CANCERBIO 224

Intro to Molecular and Cell Biology

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

18.1 A CANCER OF THE PANCREAS

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

SOURCE: WWW.CDC.GOV

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

18.2 TUMOR CLONALITY

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

INCREASED RATE OF COLON CANCER WITH AGE

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

STAGES OF TUMOR DEVELOPMENT

DEVELOPMENT OF COLON CARCINOMAS

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

STRUCTURE OF REPRESENTATIVE CHEMICAL CARCINOGENS

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

DENSITY-DEPENDENT INHIBITION

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

18.8 AUTOCRINE GROWTH STIMULATION

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

18.9 CONTACT INHIBITION

18.10 DEFECTIVE DIFFERENTIATION AND LEUKEMIA

DETECTION OF A HUMAN TUMOR ONCOGENE BY GENE TRANSFER

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

18.22 POINT MUTATIONS IN RAS ONCOGENES

18.23 TRANSLOCATION OF C-MYC

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

18.24 TRANSLOCATION OF ABL

18.25 ONCOGENES AND THE ERK SIGNALING PATHWAY

18.27 THE AP-1 TRANSCRIPTION FACTOR

18.28 ONCOGENIC ACTIVITY OF THE WNT PATHWAY

18.29 ACTION OF THE PML/RAR ONCOGENE PROTEIN

18.30 ONCOGENES AND CELL SURVIVAL

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

18.31 SUPPRESSION OF TUMORIGENICITY BY CELL FUSION

18.32 INHERITANCE OF RETINOBLASTOMA

18.33 MUTATIONS OF RB DURING RETINOBLASTOMA DEVELOPMENT

18.34 RB DELETIONS IN RETINOBLASTOMA

18.35 INTERACTION OF RB WITH ONCOGENE PROTEINS OF DNA TUMOR VIRUSES

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

18.37 INHIBITION OF CELL CYCLE PROGRESSION BY RB AND P16

18.38 ACTION OF P53

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

18.39 GENETIC ALTERATIONS IN COLON CARCINOMAS

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

18.40 SURVIVAL RATES OF PATIENTS WITH COLON CARCINOMA

18.41 EGF RECEPTOR MUTATIONS ASSOCIATED WITH SENSITIVITY TO GEFITINIB

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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