Transcript Document

18 Cancer
Chapter 18 Cancer:
Student Learning Outcomes:
• Explain causes, development of cancer (clonal):
• Chemicals, radiation, virus, spontaneous
• Decribe diversity of tumor viruses (model systems)
• Explain essential features of Oncogenes:
• Derived from proto-oncogenes, examples
• Explain essential features of tumor suppressors:
• Normal cell functions, examples
• Describe molecular approaches to cancer treatment
Introduction
18.1 Cancer cells have abnormalities in
multiple cell regulatory systems.
• Breakdown of regulatory mechanisms that govern
normal cell behavior:
• Grow, divide in uncontrolled manner,
• Spread throughout body
• Interfere with function of normal tissues, organs
• Understand cancer cells at molecular, cellular levels.
• Studies of cancer cells illuminate mechanisms of
normal cell behavior
The Development and Causes of Cancer
Tumor: abnormal proliferation of cells:
Benign tumor
• confined to original location, not invade
normal tissue, not spread to distant sites
Malignant tumor
• invades surrounding normal tissue, spreads
through body via circulation or lymphatics
(metastasis)
• termed cancers.
Fig. 18.1Pancreatic cancer
(purple stained nuclei) in normal
Development and Causes of Cancer
Most cancers three main groups:
Carcinomas: malignancies of epithelial cells (about
90% of human cancers).
Sarcomas (rare in humans): solid tumors of connective
tissue, (muscle, bone, cartilage, fibrous tissue)
Leukemias and lymphomas: blood-forming cells and
cells of immune system, respectively.
• Tumors are further classified according to tissue of
origin and type of cell involved.
Note most common cancers; most lethal
Fig 18.2 Tumor clonality
Tumor clonality
• Fundamental feature of cancer
• Tumors develop from single cell that
proliferates abnormally (evidence from Xinactivation pattern)
Most cancers develop late in life
Cancer is multistep process:
• Cells gradually become malignant
through progressive alterations
• Multiple abnormalities accumulate
• Selection for growth advantage
Ex: colon cancer increases with age.
Fig. 18.2 clonality
Fig. 18.3 age and colon cancer
Fig 18.4 Stages of tumor development
Tumor initiation: genetic alteration → abnormal
proliferation of single cell, → population of clonal tumor cells.
Tumor progression: additional mutations occur
within cells of population
•
•
•
•
Growth advantage,
Survival
Invasion
Metastasis
Fig. 18.4
Fig 18.5 Development of colon carcinomas
EX. Colon cancer
• Proliferation of epithelial cells → small benign neoplasm
(adenoma or polyp).
• Clonal selection →
• Growth of adenomas
of increasing size,
proliferative potential
• Becomes carcinoma
• metastasis
Fig. 18.5
The Development and Causes of Cancer
Carcinogens - substances that cause cancer.
Radiation, chemicals, viruses can damage DNA,
induce mutations.
• Solar UV radiation is major cause of skin cancer.
• Aflatoxin produced by some molds that contaminate
peanuts and other grains
• Viruses can cause cancer
 People can inherit cancer-susceptibility genes (oncogenes,
damaged tumor suppressor genes)]
Tobacco smoke carcinogenic chemicals:
benzo(a)pyrene,
dimethylnitrosamine,
nickel compounds
(nearly 1/3 cancer deaths).
Fig. 18.6
The Development and Causes of Cancer
Tumor promoters stimulate cell proliferation:.
• Hormones, particularly estrogens, are tumor
promoters in some human cancers.
exposure to excess estrogen increases likelihood woman
will develop uterine cancer.
• Some viruses cause cancer:
liver (HBV), cervical carcinoma (HPV)
• Bacterium Heliobacter pylori causes stomach cancer.
* Studies of tumor viruses identify molecular events in
development of cancers.
Properties of cancer cells
Characteristic properties of Cancer cells:
1. lack density-dependent inhibition of proliferation
2. reduced requirements for growth factors
3. less regulated cell-cell, cell-matrix (less adhesive)
4. not sensitive to contact inhibition
5,6. secrete proteases for invasion, growth factors for
angiogenesis
7. don’t differentiate normally, stay undifferentiated
8, 9. not undergo apoptosis; even after DNA damage
10. unlimited DNA replication; (over) express telomerase
Cancer cells have lost normal control – 10 properties
1. Cancer cells lack Density-dependent inhibition Continue growing to high densities
•
Normal cells proliferate to finite cell density,
(availability of growth factors).
