Cancer Pathogenesis and Mouse Models
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Questions and Answers

Which of the following is NOT a step in the process of tumorigenesis?

  • Metastasis
  • Regeneration (correct)
  • Promotion
  • Initiation

Mouse models in cancer research tend to develop a higher incidence of metastases compared to other animals.

False (B)

What is the primary genetic characteristic of inbred mice used in cancer research?

Identical genetic background

The process involving the accumulation of multiple genetic aberrations that transforms normal cells is known as __________.

<p>tumorigenesis</p> Signup and view all the answers

Match the advantages of using mouse models in cancer research with their respective descriptions:

<p>Small size = Easy handling and management Cost-effective = Cheaper than larger animal models High tumor incidence = Allows observation of rapid tumor growth Genetic characterization = Best characterized of all mammals used in research</p> Signup and view all the answers

What is the primary origin of transplantable tumor models?

<p>Established cancer cell lines or patient-derived xenografts (A)</p> Signup and view all the answers

Genetically engineered tumor models (GEMMs) arise spontaneously from established cancer cell lines.

<p>False (B)</p> Signup and view all the answers

What defines humanized models?

<p>Immunodeficient animals engrafted with human cells or tissues for cancer study.</p> Signup and view all the answers

Transplantable tumor models can be derived from established cancer cell lines or patient-derived ______.

<p>xenografts</p> Signup and view all the answers

Match the following tumor models with their characteristics:

<p>Transplantable tumor models = Tumor is transplanted into host animals Genetically engineered tumor models = Arises from engineered mutations Humanized models = Immunodeficient animals engrafted with human cells Tumors from cell lines = Derived from established cancer cell lines</p> Signup and view all the answers

What is a significant strength of transplantable tumor models?

<p>Rapid tumor formation (B)</p> Signup and view all the answers

GEMMs provide a limited modeling of tumor progression and TME.

<p>False (B)</p> Signup and view all the answers

What is one limitation of humanized mice models?

<p>Logistically difficult to obtain matched donor and tumor samples</p> Signup and view all the answers

One direction for transgenic mouse cancer models is to replicate specific human cancer __________ in mouse models.

<p>mutations</p> Signup and view all the answers

Match the following models with their respective strengths:

<p>Transplantable tumors = Simplicity and rapid formation GEMMs = Genetic lesions found in human cancers Humanized mice = Human immune populations studied directly</p> Signup and view all the answers

What is a key limitation of GEMMs?

<p>They incur increased cost and complexity (A)</p> Signup and view all the answers

Humanized mice can completely reconstitute the human immune response.

<p>False (B)</p> Signup and view all the answers

Name one of the current directions for transgenic mouse cancer models.

<p>Personalizing humanized mice</p> Signup and view all the answers

What is one of the general limitations of GEMMs regarding tumor development?

<p>Latent development can vary dramatically (A)</p> Signup and view all the answers

GEMMs allow for the invasive monitoring of tumor development.

<p>False (B)</p> Signup and view all the answers

What gene construct is used as a positive selective marker in gene targeting by homologous recombination?

<p>Neomycin resistance gene</p> Signup and view all the answers

The _____ gene is used as a negative selective marker in gene targeting.

<p>TK</p> Signup and view all the answers

Match the following steps in the process of targeted manipulation of mouse embryonic stem cells with the corresponding actions:

<p>1 = Selection of transgenic cell line (neor &amp; TK gene) 2 = Injection into blastocysts 3 = Obtain chimeric mouse 4 = Crossing to obtain homozygous genetically engineered mouse</p> Signup and view all the answers

Which technology is used for conditional gene modification?

<p>Cre-Lox technology (A)</p> Signup and view all the answers

The process of Cre-Lox Technology involves the use of a promoter that can be tissue-specific.

<p>True (A)</p> Signup and view all the answers

What is the primary purpose of the TK gene in gene targeting?

<p>To initiate cell death in randomly integrated gene constructs</p> Signup and view all the answers

What type of cells are used in an allograft model?

<p>Mouse cancer cell lines or tissues (C)</p> Signup and view all the answers

The xenograft model can use human tumor cells derived from a patient.

