Robert A.

Weinberg

The Biology of Cancer

First Edition

Copyright © Garland Science 2007

Textbook: The Biology of Cancer by Robert A. Weinberg, Garland science (2007)
 張久瑗 傅淑玲
中央研究院 國立陽明大學
生物醫學研究所 傳統醫藥學研究所
副研究員 助理教授

1. Cancer Genomics 1. Molecular Biology in

2. Tumor and Tumor
Tel. (02)27899046 Molecular Biology Tel. (02)28267177 2. Oncogenesis and
Fax. (02)27858594 Fax. (02)28225044 Cell Transformation
bmchen@ibms.sinica.edu.tw slfu@ym.edu.tw

翁芬華 陳俊銘
國立陽明大學 國立陽明大學
生命科學系 生命科學系
暨基因體科學研究所 暨基因體科學研究所
副教授 助理教授

1. Tumor Biology 1. Developmental Biology

Tel. (02)28267240 2. Signal Transduction Tel. (02)28267339 2. Cancer Genetics
Fax. (02)28202449 Fax. (02)28202449
fhwa@ym.edu.tw cmchen@ym.edu.tw
Outlines

Chapter 1. The Biology and Genetics of Cells and Organisms

-Mendel’s rules of genetics

-Cancer cells are often aneuploid
-Mutations causing cancer occur in both the germ-line and the soma

Chapter 2. The Nature of Cancer

-Tumors arise from normal tissues

-Tumors arise from many specialized cell types throughout the body
-Clonal evolution vs. Cancer stem cells
-Tumors are monoclonal growths
-Etiologic factors of cancer
-Carcinogens vs. mutagens
 Basic Rules of Genetics – Mendelian Genetics

7 “characters” of garden peas

Figure 1.2 The Biology of Cancer (© Garland Science 2007)

-Genetic information is organized in discrete parcels, each is responsible for a distinct trait.
-genes
-A given trait can have two alternative phenotypic manifestations.
-alleles
-homozygous vs. heterozygous
-dominant vs. recessive
 Mendel’s 1st Law: Segregation and Dominance

Each individual pea plant must carry two copies (alleles) of the gene controlling
a single inherited trait, and each allele varies in its strength to dictate the
physical outcome.
Mendel’s 2nd Law: Independent Assortment

Different traits are independently transmitted to the gametes.

 Monohybrid crosses

one type of progeny

both types of progeny

(in a ratio of 3:1)

Phenotype 3 : 1 1 : 2 : 1
Dihybrid crosses
Mendel’s Law:
1. Each gamete receives only one of the two parental alleles.

2. Different genetic traits are assorted among offsprings independently

of each other.
 Evolutionary development of gene families

The evolution of organistic complexity is

driven, in part, by the development of
increasingly specialized proteins, through
the process of gene duplication.

Homologs:
genes that are related to one another
within a single species’ genome, or
genes that are related to one another in
the genomes of two distinct species.

Paralogs:
genes that are related to one another
within a single species’ genome.

Orthologs:
the precise counterparts of genes in
different species
Figure 1.20 The Biology of Cancer (© Garland Science 2007)
 Genetic alterations in cancer

Dominant oncogenes (Oncogenes)

- promote cell growth
- gain-of-function mutation in cancers
- one allele mutated is enough
Recessive oncogenes (Tumor suppressor genes)
- suppress cell growth or suppress oncogene-mediated
cell transformation process
- loss-of-function mutation in cancers
- both alleles are involved in cancer formation
 Foci formation by transformed cells

Control RSV infected

chicken embryo fibroblasts

Properties of transformed cells

Figure 3.7a The Biology of Cancer (© Garland Science 2007)

 Hallmarks of Cancer

Other phenotype:

Genomic instability
Altered metabolism
Cancer stem cells

The Hallmarks of Cancer. Cell (2000) 100:57

Rules for Making Human Tumor Cells. N Engl J Med (2002) 14:1593
 Germ-line vs. Somatic Mutations

-occurs in new-born
-bilateral
-multi-focal

-occurs at 2-3 yr old

-unilateral
-uni-focal

Knudson proposed that two “hits”, or mutagenic events, were necessary for
retinoblastoma development in all cases.
 Human metaphase chromosomes
Chromosome painting by SKY
(spectral karyotype analysis)
normal cell

breast cancer
cell
Figure 1.11 The Biology of Cancer (© Garland Science 2007)

Euchromatin vs. heterochromatin (tightly packed DNA, lack of transcription)

 Aneuploid – change in chromosome numbers
Amplification
DM of HER2/Neu gene

DM and HSR

Gene amplification: increased copy numbers of gene

DM: double minute
HSR: homogeneously deleted region

Figure 1.12 The Biology of Cancer (© Garland Science 2007)

 Numeric and Structural changes of chromosomes
Chromosome painting by SKY (spectral karyotype analysis)

normal cell

breast cancer
cell

invertion of subregions on Interstitial deletion

5q

Figure 1.11 The Biology of Cancer (© Garland Science 2007)

 Tumors: Benign vs. Malignant

Tumors are segregated into two broad categories depending on their

aggressive growth.