– cease proliferating, arrest in G0
Fig. 18.7
The Development and Causes of Cancer
2. Cancer cells reduced requirements for growth
factors contributes to unregulated proliferation.
Can stimulate own proliferation (autocrine stimulation).
Fig. 18.8
The Development and Causes of Cancer
3. Cancer cells are less regulated by cell-cell, cellmatrix interactions:
• Reduced expression of adhesion molecules contributes to
invasion, metastasis
• Loss of E-cadherin (main adhesion molecule), aids
development of carcinomas (epithelial cancers).
4. Cancer cells lack
Contact inhibition
• Normal fibroblasts migrate until
contact neighbor cell, stop, adhere.
• Tumor cells move after contact
with neighbor cells, migrate over
adjacent cells, grow in disordered,
multilayered patterns.
Fig. 18.9
The Development and Causes of Cancer
5,6. Cancer cells secrete:
Proteases to digest extracellular
matrix
Growth factors for angiogenesis
• Permits invasion of normal tissues
• Digest collagen allows penetration of
basal laminae, invasion of connective
tissue.
• New blood vessels needed after tumor
about 106 cells; penetrate capillaries
The Development and Causes of Cancer
7. Cancer cells don’t differentiate normally.
Most fully differentiated cells cease cell division.
Ex. Leukemias:
• Blood cells from hematopoietic
stem cells in bone marrow.
• Leukemic cells don’t undergo
terminal differentiation;
arrest at early stages,
retain capacity for proliferation
Fig. 18.10
The Development and Causes of Cancer
8.9. Cancer cells fail to undergo programmed cell
death or apoptosis:
• Longer life span than normal; not require growth factors
• Lack of apoptosis after DNA damage increases resistance of
cancer cells to irradiation, chemotherapeutic drugs, (which
damage DNA)
10. Cancer cells overexpress telomerase:
• Capacity for unlimited DNA replication
• Telomerase required to maintain
ends of chromosomes after replication
Fig. 6.16 telomerase
The Development and Causes of Cancer
Ex. Assay for cell
transformation in vitro:
• Study of tumor induction by radiation,
chemicals, or viruses
• Detect conversion of normal cells to
tumor cells in culture (altered growth
properties)
• Focus assay (1958) recognizes group of
transformed cells morphologically distinct
“focus” versus normal cells on dish.
Fig. 18.11 Focus: RSV and
chicken fibroblasts
Tumor Viruses
18.2 Tumor viruses
directly cause cancer in humans or animals
• Critical role in research - models for cellular, molecular study
• Small genomes allowed identification of viral genes
responsible for cancer induction.
Tumor Viruses
Hepatitis B and C viruses
• Principal causes of liver cancer.
• Viruses infect liver cells, long-term chronic infections,
associated with high risk of liver cancer.
• HBV is DNA virus
HCV is RNA virus
Tumor Viruses
Simian virus 40 (SV40, monkey)
(and polyomavirus, mice)
•
•
•
•
not cause human cancer, important model
small genome sizes
Replicates in permissive host
Transforms non-permissive host
(inactivates Rb)
Early region encodes proteins
(small and large T antigens)
Proteins stimulate host cell
gene expression,
DNA synthesis.
Figs. 18.12,13
Tumor Viruses
Papillomaviruses are small DNA viruses.
• About 100 different types infect epithelial cells.
• Some cause benign tumors (warts); others cause
malignant carcinomas, particularly cervical cancer
• Transformation by expression of early genes, E6,E7:
• E7 binds Rb; E6 stimulates degradation of p53.
Fig. 18.14
Tumor Viruses
Adenoviruses large family of DNA viruses not
associated with human cancer, important models.
• Adenoviruses lytic in cells of their natural hosts, can
induce transformation in nonpermissive cells.
