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OVERVIEW
• Loss of regulation of normal cell behavior can have undesirable consequences
• Cells that lose regulation may grow and divide in an uncontrolled manner
• Uncontrolled cell growth can lead to formation of masses of cells
• Masses which continue to grown unchecked interfere with normal tissue function and may become known as cancer
OVERVIEW OF CANCER
• The primary abnormality involved in cancer development is loss of regulation of cell proliferation
• Many of the molecules used for cell regulation were identified due to abnormalities in function which led to cancer
• The uncontrolled growth of cancer cells generally occurs as a result of abnormalities in multiple regulatory systems of cells
CANCER TYPES
• Any of the body’s cell types may proliferate to become cancer
• There are over 100 different types of cancer that have been identified
• Behavior and response to treatment can vary greatly due to this variability
• An important factor in identifying cancer is the distinction between tumor types
TUMORS
• A tumor is any abnormal proliferation of cells• A benign tumor remains confined to its
original location– Benign tumors do not invade surrounding normal
tissue or spread to other sites• A malignant tumor can invade normal tissue
and spread by metastasis– Spreading via circulatory or lymphatic systems
• Malignant tumors are referred to as cancer
TUMOR CLASSIFICATION
• Carcinomas: malignancies of epithelial cells– Make up about 90% of human cancers
• Sarcomas: solid tumors of connective tissues– Rare in humans, about 3% or less
• Leukemias and lymphomas: arise from blood-forming and immune cells– Make up about 7% of human cancers
• Tumors are further classified according to tissue of origin and cell type involved
CANCER DEVELOPMENT
• Cancer cells exhibit clonal development– All cells in a given tumor develop from abnormal
proliferation of a single cell– This does not indicate that the original cell
acquired all characteristics common to cancer cells
• Cancer development is a process requiring multiple steps resulting in progressive cellular alteration
• Cancer develops as a result of mutation and selection for cells with increasing capacity for proliferation, survival, invasion, and metastasis
CANCER DEVELOPMENT
• Most cancers do not occur until later in life, and incidence increases dramatically with each decade humans live
• The changes leading to the development of cancer typically accumulate over the course of an organism’s lifetime
• A defined series of steps has been identified which will result in tumor development
CANCER DEVELOPMENT
• Tumor initiation is the first step involved in the development process– It is thought to be the result of abnormal
proliferation of a single cell due to mutation• Proliferation provides a clonally-derived
population of new tumor cells• Tumor progression occurs as additional
mutations accumulate within the cells in the tumor population
CANCER DEVELOPMENT
• Mutations acquired during tumor progression confer selective advantages to those cells
• The cells with the most advantageous characteristics will become the dominant members of the population: clonal selection
• Clonal selection continues until tumors become more rapid-growing and increasingly malignant
CANCER CAUSES
• Substances capable of inducing cancer are called carcinogens
• Identification of carcinogens has occurred both experimentally and epidemiologically
• Since cancer development is a multistep process, identifying a single cause is overly simplistic and unrealistic
• Carcinogens contribute to cancer develop-ment by various mechanisms
MECHANISMS OF CARCINOGENS
• Radiation and some chemical carcinogens act as mutagens UV radiation, chemicals in tobacco smoke
• Some carcinogens act as mitotic agents, or tumor promoters Hormones
• Some pathogens induce cancer in the host HPV, H. pylori
CANCER CELL PROPERTIES
• Cancer cells have abnormalities in many mechanisms of regulation
• Cells in culture (in vitro) display characteristics seen in cancer cells in the host (in vivo)
• Cancer cells lack sensitivity to density-dependent inhibition
• Cancer cells also have reduced requirements for extracellular growth factors
CANCER CELL PROPERTIES
• Some cancer cells produce growth factors that mediate autocrine growth stimulation
• Some cells have abnormal intracellular signaling systems which decrease their need for external growth factors
• Cancer cells have reduced expression of CAMs which allows their movements to be nearly unrestrained
CANCER CELL PROPERTIES
• Cancer cells lose contact inhibition displayed by normally dividing cells
• Cancer cells may secrete proteases capable of digesting extracellular matrix components
• Cancer cells may secrete growth factors promoting angiogenesis
