chapter 16
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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. - PowerPoint PPT PresentationTRANSCRIPT
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.
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 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.
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
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.
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.
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.
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 (proto-
oncogene).– Proto-oncogenes encode proteins that function in
a cell’s normal activities.
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 proto-oncogene 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 tumor-
suppressor 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.
The Genetics of Cancer (9)
• The role of pRB in regulating the cell cycle– The protein encoded by the RB gene (pRB)
regulates the G1 to S transition.
– Transcription factors of E2F family are targeted by pRB.
– The arrest of the cell cycle in G1, required for normal cell differentiation, is directed by pRB.
– Animals with one mutated copy of RB gene have an elevated risk of developing cancer.
The Genetics of Cancer (10)
• The role of p53: Guardian of the genome– The p53 protein suppresses the formation of
tumors and maintains genetic stability.• The p53 gene may be the most important tumor
suppressor gene in the human genome.• Proper functioning of the p53 protein is very sensitive
to even slight changes in the amino acid sequence.
The Genetics of Cancer (11)
• p53 (continued)– The p53 protein acts a transcription factor,
activating the expression of a gene that inhibits the G1-S transition.
– When a cells sustains damage to its DNA, the concentration of p53 rises so that the damage can be repaired before initiating DNA replication.
– The p53 protein triggers apoptosis in cells whose DNA is damaged beyond repair.
The Genetics of Cancer (12)
• Other tumor-suppressor genes– Mutations of tumor-suppressor genes that are not
RB or p53 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.
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 (erbB) 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
G0 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.
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)
• MicroRNAs: A New Player in the Genetics of Cancer– Two miRNAs are inhibit expression of the mRNA
that encodes the anti-apoptotic proteins BCL-2.– Some miRNAs act more like oncogenes than
tumor suppressors.– One cluster of miRNA 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 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 cDNA is prepared from cancer cells and
allowed to hybridize with the spots.• Spots corresponding to actively transcribed genes
fluoresce.
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.
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.
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.
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 (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.