Tumorigenesis and
Cancer Development
• Pin Ling (凌 斌), Ph.D.
ext 5632; lingpin@mail.ncku.edu.tw
• References:
1. Chapter 23 Cancer in “Molecular Cell Biology” (Lodish
et al., 5th edition)
2. Chapter13 Cancer in “Cells” (Benjamin et al., 1st
edition)
Outline
1. Overview of Tumorigenesis to Cancer
-Progression, Types, & Properties
2. The Genetic Basis of Cancer
3. Metastasis
4. Cancer Stem cells
5. Cancer metabolism
Key Concepts about Cancer-I
1. All cancer cells share certain fundamental properties.
2. Various types of cancers have their distinctive traits
& behaviors.
=> Different therapies
3. Cancer cells and normal cells still share a lot of
properties.
=> Difficult to kill cancer cells w/o hurting normal
cells
4. The Goal of Cancer therapy => increase targeting
specificity.
Overview of Tumor formation to Cancer
Cancer is a complex and progressive disease.
Adapted from “Cells”
Cancer incidence is related to age
Phenotypical Properties of
Normal and Cancerous Cells
Adapted from “Cells”
Adapted from “Cells”
Lung cancer cells in liver
Four Major Types of Tumors
Classified by the cell type from which neoplasms arise
•
Caricnomas – the most frequent, transformed Epithelial
•
Sarcomas – Mesenchymal tissues (Fibroblasts & related
•
Hematopoietic Cells & Organs – eg. Leukemias,
•
Neuroectodermal cells – e.g. neuroblastomas,
cells lining organ cavities and surfaces; e.g. Lung, Colon,
Breast, Prostate, ….etc.
cell types); e.g. Bone, Muscle, …etc
Lymphomas, Myelomas, … etc
glioblastomas, melanomas, ….etc
Outline
1. Overview of Tumorigenesis to Cancer
-Progression, Types, & Properties
2. The Genetic Basis of Cancer
- Oncogenes & Tumor Supressor Genes
3. Metastasis
4. Cancer Stem cells
5. Cancer metabolism
Key Concepts about Cancer-II
1.
Early in the 20th century => Cancer as the result of
viruses.
2.
In the mid to late 20th century concept of cancer
=> A complex & progressive genetic disease that requires
a series of genetic mutations (at least 4-6, most >10).
3.
Cellular genomes contain multiple proto-oncogenes &
tumor suppressor genes.
4.
Genetic mutations on these critical genes lead to
dysregulated cell growth & division.
5.
Cancers mostly arise from genetic mutations in somatic
cells.
Acquired Abilities for Cancer Progression:
Cancer Hallmarks 2000 vs 2011
Chromosome disorder in
cancer cells
Somatic vs Germline Mutation
Tumor Viruses & Oncogenes-History
1. Avian and murine retroviruses (Rous in 1911) and
DNA tumor viruses gave the first experimental
handle on specific cancer causing genes.
2.
Viruses were a way to achieve experimentally
reproducible cancers before molecular techniques
developed.
3.
Isolation of tumorigenic viruses in the laboratory
allowed cancer causing genes to be isolated.
The Discovery of Tumor-Inducing
Viruses (Rous Sarcoma Virus)
Retroviruses & Oncogenes-History II
1.
Early 1970s RSV=> Retrovirus containing v-Src as an
oncogene for tumorigenesis
2.
In 1975 scientists found a normal version of v-Src
in healthy cells
3.
This normal version of v-Src, called c-Src, was
defined a proto-oncogene, playing an essential role
in cell growth.
4.
RSV picked up c-Src => mutation => RSV w/v-Src
=> tumor-inducing virus
The Discovery of Cellular Oncogenes
Schematic structures of c-Src vs
v-Src
The Strategy for Identification
of Cellular Oncogenes
Identification of Ras Oncogene
Chiaho Shih, PhD
Robert A. Weinberg, PhD
Identification of Her2/Neu Oncogene
Mien-Chie Hung, PhD
Robert A. Weinberg, PhD
Mechanisms of Oncogene Activation
1. Overexpression
2. Point mutation
3. Translocation
Many Cellular
Proto-Oncogenes
Proteins
Cell growth &
proliferation
Oncogenes vs. Tumor Suppressor Genes
1.
Oncogenes promote cell growth & division.
2.
Oncogene activation: (1) Overexpression &
amplification, (2) Point mutation, (3) Translocation
3.
