Molecular Basis of Cancer

Mircoles 12 dic 2007 ARTICULO

Summary
Cell cycle n Cellular proliferation and cancer n Cancer and the environment n Genes and cancer
n

The Cell Cycle

n

The cell cycle consists of:

G1 = growth and preparation of the chromosomes for replication; S = synthesis of DNA (replication) and duplication of the centrosome; G2 = preparation for mitotic division M = mitosis.

Cell Cycle Control

n

The passage of a cell through the cell cycle is controlled by proteins in the cytoplasm. Among the main players in animal cells are:

Cyclins - Their levels in the cell rise and fall with the stages of the cell cycle. Cyclin-dependent kinases (Cdks) - Their levels in the cell remain fairly stable, but each must bind the appropriate cyclin (whose levels fluctuate) in order to be activated. They add phosphate groups to a variety of protein substrates that control processes in the cell cycle. The anaphase-promoting complex (APC). (The APC is also called the cyclosome. - Triggers the events leading to the separation of sister chromatids and degrades the mitotic cyclin B.

Checkpoints: Quality Control of the Cell Cycle

n

All the checkpoints require the services of a complex of proteins. Mutations in the genes encoding some of these have been associated with cancer; that is, they are oncogenes. DNA damage checkpoints. These sense DNA damage before the cell enters S phase (a G1 checkpoint) as well as during S phase. Damage to DNA inhibits the action of CDK2 thus stopping the progression of the cell cycle until the damage can be repaired (with the aid of BRCA2). If the damage is so severe that it cannot be repaired, the cell self-destructs by apoptosis.

Normal (left) versus cancerous (right) mammography image.

Normal (left) versus cancerous (right) microscopy image.

US Mortality, 2004
Rank
n n n n n n n n n n

Cause of Death

No. of deaths

% of all deaths

1. 2. 3. 4. 5. 6. 7. 8. 9.

Heart Diseases Cancer Cerebrovascular diseases

652,486 553,888 150,074

27.2 23.1 6.3 5.1 4.7 3.1 2.8 2.5 1.8 1.4

Chronic lower respiratory diseases 121,987 Accidents (Unintentional injuries) Diabetes mellitus Alzheimer disease Influenza & pneumonia Nephritis 112,012 73,138 65,965 59,664 42,480 33,373

10. Septicemia

Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

Different Kinds of Cancer

Some common carcinomas:

Lung Breast (women)

Leukemias:
Bloodstream

Lymphomas:
Lymph nodes

Colon Bladder Prostate (men)

Some common sarcomas:

Fat Bone Muscle

http://www.cancer.gov/cancertopics/understandingcancer/cancer

2007 Estimated US Cancer Deaths

31% Lung & bronchus 9% Prostate 9% Colon & rectum 6% Pancreas 4% Leukemia 4% Liver & intrahepati bile duct 4% Esophagus 3% Urinary bladder 3% Non-Hodgkin lymphoma 3% Kidney 24% All other sites Men 289,550 Women 270,100

26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Brain/ONS* 2% Liver & intrahepatic bile duct 23% All other sites
*ONS=Other nervous system.

Source: American Cancer Society, 2007.

Cellular Basis of Cancer

n

Cancer is a collection of diseases characterized by abnormal and uncontrolled growth Cancer arises from a loss of normal growth control In normal tissues, the rates of new cell growth and old cell death are kept in balance In cancer, this balance is disrupted This disruption can result from 1) uncontrolled cell growth or 2) loss of a cell's ability to undergo apoptosis

n n

Cellular Equilibrium
Proliferation Differentiation
Normal Cells

Death

Cancer Cells: disruption of cellular equilibrium

Los Genes y el Cncer

Virus Radiacin

Herencia

Cromosomas y molculas de DNA

Leading Causes of Death in US Percent of All Causes of Death1975 vs 2004

SEER Incidence and US Death Rates

SEER Cancer Incidence (per 100,000 inhabitants) and US Death Rates, 2000-2004 By Cancer Site and Race

Heredity? Behaviors? Other Factors?

Colon Cancer
(Number of new cases per 100,000 people)

Stomach Cancer
(Number of new cases per 100,000 people)

100

100 70

50

5 0

7 0 Japan Japanese families in U.S. U.S. Japan Japanese families in U.S. U.S.

