Week 7 Cancer

Cancer
BIO255
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
Basic Properties of a Cancer Cell
• Malignant cells keep growing and dividing.
– 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.
Growth properties of normal
and cancerous cells
Basic Properties of a Cancer Cell
• The phenotype of a cancer cell:
– Different types of cancer cells share a number of
similarities:
• Aberrant chromosome numbers (aneuploidy)
• Fail to die
• High energy requirements
The effects of serum deprivation on the growth
of normal and trasformed cells
Cancer cells have abnormal chromosomes
What causes 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 in persons of
Japanese descent following migration to Hawaii
The Genetics of Cancer
• The development of a malignant tumor
(tumorigenesis) is a multistep process.
– Cancer results from an uncontrolled proliferation
of a single cell.
– Tumorigenesis occurs by a cumulative progression
of genetic alterations.
• 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 but cannot metastasize to
other sites.
• Tumorigenesis (continued)
– The products of the genes involved in
carcinogenesis are usually responsible for cell
cycle regulation, cell adhesion, and DNA repair.
• 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
• 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.
Oncogenes
• 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.
• Tumor-Suppressor Genes
– Most of the proteins encoded by tumor-suppressor genes
act as negative regulators of cell proliferation.
• 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.
p53 function is sensitive to mutations in its
DNA-binding domain
• 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.
A model for the function of p53
Experimental demonstration of the role of p53
in the survival of cells under chemotherapy
• 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.
Premalignant polyps in the epithelium
of the human colon
• Oncogenes
– Oncogenes that encode growth factors or their
receptors
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.
• 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.
• 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.
Angiogenesis and tumor growth

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Cancer

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