• Most cancer cells fail to differentiate normally• Many cancer cells fail to undergo apoptosis• Cancer cells usually acquire the capacity for
unlimited replication
CELL TRANSFORMATION STUDIES
• Cell culture is used to study induction of tumors by exposing cells to known carcinogens
• The conversion of normal cells to cancer cells is called transformation
• In vitro study of cell transformation has allowed greater understanding of cancer development
ONCOGENES
• Specific genes capable of inducing cell transformation are called oncogenes
• Viral oncogenes are involved with virus-induced cancers
• Cellular oncogenes are involved with non-virus induced cancer development
• Proto-oncogenes are the normal genes, that when mutated, become activated oncogenes
ONCOGENES
• Studies of human bladder carcinoma provided the first evidence of cellular oncogenes
• Tumor cells contain active oncogenes that are passed to their progeny
• Families of oncogenes have been identified in humans
• Oncogenic conversion typically occurs as a result of mutation acquired through exposure to carcinogens
ONCOGENE PRODUCTS
• Many oncogene proteins affect abnormal cell proliferation– One oncogene leads to unregulated progression
through the G1 checkpoint
• Some oncogene products contribute to inability to undergo apoptosis – Changes in bcl-2 allow for blockage of apoptosis
• Some oncogene products lead to defective differentiation– Mutations in receptor genes lead to blocks in
differentiation for some leukemias
TUMOR SUPPRESSOR GENES
• Tumor suppressor gene inactivation or loss can lead to cancer development
• Normal tumor suppressor gene products inhibit cellular proliferation and tumor development
• Lost or inactivated tumor suppressor genes are seen in a variety of tumors
TUMOR SUPPRESSOR GENES
• Hybridization experiments combining tumor cells and normal cells were done in 1969
• Most of the hybrid cells were nontumorigenic, providing evidence that normal genes could suppress tumor development
• Studies of retinoblastoma provided identification of the first tumor suppressor gene– Both copies of Rb to be mutated or lost in order for
retinoblastoma to develop
TUMOR SUPPRESSOR GENE PRODUCTS
• Proteins encoded by tumor suppressor genes are responsible for inhibition of cell proliferation or survival
• Inactivation of tumor suppressor genes eliminates production of negative regulatory proteins
• Most tumor suppressor proteins inhibit the same regulatory pathways that are stimulated by oncogenic proteins
TUMOR SUPPRESSOR GENE PRODUCTS
• Rb and INK4 tumor suppressor gene products are involved in regulation of cell cycle progression at points affected by cyclin D and Cdk4, which can act as oncogenes
• The product of the p53 gene regulates cell cycle progression and apoptosis
• BRCA1 and BRCA2 gene products function as stability genes
GENES IN TUMOR DEVELOPMENT
• Mutations leading to activation of oncogenes and inactivation of tumor suppressor genes are critical in tumor initiation and progression
• Accumulated damage to multiple genes results in the overall characteristics of cancer cells
• Colon cancer is a well-characterized example of how multiple steps lead to cancer development
DETECTION AND OUTLOOK
• Second to prevention, early detection is the most effective way to hope for a positive prognosis in cancer
• Premalignant tumors typically respond well to treatment like radiation or surgery
• Tumors that have not spread or metastasized may respond well to localized treatment
• Malignancies that have spread have lower survival rates associated with them
• Metastatic tumors have markedly decreased survival rates associated with them
EARLY DETECTION
• Molecular methods of early detection are aimed at identification of individuals with increased risk for development of cancer
• Monitoring of high risk individuals may allow early detection and more effective treatment for some cancer types
• Identification and monitoring may allow patients to make life changes to decrease their likelihood of developing cancer
MOLECULAR DIAGNOSIS
• Detection of markers known to be associated with specific types of cancer is important in differential diagnosis
• Finding mutations in specific oncogenes or tumor suppressor genes may aid in developing a successful therapeutic course for the patient
• Distinction between similar tumors can help predict clinical outcome for patients
TREATMENT
• Most cancer treatment drugs bring about DNA damage or inhibition of DNA replication
• Therapies are toxic not only to target cells but also normal cells
• Newer treatments aimed at interference of angiogenesis have shown promise
• Anti-oncogenic drugs have also been developed with some success
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