Section 12
Etiology and Oncogenesis of Tumors
Normal cell
Acquired (environmental)
DNA damaging agents:
Chemicals
Radiation
viruses
Successful DNA repair
DNA Damage
Failure of DNA repair
Inherited mutations in:
Genes affecting DNA
Mutations in the genome
repair
of somatic cells
Activation of growthpromoting oncogenes
Alterations of genes
that regulate apoptosis
Inactivation of cancer
suppressor genes
Expression of altered gene products and
loss of regulatory gene products
Clonal expansion
Additional mutations (progression)
Quoted from Robbins
《 Pathology Basis of
disease》
Heterogeneity
Malignant neoplasm
1. Molecular Basis of Tumor
Nonlethal genetic damage lies at the
core of carcinogenesis
 Four classes of regulatory genes,
protooncogene, cancer suppressor gene,
regulated apoptosis gene, and DNA
repair gene, are the principal targets of
genetic damage.
 Carcinogenesis is a multistep process at
both the phenotypic and genetic levels.

(1) Oncogenes and cancer
① Protein products of oncogenes
a. Growth factors
b. Growth factors receptors
c. Signal transducing proteins
d. Nuclear transcription proteins
e. Cyclones and cyclic-dependent kinases
② Activation of oncogenes
a. Point mutations
b. Chromosome rearrangements
Translocations
Inversions
C. amplification
(Quoted from Robbins
《 Pathology Basis of disease》)
(Quoted from Robbins
（quoted from Robbins
Basic Pathology, 2003）
Table Selected oncogenes their mode of
activation and associated human tumors
Category
Growth Factors
PDGF-β chain
Fibroblast growth factors
Protooncogene
Mechanism
Associated
Human Tumor
Sis
Overexpression
Hst-1
Int-2
Overexpression
Amplification
Astrocytoma
Osteosarcoma
Stomach cancer
Bladder cancer
Breast cancer
Melanoma
Category
Protooncogene Mechanism
Growth factor Receptors
EGF-receptor family
Erb-B1
erb-B2
erb-B3
fms
ret*
CSF-1 receptor
Overexpression
Amplification
Overexpression
Point mutation
Point mutation
Rearrangement
Associated
Human Tumor
Squamous cell carcinomas of
lung
Breast, ovarian, lung, and
stomach cancers
Breast cancers
Leukemia
Multiple endocrine neoplasia
2A and B. Familial medullary
thyroid carcinoma
Sporadic
papillary
carcinomas of thyroid
Proteins involved in
signal transduction
GTP-binding
ras
Point mutations
A variey of human
cancers, including lung,
colon, pancreas; many
leukemias
Category
Nonreceptor
tyrosine kinase
Protooncogene Mechanism
abl
Associated
Human Tumor
Translocation
Chronic myeloid leukemia
Acute lymphoblastic leukemia
Myc
N-myc
Translocation
Amplification
L-myc
Amplification
Burkitt lymphoma
Neuroblastoma
Small cell carcinoma of lung
Small cell carcinoma of lung
Nuclear regulatory
proteins
Transcriptional
activators
Category
Protooncogene Mechanism
Associated
Human Tumor
Cell cycle regulators
Cyclins
Cyclin-dependent kinase
Cyclin D
CDK4
Translocation
Amplification
Amplification
point mutation
Mantle cell lymphoma
Breast,
liver,
or esophageal cancers
Glioblastoma,
melanoma, sarcoma
PDGF, platelet-derived growth factor; EGF, epidermal growth factor;
CSF, colony-stimulating factor; GTP, guanosine triphosphate.
* ret protooncogene is a receptor for glial cell line-derived
neurotrophic factor.













