 🔬

🎯 Defining Metastasis Models

🧬 Mimicking Human Pathology

🔬 Research Significance

The Metastatic Cascade 🌊

➡️ Process of Dissemination

📍 Organ Tropism

🧩 Tumor Heterogeneity

Genetic Underpinnings of Metastasis 🔬

🔑 Key Genes and Pathways

🔗 Clonal Pertinence

Generating Metastatic Mouse Models 🛠️

📜 Historical Context

💡 Engineering Approaches

🔄 Genetic Modifications

Human vs. Mouse Genomics ⚖️

📊 Comparative Genomics

⚠️ Model Limitations

Types of Metastasis Models 📚

🧬 Genetically Engineered Models (GEMs)

🔬 Cell Line and Tissue Transplantation

➕ Multi-Gene Models

Applications in Research 💡

🔍 Gene Discovery

tracing Lineage Tracing

🩸 Circulating Tumor Cells (CTCs)

In Vivo Imaging Techniques 📸

🌟 Bioluminescence Imaging (BLI)

🌈 Fluorescent Imaging

☢️ Radioisotopic and MRI Imaging

Model Limitations & Considerations ⚠️

🤔 Precision and Specificity

🎛️ Technical Constraints

Teacher's Corner 🧑‍🏫

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❓ Test Your Knowledge! ❓

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References

📜 References

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📜 Important Notice

Dive in with Flashcard Learning!

Introduction to Metastasis Models

Defining Metastasis Models

Mimicking Human Pathology

Research Significance

The Metastatic Cascade

Process of Dissemination

Organ Tropism

Tumor Heterogeneity

Genetic Underpinnings of Metastasis

Key Genes and Pathways

Clonal Pertinence

Generating Metastatic Mouse Models

Historical Context

Engineering Approaches

Genetic Modifications

Human vs. Mouse Genomics

Comparative Genomics

Model Limitations

Types of Metastasis Models

Genetically Engineered Models (GEMs)

Cell Line and Tissue Transplantation

Multi-Gene Models

Applications in Research

Gene Discovery

Lineage Tracing

Circulating Tumor Cells (CTCs)

In Vivo Imaging Techniques

Bioluminescence Imaging (BLI)

Fluorescent Imaging

Radioisotopic and MRI Imaging

Model Limitations & Considerations

Precision and Specificity

Technical Constraints

Teacher's Corner

True or False?

Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Notice