Transcript Biology of Cancer

Chapter 11
Multi-Step Tumorigenesis
-11.1 ~ 11.5 -11.9 ~ 11.17 -
May 22 & 24, 2007
In the survival of favoured individuals and races,
during the constantly-recurring struggle for existence,
we see a powerful and ever-acting form of selection.
~ Charles Darwin, 1859 ~
Tumor progression
Normal cells evolve into cells with increasingly
neoplastic phenotypes through a process termed
tumor progression.
Tumor progression is driven by a sequence of
randomly occurring mutations and epigenetic
alterations of DNA that affect the genes controlling
cell proliferation, survival, and other traits associated
with the malignant cell phenotype.
How many different sequential changes are
actually required in cells and tissues in order
to create a human cancer?
11.1 most human cancers develop over many
decades of time
Figure 11.1 The Biology of Cancer (© Garland Science 2007)
11.2 Histopathology provides evidence of
multi-step tumor formation
The notion of human tumor development as
a multi-step process has been documented most
clearly in the epithelia of the intestine.
Microanatomy of the normal intestinal wall
villi
columnar epithelium
basement membrane
mesenchymal core
(fibroblasts, endothelial cells, macrophages, etc.)
The epithelial layer is the site of most of the pathological (disease-associated)
changes associated with the development of colon carcinomas.
Figure 11.5 The Biology of Cancer (© Garland Science 2007)
Four major types of new tissue growth
肥大
增生
grow faster
thicker epithelium
不正常發育
惡性增生
(腫瘤形成)
Kleinsmith, L. J. Principles of Cancer Biology. Pearson Education, Inc. 2006 Fig. 1-3
Normal colonic epithelium → adenomas
crypts (腺窩)
adenomatous crypt
normal crypts
Figure 11.6 part 1 of 2 The Biology of Cancer (© Garland Science 2007)
Pre-invasive adenomas (pedunculated polyps)
含肉莖的息肉
Adenomatous growths are considered benign, in that none
has broken through the basement membrane and invaded
underlying stromal tissues.
Figure 2.15a The Biology of Cancer (© Garland Science 2007)
adenoma
→ invasive carcinoma
→ metastatic carcinoma
normal liver
tissue
evidence for adenoma-to-carcinoma progression
Figure 11.6 & 8 The Biology of Cancer (© Garland Science 2007)
Two more evidences for adenoma-to-carcinoma progression
hundreds of polys on the wall of the
colon from an individual with familial
adenomatous polyposis (FAP)
→ high risk of colon cancer
FAP individuals contain a hereditary
mutation of adenomatous polyposis
coli (APC) tumor suppressor gene
Figure 11.8b & 7.22 The Biology of Cancer (© Garland Science 2007)
Multi-step tumorigenesis in a variety of organs
(carcinoma in situ)
prostatic intraepithelial neoplasia
cervical intraepithelial neoplasia
Figure 11.7 The Biology of Cancer (© Garland Science 2007)
ductal carcinoma in situ
11.3 Colonic growths accumulate genetic
alterations as tumor progression proceeds
LOH in colon cancers
17p: p53
5q: APC
Figure 7.14 The Biology of Cancer (© Garland Science 2007)
Molecular alterations during human
colon tumor progression
(~ 40-50 %)
(~ 90 %)
*
(~ 60 %)
*(~ 50-70 %)
* tumors bearing K-ras oncogenes rarely have
mutant p53 alleles, and vice versa.
The precise contribution of
hypomethylation to tumor
progression remains unclear;
some evidence suggests that it
creates chromosomal instability.
Figure 11.10 The Biology of Cancer (© Garland Science 2007)
Alternative genetic paths during
colon cancer progression
almost always the
1st inactivation in
the progression
Individuals with familial adenomatous
polyposis (FAP) start here !
Figure 11.11a The Biology of Cancer (© Garland Science 2007)
Darwinian evolution and clonal successions
Figure 11.12 The Biology of Cancer (© Garland Science 2007)
Paradox
- A mutated, activated H-ras oncogene from a human
bladder carcinoma could fully transform NIH3T3 mouse
fibroblasts.
→ the acquisition of a single ras oncogene (a point
mutation on ras) sufficed to convert NIH3T3 cells
to a transformed, tumorigenic state.
- Why is cancer formation in humans a multi-step process ?