Environmental vs. Hereditary Cancer

100 80 60 40 20 0

85

15

Cancer Etiology Environmental Hereditary

Substances in the environment known to cause cancer

n n n n n n n n n

Tobacco Diet/weight/physical inactivity Alcoholic drinks Ultraviolet radiation Virus and bacteria Ionizing radiation

n n n n n n n n

Special case: Radon

Pesticides Medical drugs Solvents

Dioxins Fibers, fine particles, and dust Polycyclic aromatic hydrocarbons Metals Diesel exhaust particles Toxins from fungi Benzidine Vinyl chloride

Tobacco Use and Cancer

Some Cancer-Causing Chemicals in Tobacco Smoke

http://www.cancer.gov/cancertopics/understandingcancer/cancer

HOMEWORK!

U.S. Department of Health and Human Services National Institutes of Health National Cancer Institute

http://www.cancer.gov/images/Documents/5d17e03e-b39f-4b40-a214-e9e9099c4220/Cancer%20and%20the%20Environment.pdf

Multimedia: Cancer and Environment

http://www.cancer.gov/newscenter/benchmarks-vol4-issue3/Video

Viruses

Virus inserts and changes genes for cell growth Cancer-linked virus

Examples of Human Cancer Viruses

Some Viruses Associated with Human Cancers

AIDS and Kaposis Sarcoma

Without disease

HIV infection
Depressed immune system

KSHV infection
Kaposis sarcoma

Bacteria and Stomach Cancer

Patients tissue sample

H. pylori

Cancer: General Etiology and Pathogenesis

Genetic Instability in Tumors

n n

Activation of Oncogenes Inactivation of Tumor Suppressor Genes Mismatch repair (MMR) Genes

n n n

Chromosomal Instability Telomere Shortening Microsatellite (variable

tandem repeats, VTRs)

Instability Apoptosis

Possible Causes of Tumor Progression

Telomeres and Cancer

n n

The ends of human chromosomes, telomeres, contain long stretches of a tandemly arranged hexameric sequence, TTAGGG. In normal human cells, telomeres progressively shorten with each successive cell division, ultimately leading to growth arrest. In tumor cells and embryonic stem cells, this decline is halted by activation of telomerase, a reverse transcriptase that extends the telomeric TTAGGG repeat. Telomerase is a ribonucleoprotein (RNP) complex minimally composed of a conserved protein subunit containing a reverse transcriptase domain (human telomerase reverse transcriptase, hTERT) and a template-containing RNA (human telomerase RNA component, hTERC, or hTR, hTER).

(human telomerase RNA component)

(human telomerase reverse t ranscriptase)

Greater telomere length is associated with immortalized cell lines such as embryonic stem cells and cancer cells.

http://stemcells.nih.gov/info/scireport/appendixC.asp

Genes and Tumor Development

Inherited or acquired alterations in genes Oncogenes growth
promoting genes Tumor suppressor genes brakes for cell division

Tumor Suppressor Genes

(The damage is mainly associated to the recessive form of the gene.)

Rb p53

Retinoblastoma Sndrome Li-Franmeni

APC Adenomatous polyposis coli (Casos de familias con mtiples polipos en el colon) DCC Ausente en el carcinoma del colon WT-1 Tumour Wilm (rin) BRACA1 Cncer en los senos

The role of p53 in the cell cycle ((guardin guardi guardi n del genoma ) del genoma genoma)
apoptosis (cell death) DNA synthesis UV irradiation leads

p53
to cell cycle arrest

phase

G0
Quiescent cells
p53 p53 is is a a tumor tumor suppressor suppressor protein protein,, also also known known as as "Guardian "Guardian of of the the Genome". It plays an important Genome". It plays an important role role in cell cycle control and in cell cycle control and apoptosis. apoptosis. Defective Defective p53 p53 could could allow allow abnormal abnormal cells cells to to proliferate, proliferate, resulting resulting in in cancer. cancer. As As many many as as 50% 50% of all human tumors contain p53 of all human tumors contain p53 mutants. mutants.

G1
phase

phase

phase

G2

Growth and preparation for cell division

Mitosis

Roles of p53 in growth arrest and apoptosis

a) Growth Arrest
The cell cycle progression into the S phase requires the enzyme Cdk2, which can be inhibited by p21. The progression into the M phase requires Cdc2 which can be inhibited by p21, GADD45 or 14-3-3s. p53 regulates the expression of these inhibitory proteins to induce growth arrest.

b) Apoptosis
Apoptosis can be induced by the binding of Caspase 9 to cytochrome c and Apaf1. p53 may activate the expression of Apaf1 and Bax. The latter can then stimulate the release of cytochrome c from mitochondria.

p53 protein works as a transcription factor

Apoptosis
n

Apoptosis, or programmed cell death, is a highly regulated process that allows a cell to self-degrade in order for the body to eliminate unwanted or In a healthy cell, the caspases are all present as zymogens and dysfunctional cells.

