BISC 313 - Carcinogenesis

Carcinogenesis Dr. Onkar S. Bains

BISC 313

SFU

Spring 2013

1 in 3 people will develop cancer

1 in 4 males will die of it

1 in 5 females will die of it

More than 200 different types of cancer, but four of them (breast, prostate, lung and colorectal) account for over half of all new cases

World Health Organization estimates that 80% of cancers are caused by occupational or environmental factors, including exposure to hazardous chemicals

Introduction

Cancer, 29.6%

Diseases of the heart,

21.5%

Cerebrovascular

diseases, 5.9%

Chronic lower

respiratory diseases,

4.5%

Accidents, 4.2%

Diabetes, 3.1%

Influenza and

pneumonia, 2.3%

Alzheimer's disease,

2.5%

Suicide, 1.5%

Kidney disease, 1.6%

Other, 23.1%

Proportion of deaths due to cancer and other causes,

Canada, 2007

Adapted from: Ten leading causes of death, Canada, 2007, Statistics Canada

0 10 20 30 40 50 60 70 80 90 100

Thyroid

Testis

Prostate

Melanoma

Breast

Hodgkin lymphoma

Body of Uterus

Bladder

Cervix

Kidney

Larynx

Oral

Colorectal

Non-Hodgki lymphoma

Leukemia

Ovary

Multiple myeloma

Stomach

Brain

Liver

Lung

Esophagus

Pancreas

RSR (%)

Five-year relative survival ratio (RSR) for most common cancers, by sex, Canada, 2004-2006

Males

Females

Tie

r 2

Tie

r 3

(

80%

)

Data source: Canadian Cancer Statistics 2011

Cancer = malignant tumor that has the ability to metastasize or invade into surrounding tissues

Tumor = abnormal mass of tissue, in which growth 1. exceeds and is uncoordinated with that of the surrounding normal tissues,

2. continues after cessation of stimuli that initiated new growth

Tumors can be cancerous (malignant) or non-cancerous (benign)

Neoplasm = same as tumor

Neoplasia = formation of a neoplasm

Metastasis = spread of a cancer from one organ or part to another non-adjacent organ or part via circulatory or lymphatic system

Terminology

Metastasis

In general, a cancer is named according to the type of tissue in which it first forms

o Carcinomas: cancer arising from epithelium

Constitute ~90% of cancers

o Sarcomas: cancer of connective tissue

Rare

Connective tissue supports, connects or separates different types of tissues and organs (i.e., adipose tissue, cartilage, bone, blood)

o Lymphomas: cancer of lymphoid tissue

o Leukemias: cancer arise from blood- forming cells

o Gliomas: cancer of brain glial cells

Constitute ~8% of cancers

Prefix Meaning

adeno- gland

chondro- cartilage

erythro- red blood cell

angio- blood vessels

hepato- liver

lipo- fat

lympho- lymphocyte

melano- pigment cell

myelo- bone marrow

myo- muscle

osteo- bone

Cancer prefixes point to location

Naming of cancers

Benign versus malignant tumors

(encapsulated)

(similar to cell of origin)

(dissimilar from cell of origin)

Patient survival Poor survival rates (tendency for local or distant recurrence)

High survival rates after removal

Also referred to as oncogenesis or tumorigenesis

Process by which normal cells are transformed into cancer cells (malignant neoplasm)

Characterized by a progression of changes on cellular and genetic level that ultimately reprogram a cell to undergo uncontrolled cell division

What is carcinogenesis?

Initiation: Alteration of the DNA (mutation)

of a normal cell, which is an irreversible change

Initiated cell has developed a capacity for individual growth

Initiated cell is indistinguishable from other similar cells in tissue

Initiating event can consist of a single exposure to a carcinogenic agent or in some cases, it may be an inherited genetic defect

Initiated cell may remain dormant for months to years and unless a promoting event occurs it may never develop into a cancer

Stages of carcinogenesis

Promotion/Conversion: Specific agents (referred to as

promoters) often, but not always, interact with the cell's DNA and influence the further expression of mutated DNA so that initiated cell proliferates and progresses further through carcinogenesis process

The clone of proliferating cells in this stage takes a form consistent with a benign tumor

The mass of cells remains as a cohesive group and physically keeps in contact with each other

Progression: Development of initiated cell into a

biologically malignant cell population

In this stage, a portion of benign tumor cells may be converted into malignant forms so that a true cancer has evolved

Individual cells in this final stage can break away and start new clones of growth distant from the original site of development of the tumor (this is known as metastasis)

While three-stage pathogenesis scheme describes basic sequence of events in carcinogenesis process, the actual events that take place are due to activities of specific gene within DNA of cells

Cellular DNA contains two types of genes:

Structural direct production of specific proteins within cell

Regulatory control activity of structural genes and direct proliferation process of cell

Three types of regulatory genes considered to have major roles in carcinogenesis are:

Proto-oncogenes (growth promoting)

Oncogenes

Tumor suppressor genes (growth inhibitory)

Normal or good cellular genes that encode and instruct production of the regulatory proteins and growth factors within cell or its membrane

Proteins encoded by proto-oncogenes are necessary for normal cellular cell growth and differentiation

Activation of a proto-oncogene can cause alteration in the normal growth and differentiation of cells, which leads to neoplasia

