Transcript 9. Carcinogenesis

9.
การเริม
่ ต้นการเกิดมะเร็ง
(Carcinogenesis)
ว ัตถุประสงค์
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สามารถอธิบาย multi-step tumorigenesis ได้
สามารถอธิบายบทบาทของ tumor promoter ในการเริม
่ ต้นการ
เกิดมะเร็ง
้ หา
เนือ
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Multi-step tumor formation
Cancer development and Darwinian evolution
Nonmutagenic agents and tumorigenesis
Chronic Inflammation and tumorigenesis
9. Carcinogenesis
 Carcinogenesis is the process by which normal cells are
transformed into cancer cells.
 The formation of tumor is a complex process that usually
proceeds over a period of decades.
9.1 Most human cancers develop over many decades of
time
9.2 Histopathology provides
evidence of multi-step tumor
formation
 most clearly in the epithelia of the
intestine ( the intestinal epithelial cells form
a layer that is only one cell thick in many
places).
 carcinoma grows directly from an
adenomatous polyp.
normal colonic crypts (20x)
small tubular adenoma (4x)
early adenomatous crypt (20x)
villous adenoma (4x)
head
Stalk attaching
Head of polyp
To wall of colon
invasive carcinoma (20x)
large tubular adenoma (1x)
same tubular adenoma (20x)
liver metastases (4x)
 Multi-step tumorigenesis (carcinogenesis) in a variety of organ sites.
CIS = Carcinoma in situ
DCIS = Ductal Carcinoma in situ
CIN = Cervical intraepithelial neoplasia
PIN = Prostatic intraepithelial neoplasia
9.3 Colonic growths accumulate genetic alterations as
tumor progression proceeds
 Many of the steps of tumor progression are driven by genetic
alterations accumulated in the genomes of developing tumor cells.
Normal
epithelium
TSG = tumor suppressor gene
 Loss of APC function (or the functionally equivalent gain of catenin function) represents a starting point that is common to
almost all human colon carcinomas.
APC
9.4 Cancer development seems to follow the rules of
Darwinian evolution
 Darwinian evolution involves expansion of organisms that are
endowed with advantageous genotypes and thus phenotypes; a
similar scheme seems to describe how tumor progression occurs.
FIRST CLONAL EXPANSION
SECOND CLONAL EXPANSION
THIRD CLONAL EXPANSION
FOURTH CLONAL EXPANSION
9.5 Tumor stem cells further complicate the Darwinian
model of clonal succession and tumor progression
“Progenitor”
9.6 A linear path of clonal succession oversimplifies the
reality of cancer
 The rate of generation of new mutant alleles may exceed the
rate at which Darwinian selection eliminates less-fit clones.
----> the tumor mass becomes composed of an increasing number
of distinct subclones.
----> the genotypes of
tumors of the same type
that arise in different
patients are likely to be
markedly different from on
another.
9.7 The Darwinian model of tumor development is
difficult to validate experimentally
 Analyses of the genomes of cells at different states of tumor
progression are unlikely to converge on the critical genetic
changes that are responsible for many clonal successions.
----> inactivation of tumor suppressor gene by the epigenetic
process of gene silencing via promoter methylation is difficult to
identified.
----> the kinetics of each step of the multi-step progression are
extremely difficult to measure.
9.8 Multiple lines of evidence reveal that normal cells are
resistant to transformation by a single mutated gene
 Single mutations are necessary but not sufficient for the
development of cancers.
----> primary cells transfected with ras oncogene.
----> multiple changes seem to be required in order for cell to
reach a tumorigenic state.
