Cancer Pathology and Signal
Mechanisms
Kung-Chao Chang (張孔昭), MD, PhD
Associate Professor
Department of Pathology
Programs
(A) Definitions of tumors, benign and malignant.
(B) Carcinogens: chemicals, virus, hereditary, and
inflammation
(C) Mechanism of carcinogenesis
(D) Kinetics of tumor growth
(E) Cancer invasion and metastasis
(F) Therapy for cancers : conventional vs. target
therapy
九十五年臺灣地區主要死亡原因
順位
死亡原因
所有死亡原因
1
2
3
4
5
6
7
8
9
10
惡性腫瘤
腦血管疾病
心臟疾病
糖尿病
事故傷害
肺炎
慢性肝病/肝硬化
腎臟疾病
自殺
高血壓性疾病
*每十萬人口
死亡人數 死亡率*
135,071
591.8
37,998
12,596
12,283
9,690
8,011
5,396
5,049
4,712
4,406
1,816
166.5
55.2
53.8
42.5
35.1
23.6
22.1
20.6
19.3
8.0
%
100.00
28.1
9.3
9.1
7.2
5.9
4.0
3.7
3.5
3.3
1.3
NEOPLASIA
• New growth
• “an abnormal mass of tissue, the growth
of which exceeds and is uncoordinated
with that of the normal tissues and
persists in the same excessive manner
after the cessation of the stimuli which
evoked the change”
Loss of Normal Growth Control
NEOPLASIA

Fundamental to the origin of all
neoplasms is loss of
responsiveness to normal growth
control.
上皮癌症前期病灶變化
Benign tumor
Malignant tumor
CLASSIFICATION OF
NEOPLASMS
• Differentiation is a term referring to
the degree to which a neoplasm
resembles, in structure and function,
its normal counterpart (cell of origin).
–
–
–
–
well differentiation
moderately differentiation
poorly differentiation
undifferentiation (anaplastic)
Degree of Cellular
Differentiation
• Benign – more differentiated
• Malignant – less differentiated
Growth Rate of Neoplasm
• Benign:
slow
• Malignant: fast
Mode of Growth
• Benign:
capsule
expansion with fibrous
• Malignant: invasion and infiltration
without capsule
• Benign neoplasms do not
metastasize
• Malignant neoplasms do
metastasize (or have the capacity to
metastasize)
大腸癌病理分期
Mucosa
Muscularis
mucosae
Submucosa
Muscularis
propria
Subserosa
Serosa
Lymph node
Stage I Stage II Stage III
AJCC, 臨床分期 and Survival
Different Kinds of Cancer
Some common
carcinomas:
Lung
Breast (women)
Colon
Bladder
Prostate
(men)
Leukemias:
Bloodstream
Lymphomas:
Lymph nodes
Some common
sarcomas:
Fat
Bone
Muscle
Classification of cancers by origin
1. Epithelial
carcinoma
2. Mesenchymal
sarcoma
3. Hematopoietic (blood cancer)
lymphoma, leukemia
Epithelia and derived carcinomas
Cervix
Skin
Figure 2.6a-b The Biology of Cancer (© Garland Science 2007)
Esophageal Ca.
Squamous cell carcinoma (SCC)
Epithelia and derived carcinomas
Stomach Ca.
Small intestine Ca.
Figure 2.6c-d The Biology of Cancer (© Garland Science 2007)
Lung carcinoma classification
Table 2.2 The Biology of Cancer (© Garland Science 2007)
Liposarcoma
Osteosarcoma
Figure 2.7a The Biology of Cancer (© Garland Science 2007)
Pleomorphic rhabdomyosarcoma
(ALL)
(AML)
(CML)
(CLL)
(MM)
Table 2.3 The Biology of Cancer (© Garland Science 2007)
Etiology of Cancers: Carcinogenic Agents
• Chemical carcinogens：
Direct-acting carcinogens
Natural products：Betel nuts, aflatoxin, smoking
• Radiation carcinogenesis：
Ionizing radiation：chromosome breakage, translocation,
mutation
UV ray：pyrimidine dimer, leading to mutation
• Viral and microbial carcinogens：
DNA viruses
RNA viruses
Helicobacter pylori
• Hereditary cancers：
Xeroderma pigmentosa
Retinoblastoma (Rb)
Colon, breast, ---et al
Betel nut-associated oral cancer
Arsenic skin cancer in Southwestern Taiwan:
Multiple at different stages
High prevalence of several
cancers in blackfoot disease areas
Viral and Microbial Carcinogenesis
•Oncogenic RNA viruses：
HTLV-1 (human T-lymphotropic virus type I)：
adult T cell leukemia/lymphoma Tax protein as Oncoprotein
HCV (hepatitis C virus)：hepatoma, lymphoma
