CHAPTER 16 Cancer Introduction Cancer results from alterations

CHAPTER 16 Cancer

Introduction • Cancer results from alterations in the DNA of a somatic cell during the lifetime of the affected individual. – Gene expression in cancer cells is altered. – Cancer cells proliferate in an uncontrolled manner, forming malignant tumors. – Malignant tumors tend to metastasize (establish secondary tumors). • Cancer is the focus of a massive research effort.

The invasion of normal tissue by a growing tumor

The incidence of new cancer cases and deaths in the United States (2000– 2003)

16. 1 Basic Properties of a Cancer Cell (1) • Malignant cells are not responsive to influences that cause normal cells to stop growth and division. – The capacity for growth and division is similar between cancer cells and normal cells. – When there are no growth factors in the medium or when cells contact surrounding cells: • Normal cells stop growing. • Malignant cells continue to grow.

Growth properties of normal and cancerous cells

Basic Properties of a Cancer Cell (2) • The phenotype of a cancer cell: – In culture, normal cells can be transformed by chemicals or viruses. – Different types of cancer cells share a number of similarities: • Aberrant chromosome numbers (aneuploidy) • Fail to elicit apoptosis • High metabolic requirements

The effects of serum deprivation on the growth of normal and trasformed cells

Karyotype of a cell from a breast cancer line showing a highly abnormal chromosome complement

16. 2 The Causes of Cancer • Mutagenic agents, such as carcinogenic chemicals and radiation, can cause cancer by altering the genome. • DNA tumor viruses and RNA tumor viruses carry genes whose products interfere with cell growth regulation. • Causes of most cancers still unknown • Diet can influence risk of developing cancer.

Changing cancer incidence I persons of Japanese descent following migration to Hawaii

16. 3 The Genetics of Cancer (1) • The development of a malignant tumor (tumorigenesis) is a multistep process. – Cancer results from an uncontrollled proliferation of a single cell. – Tumorigenesis occurs by a cumulative progression of genetic alterations.

The Genetics of Cancer (2) • Tumorigenesis (continued) – Cells become less responsive to growth regulation and better able to invade normal tissues. – First step is the formation of a benign tumor, which is a tumor composed of cells that proliferate uncontrolled by cannot metastasize to other sites.

The Genetics of Cancer (3) • Tumorigenesis (continued) – The products of the genes involved in carcinogenesis are usually responsible for cell cycle regulation, cell adhesion, and DNA repair. – The sequence in which genes mutate influences the development of cancer.

Detection of abnormal (premalignant) cells in a Pap smear

One of a variety of possible sequences of genetic changes leading to colon cancer

The Genetics of Cancer (4) • Tumor-Suppressor Genes and Oncogenes: Brakes and Accelerators – Tumor-suppressor genes encode proteins that restrain cell growth. • A normal cell fused to a cancer cell can suppress malignant characteristics in the latter. • Specific regions of chromosomes are deleted in cells of certain cancers.

Tumor-suppressor genes

The Genetics of Cancer (5) • Oncogenes encode proteins that promote the loss of growth control and the conversion of a cell to a malignant state. – Oncogenes were first discovered in the genomes of tumor viruses. – An oncogene is an altered cellular gene (protooncogene). – Proto-oncogenes encode proteins that function in a cell’s normal activities.

Oncogenes

Activation of a proto-oncogene to an oncogene

The Genetics of Cancer (6) • Oncogenes (continued) – Oncogenes act dominantly. – For a cell to become malignant, both alleles of a tumor-suppressor gene must be lost, and a protooncogene must be converted into oncogene.

The Genetics of Cancer (7) • Tumor-Suppressor Genes – Most of the proteins encoded by tumor-suppressor genes act as negative regulators of cell proliferation.

The Genetics of Cancer (8) • Tumor-suppressor genes (continued) – Retinoblastoma (RB) gene was the first tumorsuppressor gene to be discovered. • RB is inherited in certain families, and occurs sporadically in the population at large. • The cells of children with inherited RB have a deletion in one copy of the RB gene. • The development of RB requires both copies of RB to be altered or eliminated. • The reintroduction of a wild-type RB gene allows suppression of a cell’s cancerous phenotype.