编码的蛋白质
生长因子：
PDGF-β链
FGF
几种常见的癌基因及其激活方式和相关的人类肿瘤
原癌基因
激活机制
sis
过度表达
HST-1
过度表达
INT-2
扩增
TGF-α
TGF-α
过度表达
HGF
HGF
过度表达
生长因子受体：
EGF受体家族 erb-B1（ECFR） 过度表达
erb-B2
扩增
CSF-1受体
FMS
点突变
神经营养因子受体 RET
点突变
















PDGF受体
PDGF-R
干细胞因子受体
KIT
信号转导蛋白：
GTP结合蛋白
K-RAS
H-RAS
N-RAS
非受体酪氨酸激酶 ABL
RAS信号转导
BRAF
WNT信号转导
β-catenin
核调节蛋白：
转录激活蛋白
C-MYC
N-MYC
L-MYC
细胞周期调节素：
细胞周期素
Cyclin D




Cyclin E
周期素依赖激酶 CDK4
过度表达
点突变
点突变
点突变
点突变
易位
点突变
点突变 过度表达
易位
扩增
扩增
易位
扩增
过度表达
扩增或点突变
(引自Robbin Pathologic Basis of Disease,2005)
相关人类肿瘤
星形细胞瘤、骨肉瘤
胃癌
膀胱癌、乳腺癌、黑色素瘤
星形细胞瘤、肝细胞癌
甲状腺癌
肺鳞癌、神经胶质瘤
乳腺癌、卵巢癌
白血病
多发性内分泌瘤病2A和B，
家族性甲状腺髓样癌
神经胶质瘤
胃肠间质细胞瘤、其它软组织肿瘤
结肠、肺、胰腺肿瘤
膀胱与肾肿瘤
黑色素瘤、多种造血系统恶性肿瘤
慢性髓性白血病、急性淋巴母细胞性白血病
黑色素瘤
肝母细胞瘤、肝细胞癌
伯基特淋巴瘤
神经母细胞瘤、小细胞肺癌
小细胞肺癌
套细胞淋巴瘤
乳腺癌、食管癌
乳腺癌
胶质母细胞瘤、黑色素瘤、肉瘤
(2) Cancer suppressor genes
① Molecules that regulated nuclear
transcription and cell cycle
Rb gene: 13q14,
G1
×
S
P53 gene: 17p13.1, related to 50% of
human tumors
BRCA- l gene: 17q12-21,
BRCA-2 gene: 13q12-13
② Molecules that regulated signal
transduction
NF-1 gene: 17q11.2
APC gene: 5q21
③ Cell surface receptors
SMAD2 gene:
SMAD4 gene:
DCC gene: 18q21
④ Other tumor suppressor genes
NF- 2 gene
VHL gene: 3p
PTEN gene: 10q23,
WT- 1 gene: 11p13
(Quoted from
Robbins
《 Pathology
Basis of
disease》)
Selected tumor- suppressor genes
involved in human neoplasms
Subcellular
location
Cell surface
Gene
TGF-β receptor
E-cadherin
Function
Growth inhibition
Cell adhesion
Tumors
associated with
somatic
mutations
Tumors
associated with
inherited
mutations
Carcinomas
of Unknown
colon
Familial
gastric
Carcinoma
of cancer
stomach, breast
Under plasma NF- 1
membrane
Inhibition of ras Schwannomas
signal
transduction
Neurofibromatosi
s type Ⅰ and
sarcomas
Cytoskeleton
Unknown
Neurofibromato
sis type Ⅱ;
acoustic
schwannomas
and
meningiomas
NF- 2
Schwannomas
and
meningiomas
Subcellular
location
Cttisik
Gene
APC
Function
Inhibition
signal
transduction
Tumors
associated with
somatic
mutations
Tumors
associated with
inherited
mutations
of Carcinomas
of Familial
stomach, colon, adenomatous
pancreas;
polyposis coli;
melanoma
colon cancer
Nucleus
Rb
Regulation of cell Retinoblastoma; Retinoblastomas,
cycle
osteosarcoma;
osteosaroma
carcinomas
of
breast,
colon,
lung
P53
Regulation of cell Most
cycle
and cancers
apoptosis
in
response to DNA
damage
human LiFraumeni
syndrome;
multiple
carcinomas and
sarcomas
Subcellular
location
Gene
WT-1
Function
Nuclear
transcription
Tumors
associated with
somatic
mutations
Wukns tynir
Tumors
associated with
inherited
mutations
Wilms tumor
P16 (INK4a) Regulation of cell Pancreatic,
cycle by inhibiting esophageal
cyclindependent
cancers
kinases
Malignant
melanoma
BRCA- 1
DNA repair
Carcinomas of
female breast
and ovary
BRCA-2
DNA repair
Carcinomas of
male
and
female breast
(3) Genes that regulate apoptosis
Inhibit apoptosis: bc1- 2 gene (18q21),
bc1-Xl
Favor apoptosis: bax, bad, bc1-xS
(Quoted from Robbins
《 Pathology Basis of disease》)
(4) Genes that regulate DNA repair
Humans literally swim in a sea of
environmental carcinogens. Although
exposure to naturally occurring DNAdamaging agents, such as ionizing
radiation, sunlight, and dietary
carcinogens, is common, cancer is a
relatively rare outcome of such
encounters.