•Oncogenic DNA viruses：
HPV (human papilloma virus)：cervical cancer
HBV (hepatitis B virus)：hepatoma
EBV (Epstein-Barr virus)：lymphoma, nasopharyngeal
carcinoma
•Helicobacter pyloric and gastric lymphoma
•Inflammation (virus and bacteria)–associated
cancers：Cytokine and NFkB activation
HPV-associated papilloma and cancers:
viral genotypes HPV 6/11 or 16/18
HPV disease progression
HPV vaccination before 12 year of age
Insertional mechanism of viral
tumorigenesis
HBV/HCV and hepatocellular carcinoma
(HCC, hepatoma): HCV-core, HBx, pre-S
mutants, regeneration
Helicobacter pylori-associated
mucosa-associated lymphoid tissue
(MALT) type-lymphoma
Extranodal
Postgerminal Trisomy 18,
Arises at
marginal
center
t(11;18),
extranodal
zone
memory
t(1;14); latter
sites in adults
lymphoma
B-cell
create MALT1with chronic
IAP2 and
inflammatory
BCL10-IgH
diseases; may
fusion genes,
remain
respectively
localized;
indolent
Helicobacter pylori-associated
mucosa-associated lymphoid tissue
(MALT) type-lymphoma
Scanning EM and Warthin-Starry stain
of Helicobacter pylori (HP)
Familial Adenomatous Polyposis (FAP)
家族性多發腸息肉症侯群
• 10-15歲以前腸道（大腸為主）發生多數目的
腸息肉.
• 50歲以前這些腸息肉中會發生癌變.
• 身體其它組織也可能有不正常的情形（例如視
網膜色素細胞先天性肥大 congenital
hypertrophy of the retinal pigment epithelium 或
發生於胸、腹壁上的纖維瘤 desmoid）.
Familial polyposis and colon cancer:
cancer develops at 20 years of age
Genetic model for colorectal carcinogenesis
Stepwise progression of Tumorigenesis
Kinetics of tumorigenesis: Tumor development
usually takes a long period, a balance between
tumor cells and environment factors
Essential Alterations for Malignant
Transformation
1. self-sufficiency in growth signals: oncogenes
2. insensitivity to growth inhibitory signals: tumor
suppressor genes
3. evasion of apoptosis
4. DNA repair defects and genomic instability in
cancer cells
5. limitless replicative potential: telomerase
6. development of sustained angiogenesis
7. invasion and metastasis
Principal Targets of Genetic Damage
Oncogenes
致癌基因
Normal
Cell
Apoptosis genes
凋亡
Tumor suppressor genes
抑癌
DNA mismatch repair genes
錯誤配對修護
Cancer
Cell
Oncogenes (致癌基因), Oncoproteins
• Growth factors: PDGF, FGF, TGF…
• Growth factor receptors: EGFR, PDGFR
• Signal-transducing proteins: RAS, RAF, βcatenin
• Transcription factors: MYC
• Cyclins and cyclin-dependent kinases
Growth factors and signal-transducing proteins
Insensitivity to Growth Inhibitory
Signals: Tumor Suppressor Genes
• Retinoblastoma as a Paradigm for the Two-Hit Hypothesis
of Oncogenesis
• p53: Guardian of the Genome
• APC/b-Catenin Pathway
• Others:
– The INK4a/ARF locus, The TGF-b pathway, NF-1 gene,
NF-2 gene, VHL, PTEN, WT-1, Cadherins, KLF6,
PTCH.
Retinoblastoma as a good model for
hereditary carcinogenesis in young children
Guardian
of the
Genome
DNA Repair Defects and Genomic
Instability in Cancer Cells
• Hereditary Nonpolyposis Cancer Syndrome
• Xeroderma Pigmentosum
• Inherited Diseases with Defects in DNA
Repair by Homologous Recombination
– BRCA1 and BRCA-2 Genes
XP is an autosomal
recessive disease with
sun sensitivity, photophobia, early onset of
freckling, and
subsequent neoplastic
changes on sun-exposed
surfaces
DNA Repair Defects
MSH2, MLH1
Breast Cancer 乳癌
•
cluster in families, but extensive families with a
clear inherited basis proved difficult to identify
due to :
1. 男性很少。
2. 臨床上沒有像家族性腸息肉症侯群那樣直接可以辨
認。
3. 乳癌是常見的癌，因此除非有很明顯的家族史，否
則不易察出。
Metastatic routes of cancers:
lymphatic and hematogenous
Development of Sustained Angiogenesis (VEGF)
Treatment of cancers
•
•
•
•
Surgical removal (手術)
Radiotherapy (電療)
Chemotherapy (化療)
Targeted therapy (標靶治療)
Any question?