Tumorigenesis and Tumorigenesis and Cancer Cancer

DevelopmentDevelopment

• 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)

OutlineOutline

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 Overview of Tumor formation to CancerCancer

Adapted from “Cells”

Cancer is a complex and progressive disease.

Cancer incidence is related to Cancer incidence is related to ageage

Adapted from “Cells”

Phenotypical Properties of Normal and Cancerous

Cells

Adapted from “Cells”

Lung cancer cells in liver

Four Major Types of Four Major Types of TumorsTumors

Classified by the cell type from which neoplasms arise

• Caricnomas – the most frequent, transformed Epithelial cells lining organ cavities and surfaces; e.g. Lung, Colon, Breast, Prostate, ….etc.

• Sarcomas – Mesenchymal tissues (Fibroblasts & related cell types); e.g. Bone, Muscle, …etc

• Hematopoietic Cells & Organs – eg. Leukemias, Lymphomas, Myelomas, … etc

• Neuroectodermal cells – e.g. neuroblastomas, glioblastomas, melanomas, ….etc

OutlineOutline

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 Key Concepts about Cancer-IICancer-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 Chromosome disorder in cancer cellsin cancer cells

Somatic vs Germline Mutation

Tumor Viruses & Oncogenes-Tumor Viruses & Oncogenes-HistoryHistory

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

Robert A. Weinberg, PhDMien-Chie Hung, PhD

Identification of Her2/Neu Oncogene

Mechanisms of Oncogene Activation

1. Overexpression

2. Point mutation

3. Translocation

Many Cellular Proto-

Oncogenes

Cell growth &

proliferation

Proteins

Oncogenes vs. Tumor Suppressor Oncogenes vs. Tumor Suppressor GenesGenes

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 DNA Tumor Viruses & Tumor Suppressor genes-HistorySuppressor genes-History

1. DNA tumor viruses (SV40, EBV, HPV, …) produce cancer-inducing proteins unrelated to growth-regulating 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 & p53E6 (HPV) => p53E7 (HPV) => Rb

Robert A. Weinberg, PhDWen-Hwa Lee, PhD

Identification of 1st Tumor Suppressor Gene-Rb

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 Many TSGs keep the Genome StabilityStability

Tumor Suppressor Genes in Inherited Cancer Susceptibility

Syndromes

Acquired Abilities for Cancer Progression: Cancer Hallmarks 2000 vs

2011

Telomeres Protect Telomeres Protect Chromosomes Chromosomes StabilityStability

Telomerase Extends Telomeres

Telomerase activity is required Telomerase activity is required for immortalizating tumor cellsfor immortalizating tumor cells

OutlineOutline

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

OutlineOutline

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 Models of Heterogeneity in Cancer Cellsin Cancer Cells

Strategies for Cancer Strategies for Cancer TherapyTherapy

OutlineOutline

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 Models of MetastasisMetastasis

Six Traits for Malignancy Promoted by Macrophages

Tumor Clonal Tumor Clonal ExpansionExpansion

Oncogene Cooperation in Oncogene Cooperation in Tumor FormationTumor Formation

Signaling Signaling Networks in Networks in CancerCancer