C ANCER BIO 224 Intro to Molecular and Cell Biology

O VERVIEW 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

O VERVIEW OF C ANCER 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

C ANCER T YPES 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

T UMORS 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

T UMOR C LASSIFICATION 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

S OURCE : WWW. CDC. GOV

C ANCER D EVELOPMENT 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 T UMOR CLONALITY

C ANCER D EVELOPMENT 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

I NCREASED RATE OF COLON CANCER WITH AGE

C ANCER D EVELOPMENT 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

C ANCER D EVELOPMENT 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

S TAGES OF TUMOR DEVELOPMENT

D EVELOPMENT OF COLON CARCINOMAS

C ANCER C AUSES 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

M ECHANISMS OF C ARCINOGENS 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

S TRUCTURE OF REPRESENTATIVE CHEMICAL CARCINOGENS

C ANCER C ELL P ROPERTIES 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

D ENSITY - DEPENDENT INHIBITION

C ANCER C ELL P ROPERTIES 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 A UTOCRINE GROWTH STIMULATION

C ANCER C ELL P ROPERTIES 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 C ONTACT INHIBITION

18.10 D EFECTIVE DIFFERENTIATION AND LEUKEMIA

D ETECTION OF A HUMAN TUMOR ONCOGENE BY GENE TRANSFER

C ELL T RANSFORMATION S TUDIES 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

O NCOGENES 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

O NCOGENES 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 P OINT MUTATIONS IN RAS ONCOGENES

18.23 T RANSLOCATION OF C - MYC

O NCOGENE P RODUCTS Many oncogene proteins affect abnormal cell proliferation – One oncogene leads to unregulated progression through the G 1 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 T RANSLOCATION OF ABL

18.25 O NCOGENES AND THE ERK SIGNALING PATHWAY

18.27 T HE AP-1 TRANSCRIPTION FACTOR

18.28 O NCOGENIC ACTIVITY OF THE W NT PATHWAY

18.29 A CTION OF THE PML/RAR  ONCOGENE PROTEIN

18.30 O NCOGENES AND CELL SURVIVAL

T UMOR S UPPRESSOR G ENES 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

T UMOR S UPPRESSOR G ENES 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 S UPPRESSION OF TUMORIGENICITY BY CELL FUSION

18.32 I NHERITANCE OF RETINOBLASTOMA

18.33 M UTATIONS OF R B DURING RETINOBLASTOMA DEVELOPMENT

18.34 R B DELETIONS IN RETINOBLASTOMA

18.35 I NTERACTION OF R B WITH ONCOGENE PROTEINS OF DNA TUMOR VIRUSES

T UMOR S UPPRESSOR G ENE P RODUCTS 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

T UMOR S UPPRESSOR G ENE P RODUCTS 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 I NHIBITION OF CELL CYCLE PROGRESSION BY R B AND P 16

18.38 A CTION OF P 53

G ENES IN T UMOR D EVELOPMENT 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 G ENETIC ALTERATIONS IN COLON CARCINOMAS

D ETECTION AND O UTLOOK 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 S URVIVAL RATES OF PATIENTS WITH COLON CARCINOMA

18.41 EGF RECEPTOR MUTATIONS ASSOCIATED WITH SENSITIVITY TO GEFITINIB

E ARLY D ETECTION 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

M OLECULAR D IAGNOSIS 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

T REATMENT 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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