<p>True (A)</p> Signup and view all the answers

What is a primary advantage of the allograft model?

<p>Results can be analyzed in an environment that closely recapitulates real scenarios.</p> Signup and view all the answers

The xenograft model is typically conducted in _____ mice.

<p>immunocompromised</p> Signup and view all the answers

What is one limitation of the xenograft model?

<p>It requires immunocompromised hosts. (A)</p> Signup and view all the answers

Match the following models with their primary application:

<p>Allograft Model = Preclinical development of anti-cancer therapeutics Xenograft Model = Toxicity studies from targeted therapies</p> Signup and view all the answers

Both allograft and xenograft models allow for the study of immune responses in tumors.

<p>False (B)</p> Signup and view all the answers

What is a key characteristic of the host species in an allograft model?

<p>Immunocompetent mice</p> Signup and view all the answers

What is the purpose of immersing tumor pieces in media such as glycerol-glucose?

<p>To maintain them in a viable state for storage (B)</p> Signup and view all the answers

Retrovirus-mediated techniques lead to precise gene integration in genetically engineered mouse models.

<p>False (B)</p> Signup and view all the answers

What should be done immediately after thawing tumors?

<p>They should be inoculated in mice.</p> Signup and view all the answers

The microinjection method involves the direct injection of foreign DNA material into a __________ mouse zygote.

<p>fertilized</p> Signup and view all the answers

Match the following genetically engineered mouse model techniques with their characteristics:

<p>Retrovirus-Mediated = Random integration of genetic material Microinjection = Direct injection into fertilized zygote Targeted manipulation of mouse embryonic stem cells = Precise integration at specific loci</p> Signup and view all the answers

What is a limitation of using retrovirus-mediated techniques?

<p>Random integration can disrupt essential genes (A)</p> Signup and view all the answers

Targeted manipulation of embryonic stem cells is a time-consuming and technically challenging process.

<p>True (A)</p> Signup and view all the answers

What can be created using targeted manipulation of ES cells?

<p>Loss-of-function and conditional models.</p> Signup and view all the answers

Once the tumor develops to an appropriate size, the response to __________ can be studied in vivo.

<p>therapeutic regimes</p> Signup and view all the answers

Which of the following advantages is associated with microinjection techniques?

<p>High versatility for expressing transgenes (A)</p> Signup and view all the answers

Flashcards

Tumorgenesis

The process of normal cells transforming into cancerous cells, involving multiple genetic changes.

Initiation

A stage in tumorgenesis where an initial genetic alteration occurs, leading to abnormal cell growth.

Promotion

A stage in tumorgenesis where altered cells are stimulated to proliferate and grow.

Progression

A stage in tumorgenesis where tumors become more aggressive, exhibiting increased growth, invasion, and potential for metastasis.

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Metastasis

The spread of cancer cells from the primary tumor to other parts of the body.

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Transplantable Tumor Models

Tumors are taken from a source like a cell line or patient tissue and directly implanted into a host animal, often a mouse.

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Genetically Engineered Tumor Models (GEMMs)

These models are made by altering the animal's genes to cause cancer development. This helps scientists understand how specific genes contribute to cancer.

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Humanized Models

Human cells or tissues are transplanted into immunodeficient mice, creating an environment resembling the human immune system.

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Transplantable Tumor Model - Origin

They are derived from established cancer cell lines or samples taken directly from patients.

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Genetically Engineered Tumor Models (GEMMs) - Origin

They involve genetically modified animals where the cancer originates naturally due to the altered genes.

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Syngeneic (Allograft) Model

Tumor cells originating from the same species as the host, typically transplanted into a genetically similar mouse.

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Xenograft (PDX) Model

Tumor cells originating from different species, often human tumor cells transplanted into immunodeficient mice.

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Tumor Source (Syngeneic)

Mouse cancer cell lines or tissues used in a Syngeneic model.

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Tumor Source (Xenograft)

Human cancer cell lines or patient-derived xenografts used in a Xenograft model.

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Host Species (Syngeneic)

Immunocompetent mice, possessing a normal immune system, are used in a Syngeneic model.