Cancer may arise from the dysfunction in the apoptotic pathway.

the BH3-only proteins (BH3) are sequestered away from the Bcl2-like pro-survival proteins (Bcl-2). After an apoptotic signal, the freed BH3-only proteins associate with Bcl-2 on mitochondria, and the recruitment of Bax (activated by p53) and Bak into oligomers on the mitochondrial outer membrane then leads to its permeabilization. The released cytochrome c induces formation of the heptameric apoptosome of Apaf-1 (activated by p53) and procaspase-9 (c9), which activates caspase-3 (c3). The released Diablo/Smac and Omi/Htr2 incapacitate the IAPs in the cytosol, whereas AIF and endonuclease G (endoG) enter the nucleus, where they may aid in DNA degradation.

Genes & Dev. 2003 17: 2481-2495. http://www.genesdev.org/cgi/reprint/17/20/2481

Principios Asociados a las Bases Moleculares del Cncer

Muerte celular (apoptosis) conlleva dao celular. Clulas daadas deben ser removidas del organismo. Cncer es una enfermedad gentica asociada al control de la proliferacin celular y la muerte celular no procede como debe ser. Un slo gen daado no causa cncer, regularmente se requieren varios genes mutados para que surga la enfermedad.

El cncer casi siempre requiere ms de un gen alterado . . .

Oncogenes
n Versiones

mutadas de genes que regulan crecimiento y cuyos productos de expresin (protenas) participan en el control de procesos bioqumicos en el nivel celular

Pro-oncogenes
n

Activacin de pro-oncogenes mediante mutaciones (punto, amplificacin, translocacin, otras) provoca su conversin en oncogenes.

Los Oncogenes

Clula normal

Los genes normales regulan el crecimiento de la clula

Clula cancerosa

Los oncogenes aceleran el crecimiento y la divisin celular

Oncogen mutado/daado

Productos protenicos de los oncogenes

n n n n n

Factores de crecimiento Receptores de factores de crecimiento Protenas G Quinasas citoplasmticas Protenas para sobrevivir
Telomerasa Bcl-Bcl-x

Protenas nucleares

Factores de transcripcin

Proto-oncogenes en la clula
1. Factores de crecimiento 2. Receptores de factores de crecimiento 3. Protenas quinasas o activadoras de quinasas 4. Protenas que controlan ciclo celular 5. Protenas que afectan apoptosis

Activities and cellular locations of some protooncogenes

Genes supresores de tumores

n

Inactivacin ocurre mediante delecin de uno de los alelos y eventualmente mutaciones de punto en el alelo restante.

Genes supresores de tumores

(El dao celular asociado usualmente a forma recesiva del gen.) Rb p53 Retinoblastoma Sndrome Li-Franmeni

APC Adenomatous polyposis coli (Casos de familias con mtiples polipos en el colon) DCC Ausente en el carcinoma del colon WT-1 Tumour Wilm (rin) BRACA1 Cncer en los senos

Retinoblastoma

Los Genes Supresores de Tumores

Clula normal

Genes normales previenen el cncer

Remueve o inactiva a los genes supresores de tumor

Clula cancerosa

Dao a ambos genes conduce al cncer

Genes supresores de tumor mutados/inactivados

Hacia dnde se mueve?

Genes supresores de tumores

Oncogenes

Specific Cellular Functions in Cancer: Genetic Alterations

Genetic Instability: RER Phenotype DNA Repair

CANCER
Tumor Suppressor Genes Interstitial Deletion Inactivating Mutation Hypermethylation Oncogenes Gene Amplification Gene Overexpression Activating Mutation

El cncer casi siempre requiere ms de un gen alterado y se va desarrolando paso a paso. Cambios mltiples y sucesivos van ocurriendo en varios genes.

Inactivacin de varios genes conduce a cncer

Herencia? Comportamiento? Otros Factores?

Cncer de Colon
(Nmero de casos nuevos por 100,000 personas)

Cncer de Estmago
(Nmero de casos nuevos por 100,000 personas)

100

100 70

50

5 0

7 0 Japn Familias japonesas en EE.UU. EE.UU. Japn Familias japonesas en EE.UU. EE.UU.

Cancer Tends to Involve Multiple Mutations

Benign tumor cells grow only locally and cannot spread by invasion or metastasis Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites

Time Mutation Cells inactivates proliferate suppressor gene Mutations inactivate DNA repair genes Proto-oncogenes mutate to oncogenes More mutations, more genetic instability, metastatic disease

http://www.cellsalive.com/cell_cycle.htm