• Adenoviruses potential gene therapy vector
Tumor Viruses
Herpesviruses among the most complex viruses,
enveloped DNA genomes 100 to 200 kb:
• HSV-1, HSV-2 cause
cold sores, genital sores
• Varicella zoster virus (VZV)
causes chicken pox, shingles
• Kaposi’s sarcoma-associated herpesvirus causes
Kaposi’s sarcoma (common with AIDS)
• Epstein-Barr virus cause mononucleosis (transient)
and Burkitt’s lymphoma
Tumor Viruses
Retroviruses (RNA genome, DNA intermediate) cause
cancer in animals, including humans.
• HTLV-I causes adult T-cell leukemia
• Human immunodeficiency virus (HIV) causes AIDS.
• HIV not cause cancer directly, but infects & destroys T cells;
AIDS patients malignancies (lymphomas, Kaposi’s sarcoma)
Most retroviruses only 3 genes (gag, pol, and env):
for virus replication, not transformation; rarely induce tumors
• Other retroviruses have
specific extra genes
induce cell transformation,
oncogenes (carcinogens
Fig. 18.15
Fig 18.16 Cell transformation by RSV and ALV
18.3 Oncogenes - genes that transform cells:
• Rous sarcoma virus (RSV)
• Prototype highly oncogenic retrovirus
• 1st oncogene identified by
comparison of RSV to ALV
(avian leukosis virus does
not induce tumors)
** Cellular oncogenes are
involved in development
of non-virus-induced cancers.
Fig. 18.16
Fig 18.17 The RSV genome
RSV mutants revealed gene responsible for tumors
• RSV causes sarcomas: oncogene is src. (not in ALV)
• Src was 1st protein-tyrosine kinase identified.
Fig. 18.17
* other oncogenic retroviruses have key proteins of
cell signaling path: ras, raf, myc, erbB, fos, jun,
Fig 18.18 Isolation of Abelson leukemia virus
Viral oncogenes are derived
from genes of host cell:
• Key expt: isolation of oncogenic
retrovirus Abelson leukemia virus
from mice injected with a
nontransforming MuLV virus.
• One mouse developed lymphoma
from which a new, highly oncogenic
virus was isolated:
• Virus contained an oncogene (abl)
Abl is related to normal cell gene
Normal gene called proto-oncogene
Fig. 18.18
Oncogenes
*18.3 Proto-oncogenes:
• Normal-cell genes from which oncogenes originated
• Often proteins of signal transduction pathways that control
cell proliferation (e.g., src, ras, and raf )
Retroviral oncogenes differ from proto-oncogenes:
•
•
•
•
transcribed under control of viral promoter, enhancer
expressed at much higher levels, or in inappropriate cells.
point mutations lead to unregulated activity (ex. Ras)
can differ in structure and function from normal proteins:
Fig. 18.19 Raf oncogene: loss
of regulatory domain makes
oncogene protein unregulated
Detection of human tumor oncogene by gene transfer
Evidence cellular oncogenes in human tumors
(gene transfer experiments 1981)
• DNA from human bladder
carcinoma induced transformation
of mouse cells in culture,
indicating tumor had oncogene
• Many other examples later:
• ras, raf, c-myc
• erbB, cdk4, PDGFR
Fig. 18.20
Fig 18.21 Point mutations in ras oncogenes
First human oncogene: homolog of rasH oncogene of
Harvey sarcoma virus.
• 3 members of ras gene family (rasH, rasK, rasN) are
oncogenes most frequent in human tumors.
• ras oncogenes have point mutations critical sites:
• Mutations maintain Ras proteins constitutively in
active GTP-bound conformation
Fig. 18.21 mutation in RasH of bladder cancers
Oncogenes
*Cancer cells have abnormal chromosomes:
translocations, duplications, deletions.
• Creates oncogenes from proto-oncogenes:
altered promoters, gene fusions, amplification of normal gene
Ex Burkitt’s lymphomas:
translocations involve genes
encoding immunoglobulins.
• c-myc transcription factor
• Expressed abnormally from
immunoglobulin promoter
• Tumors of B cells
Fig. 18.22
Oncogenes
Translocations rearrange coding sequences →
abnormal gene products.
Ex: Translocation of c-abl proto-oncogene causes chronic
myeloid leukemia (CML);
• fusion protein has constitutive Abl tyr-kinase activity
Fig. 18.23 Bcr-Abl
Oncogenes
*Proto-oncogene proteins have normal roles in
growth factor-stimulated
signal transduction pathways.