Benign tumors grow locally without invading adjacent tissues, e.g. a

wart of papilloma.

Malignant tumors, neoplasms (new growth) or cancers invade nearby

tissues and spawn metastsis.
 Classification of human cancers

Carcinomas which comprise more than 90% of human cancers,

arise from epithelial cells of either endodermal or ectodermal
origin. They are further classified according to tissue of origin,
or divided into different histologic types that differ in their
patterns of growth and metastasis.

Sarcomas and the leukemias/lymphomas develop from cells of

mesodermal origin, including muscle, bone, blood vessels,
fibroblasts, and circulating cells of the blood and lymph
systems.
Fates of the Germ Layers in Animal
Gastrulation (16 dpf embryo)
Origin of Human Tumors
 Carcinomas

Squamous cell carcinoma vs. Adenocarcinoma

Epithelial cells are classified into subtypes depending on function and shape.
(1) Squamous cells: flattened and function to protect the underlying tissues
(2) Epithelial glandular cells: secret polysaccharides to protect epithelium or
function to secret proteins

Table 2.1 The Biology of Cancer (© Garland Science 2007)

 Squamous epithelia and derived carcinoma
Normal squamous epithelial cells from Esophageal carcinoma
cervix of the uterus (top) and skin (bottom)

Figure 2.6 The Biology of Cancer (© Garland Science 2007)

GI-track columnar epithelia and adenocarcinoma
Adenocarcinoma in stomach (top) and
Gastric mucosa colon (bottom)

Normal squamous epithelial cells from

cervix of the uterus (top) and skin (bottom)

Figure 2.6 The Biology of Cancer (© Garland Science 2007)

 Non-epithelail cancers

1. Sarcomas are nonepithelail cancers derived from

connective tissues. They are derived from a variety of
mesenchymal cell types, including fibroblasts, adipocytes,
osteoclasts, and myocytes.
2. Hematopoietic malignancies
3. Neuroectodermal tumors

Table 2.1 The Biology of Cancer (© Garland Science 2007)

Anatomy of human stomach
 Tumor arises from normal tissues

Small intestine

normal mammary gland (top) and

invasive ductal breast carcinoma (bottom)
Figure 2.1 The Biology of Cancer (© Garland Science 2007)
Staging of gastric carcinoma (TNM stage)

(depth of tumor invasion)

International Union Against Cancer (UICC) and

the American Joint Commission on Cancer (AJCC)
Cancer Results from Multi-Step Genetic Alterations
Cooperation of Oncogenes in Cancer Induction

Multiple mutations are required for tumor induction.

Incidence of human cancer increases markedly with age
 Clonal evolution

Figure 2.17 The Biology of Cancer (© Garland Science 2007)

 X-chromosome inactivation patterns

G6PD staining patterns

(patched patterns of expression in an

intestine section)
Figure 2.18 The Biology of Cancer (© Garland Science 2007) PNAS 100:3311-3314, 2003.
 Tumors are monoclonal in origin

Figure 2.18 The Biology of Cancer (© Garland Science 2007)

 Tumor monoclonality

A single Ig species Unique chromosomal translocation

was expressed in myeloma pattern is seen in all tumor cells

Figure 2.19a The Biology of Cancer (© Garland Science 2007)

 Inactivation of TSG:
- p53

(mu
- PTEN

lti-lin
- INK4A
- ARF

age)e
 Models of Clonal evolution vs. Cancer stem cell

Normal cellular hierarchy Clonal evoluation and Cancer stem cell

-self-renewal
-multi-lineage differentiation

Clonal evoluation

Cancer stem cell

Nature Reviews Cancer | Aop, published online 11 September 2008;

Origin of cancer stem cell?

Medical Hypothesis | published online 2008.07.041

Nature Reviews Cancer | Aop, published online 11 September 2008;
 Etiologic factors of cancer: heredity vs. environment?

Table 2.5 The Biology of Cancer (© Garland Science 2007)

Heredity vs. Environment
Cancer rates in migrant populations
 Risks of cancers increased by environmental factors

The environment includes physical environment (air, water, etc.),

lifestyle (dietary choices, reproductive habits, tobacco and alcohol
consumption, and occupational exposures).

Table 2.6 The Biology of Cancer (© Garland Science 2007)

Table 2.7 The Biology of Cancer (© Garland Science 2007)
 Ames test
(to quantitatively assess the mutagenic potential)

Mutant Salmonella:
unable to grow in his- medium, and the
mutant allele is susceptible to back-
mutation to a wild-type allele

Test compound: procarcinogen?

Estimated specificity (54%) and sensitivity

(70%)

Figure 2.24 The Biology of Cancer (© Garland Science 2007)

 Mutagenic vs. carcinogenic potency
(in mice and rats)

Figure 2.25 The Biology of Cancer (© Garland Science 2007)

 Not all carcinogens are mutagenic

-As many as 40% of carcinogens show no obvious mutagenicity in the

Salmonella mutation test.
-Some carcinogens act through their ability to disrupt DNA, while others
promote the appearance of tumors through nongenetic mechanisms.
These nontumorigenic carcinogens are often referred as tumor promoters.

Table 2.8 The Biology of Cancer (© Garland Science 2007)