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Host Species (Xenograft)

Severely compromised immunodeficient (SCID) or immunocompromised mice are used in a Xenograft model.

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Limitations (Syngeneic)

Syngeneic models closely mimic the natural tumor environment but may not represent the full complexity of human cancers.

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Limitations (Xenograft)

Xenograft models are expensive and complex, but can be used for personalized cancer studies and predict therapy responses.

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GEMMs (Genetically Engineered Mouse Models)

These models are genetically engineered mice that carry specific mutations found in human cancers. They are more complex but better mimic the genetic and environmental factors involved in human cancer development.

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Humanized Mice

These models involve transplanting human immune cells into immunodeficient mice. They allow researchers to study the interactions between human tumors and human immune cells in a more relevant setting.

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Personalizing humanized mice

This refers to tailoring humanized mouse models to mimic the specific genetic and immune characteristics of individual patients. It essentially personalizes the model to better reflect the individual's cancer.

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Replicating specific human cancer mutations in mouse models

This involves introducing specific genetic mutations that are found in human cancers into mouse models. This allows researchers to study the function of these mutations and test potential therapeutic targets.

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Improving delivery methods

This involves developing better ways to deliver genetic material or therapeutic agents into mouse models. This could involve using viruses or nanoparticles to deliver the desired genetic alterations or drugs more effectively.

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Retrovirus-Mediated GEMM

A type of genetically engineered mouse model (GEMM) that uses retroviruses to introduce genetic material into host cells, resulting in random integration.

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Microinjection GEMM

A GEMM approach where foreign DNA is directly injected into a fertilized mouse zygote, leading to random integration of the DNA into the mouse genome.

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Targeted Manipulation of ES Cells

A GEMM approach that targets specific cells in mouse embryonic stem (ES) cells, allowing for precise genetic manipulation and gene targeting.

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Random Integration

The integration of foreign DNA into the host genome in a random manner, with no specific location determined.

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Targeted Integration

The precise integration of foreign DNA into a specific location in the host genome, allowing for targeted genetic manipulation.

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Microinjection GEMM Advantages

A GEMM approach that allows for the generation of transgenic animals in a single generation, offering high versatility for expressing transgenes.

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Targeted Manipulation of ES Cells Advantages

A GEMM approach that provides high precision in targeting specific genes, allowing for the creation of loss-of-function and conditional models.

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Random Integration Limitations

A GEMM approach where random integration can disrupt essential genes or regulatory regions, potentially leading to unpredictable phenotypes.

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Targeted Manipulation of ES Cells Limitations

A GEMM approach where the time-consuming and technically challenging nature of the process requires advanced molecular techniques.

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Neoplastic Transformation

The gradual development and progression of cancer, characterized by changes in cells and the tumor microenvironment.

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Tumor Microenvironment

The environment surrounding a tumor, including cells, blood vessels, and immune cells. It can influence tumor growth and spread.

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Penetrance & Latency in GEMMs

The challenge of ensuring that the engineered gene causes tumor development in a high percentage of mice and within a reasonable timeframe.

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Non-Invasive Imaging in GEMMs

The use of imaging techniques like ultrasound or MRI to monitor tumor development, treatment progress, and immune responses in GEMMs.

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Cross-Reactivity Concerns in GEMMs

The phenomenon where the target gene used in GEMMs may differ from the corresponding human gene. Careful consideration is required to ensure the model is relevant to human disease.

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Neor & TK Gene Construct

A gene construct used in targeted gene modification, containing the neomycin resistance gene for positive selection (allow cells with the desired modification to survive) and thymidine kinase gene for negative selection (eliminates cells with random gene insertions).

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Cre-Lox Technology

A powerful technology that allows for conditional gene modification in mice. It involves using a Cre recombinase enzyme to remove specific DNA segments (loxes), enabling gene manipulation in specific tissues or at specific developmental stages.

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Study Notes

Cancer Pathogenesis and Process

  • Tumorigenesis is a complex process involving multiple genetic alterations that transform normal cells, enabling abnormal growth, proliferation, and metastasis.
  • Initiation, Promotion, Progression, and Metastasis are the four stages.