Ex. ERK pathway oncogenes:
• polypeptide growth factors,
• growth factor receptors (ErbB),
• intracellular signaling proteins
(Ras, Raf, MEK, ERK),
• transcription factors (fos),
• transcription targets (cyclin D1).
Fig. 18.24 ERK path
See also Fig. 15.34
Mechanism of Tel/PDGFR oncogene activation
Many oncogenes encode growth factor receptors,
mostly protein-tyrosine kinases.
Ex. Receptor for PDGF converted to oncogene by
chromosome translocation, replacement of amino
terminus by transcription factor Tel.
• Fusion protein
• Tel sequences
dimerize in absence
of PDGF, →
activate oncogene
tyr protein kinase.
Fig. 18.25
Oncogenes
Oncogenes can encode transcription factors
normally induced by growth factors
EX. Transcription of fos proto-oncogene is induced by
phosphorylation of Elk-1 by ERK (Fig. 18.24).
• Fos and Jun dimerize to form AP-1 transcription
factor, activates transcription of cyclin D1
• Mutant fos or jun always activate
• Cyclin D1 proto-oncogene,
can become oncogene
(CCND1) by chromosome
translocation or
gene amplification
Fig. 18.26
Oncogenes
Oncogenic activity of transcription factor
can result from inhibition of differentiation.
Ex. Mutated form of retinoic acid receptor (PML/RARa)
oncoprotein in acute promyelocytic leukemia (APL)
• Mutated receptors interfere with
action of normal homologs,
block cell differentiation,
maintain leukemic state.
• Treatment with retinoic acid
induces differentiation,
blocks cell proliferation.
Fig. 18.28
Tumor Suppressor Genes
*18.4 Tumor suppressor genes normally act to
inhibit cell proliferation and tumor development.
• In many tumors, both genes are lost or inactivated,
contributes to abnormal proliferation of tumor cells
Tumor suppression first noticed during somatic cell
hybridization experiments in 1969; hybrids did not cause tumor,
suggesting genes in normal cell suppressed tumors.
Fig. 18.30
Fig 18.31 Inheritance of retinoblastoma
• First tumor suppressor gene found was
retinoblastoma, inherited childhood eye tumor.
• About 50% of children of affected parent develop
retinoblastoma: inherited as dominant autosomal
susceptibility to tumor development:
• Need somatic mutation of other copy
photo
Fig. 18.31; retinoblastoma;
Purple, affected people
Tumor Suppressor Genes
Retinoblastoma requires loss of both functional
copies of tumor susceptibility gene (Rb gene);
• People inherit one mutated gene, later other mutates
Fig. 18.32
Mutations of Rb during retinoblastoma development
Noninherited retinoblastoma is very rare:
• needs two independent somatic mutations in cell.
Fig. 18.32
Tumor Suppressor Genes
Rb is tumor suppressor:
Deletions of chromosome 13q14 in some
retinoblastomas suggested loss (rather
than activation) of Rb gene led to tumor
development
Mutations of Rb contribute to
many human cancers
Oncogene proteins of some DNA tumor
viruses, including SV40, adenoviruses,
and human papillomaviruses, bind to
Rb and inhibit it.
.
Fig. 18.33,34
Mutations ruining tumor suppressor genes:
common molecular alterations in human tumors
Tumor Suppressor Genes
Mutations ruining tumor suppressor genes are
common molecular alterations in tumors
p53 - second tumor repressor gene identified.
• inactivated in many cancers, leukemias, lymphomas,
sarcomas, brain tumors, carcinomas.
• Mutations of p53 in about 50% of all cancers.
Proteins encoded by most tumor suppressor genes
inhibit cell proliferation or survival.
Tumor suppressor proteins inhibit regulatory
pathways stimulated by products of oncogenes.
Tumor Suppressor Genes
Tumor suppressor proteins inhibit pathways
stimulated by products of oncogenes.
Ex. Products of Rb and INK4 (p16)
tumor suppressor genes regulate
cell cycle at restriction point in G1
Point affected by
cyclin D1/ Cdk4
(which can be oncogenes).