This happy state of affairs results from the
ability of normal cells to repair DNA damages
and thus prevent mutations in genes that
regulate cell growth and apoptosis. In
addition to possible DNA damage from
environmental agents, the DNA of normal
dividing cells is also susceptible to alterations
resulting from errors that occur
spontaneously during DNA replication. Such
mistakes, if not repaired promptly, can also
push the cells along the slippery sloe of
neoplastic transformation.
The importance of DNA repair in
maintaining the integrity of the
genome is highlighted by several
inherited disorders in which genes
that encode proteins involved in DNA
repair are defective. Those born with
such inherited mutations of DNA
repair proteins are at a greatly
increased risk of developing cancer.
Several examples are discussed next.
(5) Telomere and tumor
telomerase activity increased
in majority of human tumors.
(Quoted from Robbins《 Pathology Basis of disease》)
(6) Molecular Basis of
Multistep Carcinogenesis
2. Carcinogenic agents
A large number of agents cause genetic
damage
and
inchece
neoplastic
transformation of cells
(1) Chemical carcinogens
Chemical carcinogenesis is also a
multistep process.
① Inition of carcinogensis
Chemical carcinogens are diverse in structure,
but they fall into one of two categories:
a. Direct-acting chemical carcinogenes
b. Indirect-acting chemical carcinogens
(procarcinogenes),
Which require metabolic conversion in vivo to
produce.
Ultimate carcinogens capable of transforming
cells.
Both of them are highly reactive
electrophiles that can react with
nucleophilic (electron-rich) sites in the
cells.
These reactions are nonenzymatic and
result in the formation of covalent
adducts
between
the
chemical
carcinogen and nucleotide in DNA.
The carcinogenic potency of a chemical
is determined not only by the inherent
reactivity of its electrophilic derivative,
but also by the balance between
metabolic activation and inactivation
reactions.
If initiation occurs, carcinogen-altered
cells could be heritable.
② Promotion of carcinogenesis
Promoters earn induce tumors in
initiated
cells,
but
they
are
nontumorigenic by them selves.
Prompters render cells susceptible to
additional mutations by causing cellular
proliferation.
CARCINOGEN
Metabolic activation
Excreti
Electrophilic
intermediates
DNA
INITIATION
Binding to DNA:
Adduct formation
Permanent DNA lesion:
Initiated cell
repair
Normal cell
Cell death
Cell proliferaion:
Altered differentiation
PROMOTION
PRENEOPLASTIC CLONE
Proliferation
Additional
mutations
MALIGNANT NEOPLASM
(Quoted from Robbins
《 Pathology Basis of disease》)
Major Chemical carcinogens
① Direct acing alkylating agents(烷化剂)
a. In general they are weak carcinogens.
But they are important because many of
them are anticancer drugs.
b.
e. g. Cyclophosphamide( 环 磷 酰 胺 ),
Chlorambucil, busulfan, melphalan.
c. Induce: lymphoid neoplasms, leukemia
② Polycyclic aromatic hydrocarbons
(多环芳烃)
a. The most potent carcinogens.
b. Require metabolic activation
c. Can induce tumors in a wide variety of
tissues and species.
③ Aromatic amines(芳族胺)
and azo dyes
a. Mainly in liver
b. Can induce hepatocellular carcinomas
and bladder cancer
④ Naturally occurring carcinogens
Aflatixi(黄曲霉毒素)B1 and HBV related to
hepatocellular carcinoma
⑤ Nitrosamine(亚硝胺) and amides
Related to gastric carcinoma
⑥ Miscellaneous agents
a. Asbestos associated with increased
incidence of bronchogenic carcinomas,
mesotheliomas, gastrointestinal cancers
b. Chromium, nickel, and other metals,
when volatilized and inhaled, have
caused lung cancer
c. Arsenic associated with skin cancer
⑦ Promoters of chemical carcinogenesis
a. Hormones: e. g. estrogens as promotes of
liver tamers, postmenopausal endometrial
carcinoma
b.
