CANCER

Cancer - Definition
Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to dysregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity and, if untreated, death of the host.

At cellular level: - Excessive cellular proliferation - Uncoordinated growth - Tissue infiltration and role of tissue microenvironment
At molecular level: - Defects in various cell-cycle & growth regulatory genes - Develops in a multi-step fashion
2

Cancer
Types of changes: Immortalization: indefinite growth. Transformation: deviation from normal growth requirements and constrains; independent of anchorage and serum growth factors, not inhibited by density/contact. Invasion and metastasis: invasion of normal tissues and dissemination to distant organs.

Cancer-Terms
Benign
Harmless and limited in scope. In cancer, the opposite of malignant.

Malignant
A cancer whose scope extends beyond the initial tumor. Characterized by anaplasia, invasion and metastasis.

Invasion
Movement of cells from a tumor into immediately surrounding tissue.

Metastasis
Movement of cancer cells into tissues beyond the original tumor. Usually involves transit through the blood stream.

Cancer-Terms
Angiogenesis
Growth of new blood vessels from the existing ones.

Proto-oncogene
A normal gene whose normal product does not cause cancer, but in which a mutation (oncogene) will cause cancer.

Tumor-suppressor gene
A gene whose product impedes uncontrolled cell growth.

Apoptosis
Programmed cell death.
5

Normal and Cancer Cells

Cellular Basis of Cancer

In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted, which may be due to,

i) uncontrolled cell growth, or

ii) loss of a cell's ability to apoptosis undergo

Cell-cycle & Check Points

The Stages of Mitosis and Cytokinesis

Multiple Cdks and Cyclins Regulate Cell Cycle

the

10

Components of the Cell Cycle

11

Cancer Cause & Contributing Factors

Cause/Factor Oncogenes Impact May alter control of cell division

Faulty tumor suppressor genes

Viral infection

Fails to halt runaway cell division

Switches proto-oncogene to oncogene or inserts an oncogene into the host cell DNA Damages DNA Damages DNA Fails to tag cancer cells to destruction

Carcinogen Radiation Faulty immunity

12

Carcinogenesis Occurs in Predictable Steps

13

14

Cancer - A Multistep Process

A multistep molecular event model for the development of hereditary adenomatous polyposis, a colorectal cancer.

15

Cell Signals and Control of Cell Behavior

16

Types of Cancer Genes

Type of gene
Oncogene

Normal function
Promotes division

Mutated function
Promotes division abnormal time or cell type Fails to suppress division

Types of proteins
Growth factors

Tumor suppressor gene DNA repair gene

Suppresses cell division

Checkpoint molecules

Repair DNA mutations

Fail to repair DNA mutations

Enzymes for mismatch or excision repair

Other genes involved in apoptosis, angiogenesis, invasion and metastasis are also disrupted in cancer. 17

Comparison of the Effects of Tumor Suppressor Gene and Proto-oncogene on Mutation

18

Genes that Control Cell Growth are Either Proto-oncogenes or Tumor-Suppressor Genes Growth factors Growth factor receptors Intracellular signal transduction proteins Transcription factors Anti-apoptosis proteins Cell-cycle control proteins DNA repair proteins

19

Types of Proteins Encoded by ProtoOncogenes

Class I: Growth Factors (PDGF, TGF-alpha) Class II: Receptors for Growth Factors & Hormones (EGFR) Class III: Intracellular Signal Transducers (RAS, ABL) Class IV: Nuclear Transcription Factors (MYC) Class V: Cell-cycle Control Proteins (Cyclin D)

20

Activation Mechanisms of Proto-oncogenes

21

Translocation or Chromosomal Rearrangements

Neoplasm Translocation Proto-oncogene

Burkitts lymphoma

t (8;14)-85% of cases t (8;22)-15% of cases t (2;8)-5% of cases

c-myc translocates to the IgG locus, resulting in its activated expression

Chronic myelogenous leukemia

t (9;22)-90-95% of cases

bcr-abl fusion protein is produced, which results in constitutively active abl kinase
bcr-abl fusion protein is produced, which results in constitutively active abl kinase

Acute lymphocytic leukemia

t (9;22)-10-15% of cases

22

Gene Amplification
Oncogene Amplification Tumor

c-myc
N-myc L-myc c-abl c-myb c-erbB K-ras
23

20 fold
5-1000 fold 10-20 fold 5 fold 5-10 fold 30 fold 4-20 fold 30-60 fold

Leukemia; lung cancer

Neuroblastoma; lung cancer Small-cell lung cancer Chronic myeloid leukemia Acute myeloid leukemia; colon cancer Epidermoid carcinoma Colon carcinoma Adrenocortical carcinoma

Ras-MAP Kinase Pathway

24

Regulation of Ras Activity

25

Tyrosine Kinase Behavior

26

Jak-STAT Signaling Pathway

27

Tumor Suppressor Genes

Normal function is to inhibit cell proliferation Absence/inactivation: > cancer risk Both copies of a gene must be defective (loss of function)

28

Mechanism of Inactivation of Tumor Suppressor Genes Deletion Point mutation

DNA methylation
Loss of heterozygosity

29

Knudsons Two-Hit Mutation Model

30

Cancer Associated with Tumor Suppressor Genes

Gene Function Inherited Disorders Somatic tumors

APC
WT1

Regulates -catenin
Transcription factor

Gardner syndrome
Denys-Drash syndrome

Colorectal cancer
Wilms tumor

Rb1 p53 BRCA1

Transcription regulator Transcription factor DNA repair

Familial retinoblastoma Li-Fraumeni syndrome Inherited breast and ovarian cancer Inherited breast and pancreatic cancer

Osteosarcoma, breast and prostate cancer 50% of all cancers Breast cancer; ovarian cancer Breast and pancreatic cancer

BRCA2

DNA repair

31

Tumor Suppressor Gene - Rb

32

Tumor Suppressor Gene p53

33

DNA Repair Genes

These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as protooncogenes and tumor suppressor genes. Examples are Breast cancer susceptibility genes (BRCA1 and BRCA2). Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1, PMS1, PMS2) have DNA repair functions. Their mutation may cause tumorigenesis.
34

Importance of DNA Repair

35

Importance of DNA Repair

36

Hallmarks of Cancer
Activate H-ras oncogene

Produce IGF survival factors

Loss of Rb

Produce VEGF inducer

Inactivate E-cadherin

Turn on telomerase 37 Hanahan, D. and Weinberg, R.A. 2011. Cell