Mutations in the RB gene that can lead to retinoblastoma

The Genetics of Cancer (9) • The role of p. RB in regulating the cell cycle – The protein encoded by the RB gene (p. RB) regulates the G 1 to S transition. – Transcription factors of E 2 F family are targeted by p. RB. – The arrest of the cell cycle in G 1, required for normal cell differentiation, is directed by p. RB. – Animals with one mutated copy of RB gene have an elevated risk of developing cancer.

The role of p. RB in controlling transcription of genes required for progression of the cell cycle

The Genetics of Cancer (10) • The role of p 53: Guardian of the genome – The p 53 protein suppresses the formation of tumors and maintains genetic stability. • The p 53 gene may be the most important tumor suppressor gene in the human genome. • Proper functioning of the p 53 protein is very sensitive to even slight changes in the amino acid sequence.

p 53 function is sensitive to mutations in its DNA-binding domain

The Genetics of Cancer (11) • p 53 (continued) – The p 53 protein acts a transcription factor, activating the expression of a gene that inhibits the G 1 -S transition. – When a cells sustains damage to its DNA, the concentration of p 53 rises so that the damage can be repaired before initiating DNA replication. – The p 53 protein triggers apoptosis in cells whose DNA is damaged beyond repair.

A model for the function of p 53

Experimental demonstration of the role of p 53 in the survival of cells under chemotherapy

The Genetics of Cancer (12) • Other tumor-suppressor genes – Mutations of tumor-suppressor genes that are not RB or p 53 are detected in only a few types of cancer. – Colon cancer is often caused by a inherited deletion in a tumor-suppressor gene called APC. – Inherited breast cancer is caused by mutations in BRCA tumor-suppressor genes, which may act as transcription factors and in DNA repair.

Premalignant polyps in the epithelium of the human colon

DNA damage initiates activity of proteins encoded by both tumor-suppressor genes and proto-oncogenes

The Genetics of Cancer (13) • Oncogenes – Oncogenes that encode growth factors or their receptors • Simian sarcoma virus contains the oncogene (sis) which is derived from a cellular gene which codes for the growth factor PDGF. • Oncogene (erb. B) directs the formation of an altered EGF receptor that stimulates the cell regardless of the presence of growth factor. • Some malignant cells contain lots of surface receptors which make them sensitive to low concentrations of growth factors.

The Genetics of Cancer (14) • Oncogenes – Oncogenes that encode cytoplasmic protein kinases • Raf, a serine-threonine protein kinase in the MAP kinase cascade, can be converted into an oncogene by mutations that rurn it into an enzyme that is always “on”. • The oncogene product Src is a protein tyrosine kinase which phosphorylates proteins involved in signal transduction, control of the cytoskeleton, and cell adhesion.

The Genetics of Cancer (15) • Oncogenes – Oncogenes that encode nuclear transcription factors • A number of oncogenes encode proteins that may acts as transcription factors. • Myc protein stimulates cells to reenter cell cycle from G 0 stage. • Overexpression of Myc may cause cells to proliferate uncontrollably.

The Genetics of Cancer (16) • Oncogenes – Oncogenes that encode products that affect apoptosis • Alterations that tend to diminish the cell’s ability to self -destruct increase likelihood of a cell giving rise to a tumor. • The overexpression of Bcl-2 gene leads to suppression of apoptosis, allowing abnormal cells to proliferate into tumors.

Overview of several of the signaling pathways involved in tumorigenesis

The Genetics of Cancer (17) • The Mutator Phenotype: Mutant Genes Involved in DNA Repair – Mismatch repair defects predispose cells to abnormally high mutation rates, which increases the risk of malignancy. – A deficiency in the nucleotide excision repair (NER) system may be involved in a hereditary syndrome xeroderma pigmentosum.

The Genetics of Cancer (18) • The mutator phenotype (continued) – A deficiency in NER is implicated in hereditary colon cancer. – Tumor cells of this form of cancer often have variations in the length of microsatellite sequences, due to errors during replication.

The Genetics of Cancer (19) • Micro. RNAs: A New Player in the Genetics of Cancer – Two mi. RNAs are inhibit expression of the m. RNA that encodes the anti-apoptotic proteins BCL-2. – Some mi. RNAs act more like oncogenes than tumor suppressors. – One cluster of mi. RNA genes is overexpressed during the formation of some lymphomas; some are implicated in tumor metastasis.