11.9 Multiple lines of evidence reveal that
normal cells are resistant to transformation by a single mutated gene
- The NIH3T3 cells are not truly normal. They constitute a cell
line, a population of cells that have been adapted to grow in
culture and to proliferate in an immortalized fashion.
- The results obtained from primary rat and hamster primary cells
(transfection of ras oncogene) were very different from those
observed previously with NIH3T3 cells. These primary cells
were not susceptible to ras-induced transformation.
- Single mutations are not sufficient for the development of cancers.
11.10 Transformation usually requires collaborration between two or more mutant genes
- A line of human promyelocytic leukemia cells carry both an
activated N-ras and an activated myc oncogene.
- When a myc oncogene was introduced together with an H-ras
oncogene into rat embryo fibroblasts, the cells become
transformed and tumorigenic.
Figure 11.23 The Biology of Cancer (© Garland Science 2007)
The ras and myc oncogenes have complementary
effects on cell phenotype
ras: anchorage independence
round and refractile appearance
loss of contact inhibition
(cytoplasmic mitogenic signaling cascade)
myc: immortalization
reduction of dependence on growth factors
(perturb cell cycle control machinery)
or a
mutant
p53)
Not all “ras-like” or “myc-like” members elicit identical effects in cells.
Table 11.1 The Biology of Cancer (© Garland Science 2007)
Table 11.2 The Biology of Cancer (© Garland Science 2007)
11.11 Transgenic mice provide models of
oncogene collaboration and multi-step
cell transformation
mouse mammary
tumor virus (MMTV):
a retrovirus that
specifically targets
mammary tissues.
The viral promoter is
expressed at
significant levels only
in mammary glands,
to a lesser extent , in
salivary glands.
Figure 11.24a part 1 of 2 The Biology of Cancer (© Garland Science 2007)
Figure 11.24a part 2 of 2 The Biology of Cancer (© Garland Science 2007)
Oncogene collaboration in transgenic, cancer-prone mice
Even with mutant ras + myc
expressed in the great majority
of mammary cells from early
in development, tumors did not
appear in these mice until 4
weeks after birth.
Careful analysis of rat cells
transformed by ras + myc,
sooner or later, acquire a
mutation or methylation event
that leads to inactivation of the
p53 tumor suppressor pathway.
Figure 11.24b The Biology of Cancer (© Garland Science 2007)
Collaboration of myc and bcl-2 family genes
(anti-apoptotic) in cancer development
myc and bcl-2 (bcl-XL) genes are driven by immunoglobulin G
(IgG) promoter and lymphomas/plasma cell tumors are scored.
Figure 9.22b, c The Biology of Cancer (© Garland Science 2007)
11.12 Human cells are constructed to be highly resistant
to immortalization and transformation
- Human cells rarely, if ever, become immortalized following
extended serial passaging in culture.
- The introduction of paired oncogenes (such as ras + myc)
could transform primary rodent cells, however, such pairs
consistently fail to yield tumorigenic human cells.
a possible explanation:
- The cells of laboratory mice carry extremely long telomeric
DNA (up to ~ 40 kb) and express telomerase activity.
- In contrast, normal human cells have far shorter telomeres
(5~10 kb), and most human cell types lack telomerase activity.
Figure 11.25 The Biology of Cancer (© Garland Science 2007)
Human cells
+ hTERT gene (prevent telomere erosion)
+ SV40 large T gene (inactivate both pRb and p53)
immortalization
+ ras
morphological transformation in culture
(still unable to form tumors in nude mice)
+ SV40 small T gene (perturb the function of protein
phosphatase 2A, or PP2A)
tumorigenic
Five distinct intracellular pathways involved in
human cell transformation
1.
Mitogenic signaling pathway controlled by Ras (Ch 6)
2.
Cell cycle checkpoint controlled by pRB (Ch 8)
3.
Alarm pathway controlled by p53 (Ch 9)
4.
Telomere maintenance pathway controlled by hTERT (Ch 10)
5.
Signaling pathway controlled by protein phosphatase 2A
Figure 11.25 The Biology of Cancer (© Garland Science 2007)
alterations
are
commonly
seen in
human
cancers
Figure 11.43 The Biology of Cancer (© Garland Science 2007)
Why are mouse and human different?
a speculation:
- The cells in a mouse pass through about 1011 mitosis in
a mouse lifetime, while those in a human body pass
through about 1016 cell cycles in a human lifetime.
(Mice have only about 0.1% as many cells as humans
and live on average only about 1% of a human lifespan.)