9.9 Transformation usually requires collaboration
between two or more mutant genes
 ras-like oncogenes encode Ras-like oncoproteins that are
components of the cytoplasmic mitogenic signaling cascade.
 myc-like oncogenes encode Myc-like oncoproteins that perturb in
various ways the cell cycle control machinery, which operates in the
nucleus.
 ras was able to elicit anchorage independence, a rounded,
refractile appearance in the phase microscope, and loss of contact
inhibition.
 myc helped the cells to become immortalized and reduced
somewhat their dependence on growth factors.
ras + SV40 large T
ras + E1A
erbB + erbA
TGF- + myc
V-sea + v-ski
Bcl-2 + myc
ras + myc
raf + myc
src + myc
 Cell proliferation and cell survival are governed by a number (two or more)
of distinct regulatory circuits, all of which must be perturbed before the cell will
become tumorigenic.
9.10 Transgenic mice provides models of oncogene
collaboration and multi-step cell transformation
 Insert mutant, activated oncogene
into a germ line of laboratory mouse.
 Confine the expression of this
oncogene to a small subset of tissues
in the mouse.
 Mammary glands showed minimal
morphologic changes in the case of
myc transgene.
 Mammary glands showed
hyperplasia in the case of ras
transgene.
 The presence of a single oncogene
within a normal cell in living tissue is not
sufficient to transform this cell into a
tumor cell.
9.11 Human cells are constructed to be highly resistant
to immortalization and transformation
 Primary rodent cells become transformed in vitro following the
introduction of pairs of oncogenes (such as myc and ras), while such
pairs of introduced oncogenes consistently fail to yield tumorigenic
human cells.
 Experimentally, five distinct cellular regulatory circuits need to be
altered before human cells can grow as tumor cells.
+ Rac1
 It is unknown whether these five pathways are required for the
experimental transformation of all human cell types, and whether
deregulation of all of these five pathways occurs in spontaneously
arising human tumors.
9.12 Nonmutagenic agents,
including those favoring cell
proliferation, make important
contributions to tumorigenesis
 Nonmutagenic (nongenotoxic)
carcinogens induce skin cancers
in mice
 TPA = promoting agent
(promoter)
TPA= tetradecanoylphorbol-13-acetate
PMA= phorbol-12-myristate-13-acetate
 DMBA = initiating agent
(initiator)
---> potent mutagen
DMBA=7,12-dimethylbenz[a]anthracene
 Scheme of initiation and promotion of epidermal carcinomas in mice.
first painting with initiator
Halt
 Tumor promoters like TPA do
not directly affect the genomes of
cells, however, they can function
as important agents in driving
forward multi-step tumorigenesis.
 TPA mimics DAG (diacylglycerol) to
activate Protein kinase C (PKC ).
= potent stimulator of cell proliferation
second painting
with initiator
 Genes and proteins involved in mouse skin carcinogenesis.
first painting with initiator
second painting with initiator
9.13 Toxic and mitogenic agents can act as human tumor
promoters
 Alcohol is a toxic agent acting as a tumor promoter for cancers
of the mouth and throat (head-and-neck cancers).
(initiator = mutagenic carcinogens in cigarette smoke)
 Estrogen (and perhaps other hormones such as progesterone
and even prolactin) is a mitogenic agent acting as a tumor
promoter for breast cancers (mammary epithelial cell = MECs).
(initiator = metabolites of estrogen)
9.14 Chronic inflammation often serves to promote tumor
progression in mice and humans
 The development of adenomas and carcinomas in the colon is
strongly dependent on chronic inflammation.
 Hepatocellular carcinomas are associated with chronic HBV or
HCV infection and accompanying inflammation of the liver.
----> HBV acts as a tumor promoter and functions synergistically with
aflatoxin-B1, a highly mutagenic compound that is made by Aspergillus
fungi.
9.15 Inflammationdependent tumor
promotion operates
through defined
signaling pathway
 Chronic liver
inflammation acts
via NF-B to induce
hepatocellular
carcinomas.
9.15 Tumor
promotion is likely
to be critical
determinant of the
rate of tumor
progression in many
human tissues.
1) Promoter can
stimulate the clonal
expansions.
2) Promoter favoring cell
proliferation are
indirectly mutagenic.
3) Repeated cycles of
growth and division lead
to progressive
shortening of telomeric
DNA .
Known or suspected human promoters and their sites of action