Bile salts: high levels of dietary fat
associated with increased risk of colon cancer
that may be related to more bile acids.
(2) Radiation carcinogenesis
① UV light is clearly implicated in
causation of skin cancers; Ionizing
radiations, atomic bomb have produced
a variety of forms of malignant
neoplastic, especially in leukemia
lymphoma, thyroid cancers
② Radiation may inhibited cell division,
inactive enzymes, induce mutations.
(3) Viral carcinogens
① RNA oncogenic viruses
a. Acute transforming viruses
Which containing viral oncogene (src, abl, myb)
may directly trans form human oncogenes
b. Slow transforming viruses
Which not containing viral oncogene may
insert the sites that nearby human oncogene
and make them overdressed now only human
fell leukemia virus type 1 (HTLV-1) is firmly
implicated in the causation of human caner
② DNA oncogenic viruses
Transforming DNA viruses form stable
association with the host cell genome
and
are
important
for
cell
transformation.
a. Human papillomavirus (HPV)
HPV-1, 2, 4, 7 can cause benign squamous
papillomas in human;
HPV-16, 18 are found in approximately 85% of
severe squamous dysplasias, carcinoma in
situ, and invasine squamous cell can cars.
 E6, E7 proteins of HPV-16, 18
E6 protein can degrade the P53 gene product ;
E7
protein
may
bind
to
the
underphosphorylated form of the tumorsuppressor protein PRb.

b. Epstein-Barr virus (EBV)
EBV
has
been
implicated
in
pathogenesis of four human
Tumors: Burkitt lymphoma, B-cell
lymphoma, Hodgken disease and
nasopharyngeal carcinoma.
c. Hepatitis β virus (HBV)
Epidemiologic studies strongly suggest
a close association between HBV
infection and the occurrence of liver
cancer.
3. Influence factors of oncogenesis and
development
(1) Heredity factors
① Autosomal dominant inherited cancer
syndromes
Familial retinoblastoma
Familial adenomatous polyps of the colon
Multiple endocrine neoplasia syndromes
Neurofibromatosis types 1 and 2
Von Hipped- Lindace syndrome(cerebellar
hemengioblastomas,
retinal
angiomas,
epididymal tumors)
② Familial cancers
Breast cancer, ovarian cancer
Colon cancer other than familial
adenomatous polyps
They are associated with specific
marker phenotype.
Some of them may be linked to the
inheritance of mutant genes.
③ Autosomal recessive syndromes of defective DNA
repair gene
xeroderma pigmentosum: 着色性干皮病 易发基底细胞
癌,鳞状细胞癌,黑色素溜
Ataxia-telangiectasia:毛细管扩张共济失调,易发白血病,
淋巴瘤
Bloom syndrome:先天性脸部血管扩张性红斑,身材矮
小发育不良。隐性遗传,异常基因位於 15q26.1. 易发
白血病,恶性肿瘤
Fanconi anemia:一种罕见的常染色体隐性遗传性血液
系统疾病，属于先天性再障
(2) Host defense against tumors- Tumor
immunity
① Tumor antigen
a. Tumor- specific antigen (TSA)
b. Tumor- associated antigen (TAA)
Embryonic antigens: e. g. AFP, CEA
Differentiation antigens: CD10
Tissue-specific antigens: e. g. tyrosinase
Antigens resulting from mutations: e. g.
mutatead P53, K-ras, CDK4
Overexpressed antigens: e. g, c-erbB2
protein
Viral antigens: e. g. E7
② Antitumor effector mechanisms
Both
cell-mediated
and
humoral
immunity can have antitumor activity.
a. Major immune antitumor cells:
Cytotoxic T lymphocytes
Natural killer cells
Macrophages
b. Immunosurveillance
The tumor cells have developed mechanisms to
escape from the immune system in hosts.
Selective outgrowth of antigen-negative variants
Loss or reduced expression of histocompatibility
antigens
Lack of costimulation
Immunosuppression
Apoptosis of cytotoxic T cells.
(3) The Others
① Endocrine
② Sex
③ Age
④ Ethnic
⑤ Geography