Fig. 18.36
Tumor Suppressor Genes
Ex. p53 gene product regulates both cell cycle
progression and apoptosis (programmed cell death)
• DNA damage induces p53,
• activates cell cycle inhibitory gene p21,
• transcription of proapoptotic genes
• Cells lacking p53 do not cycle arrest,
not do apoptosis after
DNA damaging agents
• p53 mutated in many cancers
(Fig. 16.20 p21 inhibits Cdk2/cycE)
Fig. 18.37
Tumor Suppressor Genes
Ex. BRCA1 and BRCA2 genes
(responsible for some inherited breast and ovarian
cancers) function as stability genes that maintain
integrity of genome:
•
•
Checkpoints in cell cycle progression,
Repair of DNA double-strand breaks
Mutations inactivating these genes leads to a high
frequency of mutations in oncogenes or tumor
suppressor genes.
Tumor Suppressor Genes
MicroRNAs (miRNAs) also
regulate gene expression
• post-transcriptionally, inhibit translation
and/or induce mRNA degradation,
• contribute to regulation of about 1/3 of
protein-coding genes.
Expression of miRNAs is lower in tumors,
suggesting they are tumor suppressors.
Example: let-7 targets oncogene c-myc
[Other miRNAs may be oncogenes]
Fig. 18.38
Tumor Suppressor Genes
Development of cancer is multistep process:
Accumulated damage in multiple genes → increased
proliferation, survival, invasiveness, metastatic potential.
Large-scale genome sequencing detects frequency mutations
• 100 colorectal cancers: each tumor ~ 15 mutations in genes
thought to be involved in cancer development:
Oncogenes rasK and PI3K ; Tumor suppressor genes APC and p53.
• Breast cancers ~ 14 mutations per tumor, p53 tumor suppressor and
PI3K oncogene
Fig. 18.39
Molecular Approaches to Cancer Treatment
18.5. Molecular approaches to cancer treatment:
Molecular defects being deciphered-> new
approaches to prevention and treatment
• 1. prevent development of cancer
• 2. detect early premalignant, before metastasis
• 3. identify susceptible individuals (gene tests)
• 4. molecular diagnosis of oncogenes, tumor
suppressor genes in patient
• 5. drugs specifically targeted to mutant proteins
Molecular Approaches to Cancer Treatment
Early detection of cancer:
• Cured by localized treatment,
before metastasis.
Ex. Early stages of colon cancer
(adenomas) usually curable by
minor surgical procedures.
Fig. 18.40
Molecular Approaches to Cancer Treatment
Identify individuals with inherited susceptibilities
to cancer development, diagnose tumors.
• Mutations in tumor suppressor genes (p53, Rb),
oncogenes (myc and cdk4), stability genes
(BRCA1 and BRCA2) detected with genetic testing.
• Molecular analysis of oncogenes, tumor suppressor
genes used in diagnosis of tumor (Bcr-Abl, ErbB-2)
• Molecular markers monitor course of disease during
treatment (loss of PML/RAR with treatment).
Molecular Approaches to Cancer Treatment
Treat with drugs that inhibit angiogenesis:
• Blocks proliferation of endothelial cells, less toxic to
normal cells.
• Most cancer drugs damage DNA or inhibit DNA
replication, are toxic to normal cells
•
Especially cells continually replaced by division
of stem cells (hematopoietic cells, epithelial cells of
gastrointestinal tract, hair follicle cells)
New drugs targeted specifically against oncogenes
recall proto-oncogenes important roles in normal cells.
Molecular Approaches to Cancer Treatment
Small molecule inhibitors of
oncogene proteins, protein kinases:
• Imatinib or Gleevec, specific
inhibitor of Bcr/Abl protein kinase,
blocks proliferation of chronic myeloid
leukemia cells (CML).
• Imatinib inhibits PDGF receptor
and Kit protein-tyrosine kinases:
• Kit oncogene in most gastrointestinal
stromal tumors.
• Imatinib active against tumors with
PDGF receptor activated as oncogene
Catalytic
domain abl plus
imatinib
Molecular Approaches to Cancer Treatment
gefitinib and erlotinib, (small molecule inhibitors
of EGF receptor), active against some lung cancers.
• Responsive lung cancers had mutations for
constitutive activation EGF receptor tyrosine kinase.
Fig. 18.41