The Genetics of Cancer (20) • The Cancer Genome – Results of studies of cancer genomes suggest that the same tumors form different individuals express divergent combinations of genes. – Large numbers of cancer genes are components of a small number of pathways. – Cancer can be thought of as a disease of aberrant cellular pathways.

The genomic landscape of colorectal cancers

Core signaling pathways and processes genetically altered in most pancreatic cancers

The Genetics of Cancer (21) • Gene Expression Analysis – DNA microarrays (DNA chips) are used to diagnose cancer. • DNA corresponding to thousands of different genes is spotted on a glass plate so that each spot corresponds to a different gene. • Fluorescent c. DNA is prepared from cancer cells and allowed to hybridize with the spots. • Spots corresponding to actively transcribed genes fluoresce.

Gene-expression profiling that distinguishes two types of leukemia

The Genetics of Cancer (22) • Gene expression analysis (continued) – Different tumors have different transcription patterns. – DNA arrays may help doctors to design better treatment options.

The use of DNA microarray data to determining the choice of treatment

16. 4 New Strategies for Combating Cancer (1) • Conventional cancer therapies may be replaced by targeted therapies based on the molecular basis of malignancy. • New strategies include: – Antibodies against tumor cells. – Inhibition of cancer-promoting proteins. – Preventing the growth of blood vessels that nourish the tumor.

New Strategies for Combating Cancer (2) • Immunotherapy – Passive immunotherapy utilizes the strategy of using the patient’s own antibosies to respond to tumor cells. • Herceptin is an antibody against growth factors that stimulates proliferation of breast cancer cells. • Rituxan is an antibody that binds to cell surface proteins of non-Hodgkin’s lymphomas. • Vestibix id an antibody directed against the EGF receptor or colon cancer.

Monoclonal antibodies used to treat cancer

New Strategies for Combating Cancer (3) • Immunotherapy (continued) – Active immunotherapy tries to the get patient’s own immune system to against malignant cells. • Dendritic cells may be taken from cancer patients and can be made to display tumor proteins, then injected back into the patient so that the tumor can be rejected. • Another approach is to develop cancer vaccines against telomerase. • Other personalized treatments are being developed.

New Strategies for Combating Cancer (4) • Inhibiting the Activity of Cancer-Promoting Proteins – It might stop the uncontrolled growth and invasive properties of malignant cells. – Studies with protein-inhibiting drugs have shown moderate success. – A possible reason for the modest success is that agents are not targeting the appropriate cells within the tumor.

New Strategies for Combating Cancer (5) • Inhibiting the Formation of New Blood Vessels (Angiogenesis) – As a tumor grows, it stimulate the formation of new blood vessels (angiogenesis). – Compounds that inhibit angiogenesis are promising treatments for tumors. – An angiogenesis inhibitor denies the tumor access to nutrients and oxygen needed to grow.

Angiogenesis and tumor growth

Experimental Pathways: The Discovery of Oncogenes (1) • Experiments of Rous in 1911 showed that a tumor could be transmitted from one animal to another by a virus.

Experimental Pathways: The Discovery of Oncogenes (2) • RNA-dependent DNA polymerase (reverse transcriptase) is the enzyme that replicates the genetic material of RNA tumor viruses.

Experimental Pathways: The Discovery of Oncogenes (3)

Experimental Pathways: The Discovery of Oncogenes (4) • The capacity to transform a cell resides in a restricted portion of the viral genome. • The transforming genes of the viral genome (oncogenes) are not true viral genes but are cellular genes previously picked up by RNA tumor viruses.

Experimental Pathways: The Discovery of Oncogenes (5) • The src gene was the first oncogene identified; it is present in all vertebrate classes. – Both viral and cellular src genes code for protein kinases. – The viral version of the gene has higher activity than the cellular version.

Experimental Pathways: The Discovery of Oncogenes (6) • Cellular genes can be converted into oncogenes by carcinogenic chemicals or by a mutation in sequences regulating their expression. • Single base substitution mutations can convert proto-oncogenes into oncogenes.