Carcinogenesis
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Carcinogenesis. Patricia Jakel, RN,MN,OCN. What Is Cancer?. What is cancer?. A series of cellular, genetic aberrations that cause abnormal cell proliferation. Unchecked local growth (tumor formation) and invasion of surrounding tissue.

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Carcinogenesis

Carcinogenesis

Patricia Jakel, RN,MN,OCN


Carcinogenesis

What Is Cancer?


What is cancer

What is cancer?

  • A series of cellular, genetic aberrations that cause abnormal cell proliferation.

  • Unchecked local growth (tumor formation) and invasion of surrounding tissue.

  • Ability to metastasize (e.g. spread in a contiguous fashion to form secondary sites).


Changing approach and outcomes

Changing Approach and Outcomes

  • Cancer as disease change from acute to chronic

  • 20th Century Model: “Seek and Destroy”

  • 21st Century Model: “Target and Control”


Essential aberrations of malignancy

Essential Aberrations of Malignancy

  • Proliferation

  • Evading Apoptosis-avoiding programmed cell death

  • Cellular Differentiation

  • Motility and Invasion

  • Recruitment of Blood Vessels and Angiogenesis

  • Metastatic Spread

  • Cancer cells must compete successfully at each event to go forward.


Mechanism of cancer

Mechanism of Cancer

  • Apoptosis- is programmed cell death-that is, it is an active process controlled by cellular signaling. It may be triggered by the absence of a required growth factor:intercellular signals that indicate DNA damage or other injury to the cell; harmful external agents; or other intra- and extracellular events.


Mechanism of cancer1

Mechanism of Cancer

  • Angiogenesis- or the formation of new blood vessels, critical step in tumor growth. Without tumors must obtain oxygen and nutrients by diffusion and therefore cannot grow larger.

  • The tumor remains dormant until it can stimulate blood vessel growth from nearby capillaries.

  • Malignant cells can release growth factors and enzymes that stimulate rapid formation of blood vessels. These chemical include VEGF- Targeted therapy.


Carcinogenesis1

Carcinogenesis

  • Refers to the process by which cancer arises. Likely involves a series of multiple steps or cellular changes over time. This three-stage theory is the most widely used explanation of the process by which a normal cell is transformed into a cancer cell.


Pathology cancer arsies due to cumulative alteration in a cell s genes

Pathology-cancer arsies due to cumulative alteration in a cell’s genes

1. Proto-oncogenes- the genetic portion of the DNA that regulates normal cell growth and repair: mutation may allow cell to proliferate beyond normal body needs.


Pathology

Pathology

  • 2.Tumor suppressor gene- the genetic portion of the DNA that stops cell division; mutation may allow cells to proliferate beyond normal body needs.

  • 3. Oncogenes- abnormal, mutated genes responsible for the transformation of a normal cell into a cancer cell. May arise from mutations in proto-oncogenes, tumor suppressor genes, or other genes.


3 oncogenes continued

3. Oncogenes continued-

  • Different types of oncogenes may act together to induce cancers.

    • 1.p53 tumor suppressor gene-normally functions to stop cell proliferation, which allows DNA damage to be repaired.

      • When mutated, p53 restraint on cell proliferation is lost.

      • p53 mutations occur in about half of all human cancers: most common in colorectal, lung, and breast cancer.


3 oncogene continued

3. Oncogene continued

  • 2. Ras family of proto-oncogens-normally function to promote cellular growth

    • When mutated ras oncognes may allow cells to proliferate unrestrainted.

    • Ras oncogene are the most frequently detected oncogenes in human cancers; most common in pancreatic, colorectal, and thyroid cancers


Clinical implications

Clinical Implications

  • Presence of certain oncogenes may have diagnostic and prognostic value.

  • Prevention of gene mutation is one focus of chemoprevention clinical trails.

  • Understanding of genetic changes may result in new targets for treatment


Genes and cancer

Genes and Cancer

  • Proto-Oncogenes- normal genes that participate in in normal tissue repair. Molecular “bucket brigade.”

  • Oncogenes- mutated proto-oncogenes. Excessively active

    • Secreted growth factor

    • Cell-surface growth-factor receptors

    • Membrane associated G protein

  • Tumor-Suppressor Genes- normal tell the cell to stop growing, role in cell cycle activity, helps with apoptosis


  • Relationship between genes and cancer

    Relationship between genes and cancer

    • Cancer is a disease if genes gone awry. Genes that control the orderly replication of cells become damaged, allowing the cell to reproduce without restraint and eventually to spread into neighboring tissues and set up growths throughout the body.