Tumor viruses carry oncogenes.
4.
Tumor suppressors inhibits cell growth & division.
5.
Both copies of a tumor suppressor gene need to be
mutated to see a phenotype.
DNA Tumor Viruses & Tumor
Suppressor genes-History
1.
DNA tumor viruses (SV40, EBV, HPV, …) produce
cancer-inducing proteins unrelated to growthregulating proteins.
2.
These viral proteins bind and perturb another set
of cellular proteins => Tumor suppressors =>
Dyregulate cell growth & division.
3.
Large T protein (SV40) => Rb & p53
E6 (HPV) => p53
E7 (HPV) => Rb
Identification of 1st Tumor
Suppressor Gene-Rb
Wen-Hwa Lee, PhD
Robert A. Weinberg, PhD
1. Two mutations to
inactivate tumor suppressor
2. Cancer susceptibility is
increased by the inheritance
of a mutant copy of tumor
suppressor gene.
3. Loss of heterozygosity by
mitotic recombination
Rb blocks the cell cycle progression
Many TSGs keep the Genome Stability
Tumor Suppressor Genes in Inherited
Cancer Susceptibility Syndromes
Acquired Abilities for Cancer Progression:
Cancer Hallmarks 2000 vs 2011
Telomeres Protect
Chromosomes Stability
Telomerase Extends Telomeres
Telomerase activity is required for
immortalizating tumor cells
Outline
1. Overview of Tumorigenesis to Cancer
-Progression, Types, & Properties
2. The Genetic Basis of Cancer
- Oncogenes & Tumor Supressor Genes
3. Angiogenesis & Metastasis
4. Cancer Stem cells
5. Cancer metabolism
Key Concepts about Cancer-III
1. Tumor growth is limited by access to nutrients and
waste removal.
2. Tumors stimulate blood vessel growth (Angiogenesis),
which enables them to expand.
3. Some tumor cells can break neighboring tissues to
move into blood and lymphatic vessels (Intravasation).
4. Tumor cells travel and colonize into other tissues
(Metastasis).
5. Metastasis often lead to death of the individual.
Lymphoangiogenesis
& Metastasis
1. VEGFR signaling is
the key player.
2. Many primary
tumors express
VEGFR.
Chemokines and Tumor Growth
& Metastasis
Outline
1. Overview of Tumorigenesis to Cancer
-Progression, Types, & Properties
2. The Genetic Basis of Cancer
- Oncogenes & Tumor Supressor Genes
3. Angiogenesis & Metastasis
4. Cancer Stem cells
5. Cancer metabolism
Key Concepts about Cancer-IV
1.
Stem cells and cancer cells share some common
properties, e.g. self-renewal, survival, ..etc.
2.
Tumors often originate from transformation of
normal stem cells.
3.
Cancer stem cells may exist among cancer cells and
possess the unique ability to self-renew and survive.
4.
Targeting cancer stem cells is the new strategy for
cancer therapy.
Signaling Pathways in Stem Cell
Development & Transformation
Development of Cancer Stem Cells
Models of Heterogeneity in
Cancer Cells
Strategies for Cancer Therapy
Outline
1. Overview of Tumorigenesis to Cancer
-Progression, Types, & Properties
2. The Genetic Basis of Cancer
- Oncogenes & Tumor Supressor Genes
3. Angiogenesis & Metastasis
4. Cancer Stem cells
5. Cancer metabolism
Factors affecting cancer metabolism
TW Mak et al., Nat Rev Cancer, 2011
Metabolisms: Normal
vs Cancer cells
TW Mak et al., Nat Rev Cancer, 2011
PKM2 effect on Glycolysis & the
Pentose Phosphate Pathway
TW Mak et al., Nat Rev Cancer, 2011
Paper Discussion-I (3/20)
Papers related to following topics are suggested:
1.
Cancer development: (1) Cancer metabolism, (2)
Cancer stem cells, (3) Epigenetics in cancer, or (4)
MicroRNAs in cancer
2.
Inflammation & Cancer: (1) Inflammatory
regulation in cancer, (2) TAM (Tumor-associated
macrophages) in cancer, or (3) Others
3.
Check your papers with me first
The End & Thank you
Models of Metastasis
Six Traits for Malignancy
Promoted by Macrophages
Tumor Clonal Expansion
Oncogene Cooperation in Tumor
Formation
Signaling Networks
in Cancer