Mouse Models in Cancer Research

  • Advantages:
    • Small size, easy to handle.
    • Cheaper than other animal models.
    • High incidence and rapid growth of tumors.
    • Multiple mice can be treated simultaneously for dose-response studies.
    • Well-characterized genetically compared to other mammals used in research.
  • Limitations:
    • Differences in size, lifespan, organ morphology, and physiology compared to humans.
    • Differences in pharmacokinetics and pharmacodynamics (PK/PD).
    • Differences in telomerase activity (largely inactive in adult humans).
    • Tend to develop fewer metastases than humans.
    • Differences in metabolic rate and pathways lead to different drug responses.
    • Limited number of initiating genetic alterations in tumors compared to humans; mouse tumors are often more homogeneous.

Different Types of Experimental Tumor Mouse Models for Cancer Immunology Research

  • Transplantable tumor models:

    • Tumors are transplanted from established cancer cell lines or patient tissues into host animals.

  • Genetically engineered tumor models (GEMMs):

    • Tumors arise endogenously due to engineered mutations in specific genes.

  • Humanized Models:

    • Immunodeficient animals are engrafted with human cells/tissues to study human cancer.
    • Derived from human cancer cells or tissues transplanted into humanized mice.

Different Types of Transplantable Tumor Models

  • Allograft (Syngenic) Model:
    • Tumors or cancerous cells are of mouse origin transplanted into a host mouse with a specific genetic trait.
    • Mouse cancer cell lines or tissues are used.
    • Immunocompetent mice are used; results closely recapitulate the real scenario.
  • Xenograft (PDX) Model:
    • Human tumor cells are transplanted into a host.
    • The transplantation can be subcutaneous or orthotopic.
    • Human cancer cell lines or patient-derived xenografts (PDXs) are used.
    • Severely compromised/immunodeficient mice are used to mimic human tumor genetics and biology.

Steps in Preparing Transplantable Tumor Models

  • Obtain tumors and store them frozen in media such as glycerol-glucose.
  • Incubate small tumor pieces in media and place them in sterile ampoules.
  • Slowly cool ampoules to storage temperature, then quickly thaw to inoculate into mice.
  • Depending on tumor size, observe the response to therapeutic regimes.

Different Types of Genetically Engineered Mouse Models

  • Retrovirus-Mediated:
    • Retroviruses introduce genetic material into host cells; integration is random.
    • Simple and quick.
  • Microinjection:
    • Foreign DNA is directly injected into a fertilized mouse zygote.
    • Allows target gene expression; integration is random.
  • Targeted manipulation of mouse embryonic stem (ES) cells:
    • Modifies specific cells in mouse ES cells, inducing into the developing embryo.
    • Precise; targeted integration.
    • High precision.

Gene Targeting using Homologous Recombination

  • Targeting vector: includes a selectable marker (neomycin resistance gene) and a negative selectable marker (HSV-tk gene).
  • Neo gene: positive selectable marker.
  • TK gene: negative selectable marker; triggers cell death.
  • Embryogenic stem cells are targeted using electroporation and homologous recombination.
  • The process results in the generation of genetically modified mice.

Conditional Gene Modification Using Cre-Lox Technology

  • Cre-line & Floxed line: Two different mouse lines are used.
  • Floxed gene: The gene to be targeted is flanked by two LoxP sites.
  • Crossing: Crossing the Floxed line with the Cre-line results in the progeny the gene between the LoxP sites being removed, generating a knockout allele.

Humanized Murine Models

  • Hematopoietic stem cells (CD34+) from patients are injected in NSG mice.
  • The immune system and host cells are reconstructed to make the mouse more human-like.

Humanized Tumor Models

  • Advantages: Can model tumor development complexities, genomic heterogeneity, and tumor microenvironment.
  • Limitations: Requires high tumor take rates across multiple mice in a reasonable time frame. Repeated invasive sampling for hematopoietic cells might be necessary.

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Description

Explore the intricate process of tumorigenesis and the role of mouse models in cancer research. Understand the stages of cancer development and the advantages and limitations of using mice for experimental studies. This quiz will test your knowledge on both the biological processes and the methodologies in cancer research.

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