    Carcinogenesis

    Cancer Tends to Involve Multiple Mutations

    Benign tumor cells grow only locally and cannot spread by invasion or metastasis

    Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites

    Time

    Mutation inactivates suppressor gene

    Cells proliferate

    Mutations inactivate DNA repair genes

    Proto-oncogenes mutate to oncogenes

    More mutations, more genetic instability, metastatic disease


    Cancer and genetics

    Cancer and Genetics

    • All cancer is genetic, in that it is triggered by altered genes. However, just a small portion of cancer is inherited: a mutation carried in reproductive cells, passed on from one generation to the next, and present in cells throughout the body.


    Cancer and genetics1

    Cancer and Genetics

    • Most cancer is random mutations that develop in body cells division during one’s lifetime- either as a mistake when cells are going through cell division or in response to injuries from environmental agents such as radiation or chemicals.


    1 initiation

    1. Initiation

    • A cancer causing agent damages the DNA, this gene may then:

      • Undergo repair

      • Become permanently changed (mutated)but not cause cancer unless exposed to threshold levels of cancer promotors.

      • Become mutated and produce a cancer cell line.


    Carcinogenesis

    Promotion- a process by which carcinogens are subsequently introduced, resulting in one of the following changes:

    • Reversible damage to the proliferation mechanism of the cell; the effects of the promoting factors may be inhibited:

      • Cancer-reversing agent.

      • Host Characteristics

      • Time and dose limits.


    Promotion continued

    Promotion continued.

    • Irreversible damage to the proliferation mechanism, resulting in cancer cell transformation.


    Progression

    Progression

    • Invasion -cells continue to divide; increase in bulk, pressure, and secretion of enzymes result in local spread and invasion of surrounding structures.

    • Neovascularization-formation of new blood vessels.


    Metastasis the production of secondary tumors at distant sites

    Metastasis-the production of secondary tumors at distant sites.

    • Routes of metastasis

    • Sites

    • Clinical Implication

      • Metastasis is the major cause of death from cancer.

      • Most tumors have begun to metastasize at the time of detection.


    Carcinogenesis

    Invasion and Metastasis

    1

    Cancer cells invade surrounding tissues and blood vessels

    2

    Cancer cells are transported by the circulatory system to distant sites

    3

    Cancer cells reinvade and grow at new location


    Carcinogenesis

    Carcinoma in Situ

    Normal

    Hyperplasia

    Milddysplasia

    Carcinoma in situ (severe dysplasia)

    Cancer(invasive)


    Neoplasm vs tumor

    Neoplasm vs Tumor

    • Interchangeable terms

    • Refers to abnormal growth of tissue that serves no function and continues to grow unchecked.

    • Can be benign or malignant

    • Cancer- common term for all malignancies


    Tumor nomenclature

    Tumor Nomenclature

    • Hematologic Malignancies

      • Lymphomas

        • Malignancies of the lymphocyte

        • Subclassified as:

          • Hodgkin's

          • Non-Hodgkin's

      • Multiple myeloma-arises from the plasma cell (B lymphocyte) line.


    Tumor nomenclature1

    Tumor Nomenclature

    • Hematologic Malignancies

      • Leukemias

        • Arises from hematopoietic cells

        • Classified according to cell type and maturity.

        • Lympho-denotes leukemia of lymphoid origin.

        • Myleo-denotes leukemia of myeloid origin


    Carcinogenesis

    Different Kinds of Cancer

    Leukemias:

    Bloodstream

    Some common carcinomas:

    Lung

    Breast (women)

    Colon

    Bladder

    Prostate (men)

    Lymphomas:

    Lymph nodes

    Some common sarcomas:

    Fat

    Bone

    Muscle


    Carcinogenesis

    Naming Cancers

    Cancer Prefixes Point to Location

    PrefixMeaning

    adeno-gland

    chondro-cartilage

    erythro-red blood cell

    hemangio-blood vessels

    hepato-liver

    lipo-fat

    lympho-lymphocyte

    melano-pigment cell

    myelo-bone marrow

    myo-muscle

    osteo-bone


    Carcinogenesis

    Why Cancer Is Potentially Dangerous

    Brain

    Melanoma cells travel through bloodstream

    Liver

    Melanoma(initial tumor)


    Carcinogenesis

    Tumor Grading

    General Relationship Between Tumor Grade and Prognosis

    100%

    Low grade

    Patient

    Survival

    Rate

    High grade

    1

    2

    3

    4

    5

    Years


    Carcinogenesis

    Tumor Staging

    Five-Year Survival Rates forPatients with Melanoma (by stage)

    100%

    50%

    I

    II

    III

    Stage at Time of Initial Diagnosis


    Carcinogenesis

    What Causes Cancer?