- Would the 105-fold more cell divisions in humans create
a greater lifetime cancer risk ?
- Have human cells and tissues evolved to have
additional anti-tumor mechanisms than those of small,
short-lived mammals, such as mice ?
10.9 Telomeres play different roles in the cells of
laboratory mice and in human cells
- Mouse telomeres are so long that they are never in
danger of eroding down to critically short lengths
during the lifetime of a mouse.
- Therefore, laboratory mice do not relay on telomere
length to limit the replicative capacity of normal cells.
- Telomere erosion is also not a mechanism for
constraining tumor development in laboratory mice.
11.13 Non-mutagenic agents, including those
favoring cell proliferation, make important contributions to tumorigenesis
Are all mutagens carcinogens?
Are all carcinogens mutagens?
Indication of the importance of nonmutagenic
(nongenotoxic) carcinogens came from the study
of “tumor promotion” in 1940s.
Figure 11.27 The Biology of Cancer (© Garland Science 2007)
Induction of skin cancers requires certain
combinations of initiators and promoters
carcinogens, e.g.,
benzo[a]pyrene (BP),
7,12-dimethylbenz[a]anthracene (DMBA),
3-methylcholanthrene (3-MC)
TPA – 12-O-tetradecanoylphorbol-13-acetate,
a skin irritant prepared from the
seeds of croton (巴豆) oil
also called PMA
(phorbol-12-myristate-13-acetate)
Figure 11.28 part 1 of 2 The Biology of Cancer (© Garland Science 2007)
(a mutant)
from (E): The effects of promoter seem
to be reversible, thus, it may
exert a nongenetic effect on
the papilloma cells.
from (F): Additional treatments of the
promoter seem to push the
papilloma into a promoterindependent state.
Figure 11.28 part 2 of 2 and 11.29 The Biology of Cancer (© Garland Science 2007)
Explanation of the combined effect of
initiation and promotion
After 40 years,
mutagen
drive the proliferation
of ras* cells
The skin tumors that
emerge invariably
bear point-mutated
H-ras oncogenes,
indicating that this
mutation confers a
strong selective
advantage on cells in
the skin.
Figure 11.30 The Biology of Cancer (© Garland Science 2007)
Why does TPA (a tumor promoter) promote
tumor formation?
TPA acts as a functional mimic
of diacylglycerol (DAG), which
activates protein kinase C.
Figure 6.16 The Biology of Cancer (© Garland Science 2007)
DAG activates protein kinase C α (PKCα )
Figure 11.31 The Biology of Cancer
(© Garland Science 2007)
Induction of inflammation by TPA
wild type
TPA was initially
chosen because it is
an irritant of mouse
skin and thus an
inducer of localized
inflammation.
Figure 11.36 The Biology of Cancer (© Garland Science 2007)
PKCα transgenic mice
(keratin-5-promoter driven)
neutrophil
infiltration
11.14 - 17 Toxic agents, mitogenic agents and
chronic inflammation can act as
tumor promoters
cytotoxic agents : damage cells → causing the proliferation of
the cells that have survived
the toxic effects
mitogenic agents : i.e.,steroid hormones
Estrogen and progesterone are involved in the
programming the proliferation of cells in
reproductive tissues
chronic inflammation – tissue damage from inflammation
– long-term anti-inflammatory drug use
links to reduced cancer incidence
Sidebar 11.14 Hepatitis B virus infections lead to
hepatocellular carcinoma (HCC) in
Taiwanese government employees
1975: 22,707 men – 3,454 were HBsAg +
19,253 were HBsAg –
1986: 153/3,454 HBsAg + men died of HCC
9/19,253 HBsAg – men died of HCC
The relative risk of dying from HCC if one carries
HBsAg in the blood is 98.4.
Chronic inflammation leading to cancer
Inflammatory
cells
Inflammatory
cells
Figure 11.35 The Biology of Cancer (© Garland Science 2007)
B型肝炎病毒的慢性感染為何
會演變成肝硬化和肝癌?
病毒感染
對抗病毒的
免疫反應
肝臟再生
肝細胞損傷
B型肝炎病毒的慢性感染為何
會演變成肝硬化和肝癌?
病毒感染
對抗病毒的
免疫反應
肝臟再生
肝細胞損傷
DNA 突變
↓
肝癌
Fibroblast 修補
↓
肝硬化
強度不足
Table 11.3 The Biology of Cancer (© Garland Science 2007)