    Some viruses or bacteria

    Some chemicals

    Radiation

    Heredity

    Diet

    Hormones


    Carcinogenesis

    Population-Based Studies

    Regions of Highest Incidence

    U.K.:

    Lung

    cancer

    JAPAN:

    Stomach

    cancer

    CANADA:

    Leukemia

    U.S.:Colon

    cancer

    CHINA:

    Liver

    cancer

    BRAZIL:

    Cervical

    cancer

    AUSTRALIA:

    Skin

    cancer


    Carcinogenesis

    Heredity? Behaviors? Other Factors?

    Colon Cancer(Number of new cases per 100,000 people)

    Stomach Cancer

    (Number of new cases per 100,000 people)

    100

    50

    5

    0

    100

    70

    7

    0

    Japan

    Japanese familiesin U.S.

    U.S.

    Japan

    Japanese familiesin U.S.

    U.S.


    Carcinogenesis

    Tobacco Use and Cancer

    Some Cancer-Causing Chemicals in Tobacco Smoke


    Carcinogenesis

    Low-Strength Radiation

    High

    Dallas

    Skin

    Cancer

    Incidence

    Pittsburgh

    Detroit

    Low

    Least

    Most

    Annual Sunshine

    (UV radiation)


    Carcinogenesis

    High-Strength Radiation

    High

    Leukemia Incidence

    Low

    Least

    Most

    X-ray Dose(atomic radiation)


    Ultraviolet radiation a complete carcinogen

    Ultraviolet radiation-a complete carcinogen

    • Sources of UVR

      • Sunlight

      • Tanning salons

      • Industrial sources-welding arcs


    Viruses

    Viruses-

    • Infect DNA, resulting in proto-oncogene changes and cell mutation.

    • Effects modified by:

      • Age

      • Immunocompetence


    Carcinogenesis

    Viruses

    Virus inserts and changes genes forcell growth

    Cancer-linked virus


    Carcinogenesis

    Examples of Human Cancer Viruses

    Some Viruses Associated with Human Cancers


    Carcinogenesis

    AIDS and Kaposi’s Sarcoma

    Without

    disease

    HIV infection

    Depressed

    immune

    system

    KSHV infection

    Kaposi’s

    sarcoma


    Carcinogenesis

    Bacteria and Stomach Cancer

    Patient’s tissue sample

    H. pylori


    Carcinogenesis

    Heredity Can Affect Many Types of Cancer

    Inherited Conditions That Increase Risk for Cancer


    Carcinogenesis

    Mutations and Cancer

    Genes Implicated in Cancer


    What causes cancer

    What causes cancer???

    • Exposure to carcinogens-chemical, or viral, or physical or familial

      • Exposure to radiation-cellular DNA damage by physical release of energy.

        • Ionizing radiation

          • Damage to the cell by this source;

            • Is usually repaired and no mutation results.

            • May give rise to a malignancy when damage affects proto-oncogenes or tumor suppressor genes.

            • Depends on numerous factors.


    Carcinogenesis

    Cancer Prevention

    Carcinogenic chemicals

    Carcinogenic radiation

    Cancer viruses or bacteria


    Carcinogenesis

    Avoid Tobacco

    Lung Cancer Risk Increases with Cigarette Consumption

    15x

    10x

    5x

    Lung Cancer Risk

    0 15 30

    Non-smoker

    Cigarettes Smoked per Day


    Carcinogenesis

    Protect Yourself From Excessive Sunlight


    Skin cancers most common with uvr

    Skin cancers most common with UVR

    • Melanoma

    • Basal cell carcinoma

    • Squamous cell carcinoma


    Carcinogenesis

    Avoid Cancer Viruses

    HPV Infection Increases Risk for Cervical Cancer

    High

    Cervical Cancer Risk

    Low

    Noninfected women

    Women infected with HPV


    Chemical carcinogens

    Chemical Carcinogens

    • Chemical substances that alter DNA


    Carcinogenesis

    Avoid Carcinogens at Work

    Some Carcinogens in the Workplace


    Examples of ionizing radiation

    Examples of ionizing radiation

    • Most exposure is natural and unavoidable.

    • Diagnostic radiographs, radiation therapy, radioisotopes used in imaging.

    • Cosmic rays.

    • Radioactive ground minerals and gases-radon, radium, uranium.

    • Cancers linked to ionizing radiation.


    Compromised immune system

    Compromised Immune System

    • Immune surveillance against cancer

    • Surveillance occurs via recognition of tumor-associated antigens

    • Immune response may fail .

      • Age

      • Tumor burden

      • Shed substances

      • Outside factors


    Carcinogenesis

    Microscopic Appearance of Cancer Cells


    Staging of cancer

    Staging of Cancer

    • TNM

      • T-extent or size of the tumor

      • N-absence or presence and extent of regional lymph node metastasis

      • M-absence or presence of distant metastases.


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