Several agents can activate proto-oncogenes

This is result of point mutations or by DNA re-arrangements of proto-oncogenes

The product of this proto-oncogene activation is an oncogene

Proto-oncogenes

Altered or misdirected proto-oncogenes which now have ability to direct production of proteins within cell that can change or transform normal cell into a neoplastic cell

The altered DNA in oncogene results in production of an abnormal protein that can alter cell growth and differentiation

It appears that a single activated oncogene is not sufficient for growth and progression of a cell and its offspring to form a cancerous growthhowever, it is a major step in carcinogenesis process

Oncogenes

Chromosome rearrangement

Mechanisms of oncogene activation Point mutations

At coding sequence formation of abnormal oncoprotein with enhanced stability or activity

At regulatory element (promoter site) enhance transcription of proto-oncogene to form more proto-oncoprotein

Chromosome rearrangement

Mechanisms of oncogene activation Gene amplifications

End up with more copies of proto-oncoprotein

Chromosomal rearrangements

Result in gene with either new promoter and/or enhancer that can increase transcription of proto-oncogene

Sometimes referred to as anti-oncogenes actively function to effectively oppose the action of an oncogene

Present in normal cells and serve to counteract and change proto-oncogenes and altered proteins that they are responsible for

Serve to prevent a cell with damaged DNA from proliferating and evolving into an uncontrolled growth

If a tumor suppressor gene is inactivated (usually by a point mutation), its control over oncogene and transformed cell may be lost

Thus the tumor-potential cell can now grow without restraint and is free of normal cellular regulatory control

Tumor suppressor genes

The suppressor gene most frequently altered in human tumors is the p53 gene

Damaged p53 genes have been identified in over 50% of human cancers

The p53 gene normally halts cell division and stimulates repair enzymes to rebuild and restore damaged regions of DNA

If damage is too extensive, the p53 commands cell to self-destruct (apoptosis)

An altered p53 is incapable of these defensive actions and can not prevent the cell with damaged DNA from dividing and proliferating in an erratic and uncontrolled mannerthis is the essence of cancer

Another example is the retinoblastoma gene

Product of gene is called retinoblastoma protein (pRb)

pRb prevents the cell from replicating damaged DNA by preventing its progression along the cell cycle through G1 (first gap phase) into S (synthesis phase)

Blocks cell cycle at G1 checkpoint

pRb blocks checkpoint by binding and inhibiting transcription factors of the E2F family

If there is sufficient cyclin and cylcin-dependent kinase (cdk) in cell, then pRb will dissociate from E2F and cell will pass G1 checkpoint to eventually undergo division

Mutated forms of pRb will not bind and inhibit E2F cell passes G1 checkpoint, even if DNA is damaged!

Another example is the breast cancer susceptibility gene (BRCA)

BRCA1 and BRCA2

In normal cells, BRCA1 and BRCA2 help ensure stability of cells DNA and help prevent uncontrolled cell growth

Gene products encoded by BRCA1 and BRCA2 are nuclear proteins that co-localize with RAD-51 at sites of DNA damage, and play a role in homologous recombination repair of double-stranded breaks

~10% of all cases of breast and ovarian cancer are hereditary cancers, and most are due to inheritance of a germ-line mutation in either BRCA1 or BRCA2

A woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation

Most BRCA1 and BRCA2 mutations lead to frameshifts resulting in missing or non-functional protein, or, in case of BRCA2, to nonsense mutations leading to premature truncation of the protein

These mutations are all consistent with loss of function expected with tumor suppressor genes

Men with these mutations also have an increased risk of breast cancer

Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers

While a BRCA mutation results in a higher chance of developing breast and ovarian cancer, it does not cause cancernot everyone who inherits a BRCA mutation will develop breast or ovarian cancer

Risk factors for cancer

Family history (genetic predisposition)

Breast cancer gene (BRCA1 and BRCA2)

60% increased risk versus 12% risk in general population

Retinoblastoma (Rb) gene

Example: ~80% of small cell lung cancers have a Rb mutation

p53 gene

~50-75% of all cancers have a p53 mutation

Environmental factors

Chemical carcinogens (direct and indirect-acting)

Physical carcinogens (ionizing radiation, UV light)

Direct-acting agents require no metabolic conversion to become carcinogenic.

Indirect-acting agents refers to chemicals that require metabolic activation & conversion to an ultimate carcinogen before they become active

Chemical carcinogens

Some industrial chemicals linked to cancer

Ionizing radiation includes: X-rays, gamma rays, as well as particulate radiation (alpha, beta, protons, neutrons) and cosmic radiation

All forms are carcinogenic with special sensitivity in: Bone Marrow: acute leukemia occurs before other

radiation-induced neoplasia (7 year latent period in atomic bomb survivors)

Thyroid: carcinoma occurs in 9% of those exposed during infancy or childhood

Lung: increased frequency of lung cancer in miners exposed to radon gas (an alpha particle emitter)

Oncogenic properties of ionizing radiation are related to its mutagenic effects (chromosomal breakage and translocations, as well as, less frequently, point mutations)

Double-stranded DNA breaks are most important form of DNA damage caused by this radiation

Ionizing radiation

American Association for Cancer Research et al. Clin.

Cancer Res 2012;18:S1-S100

2012 by American Association for Cancer Research

Majority of ionizing radiation to which North American population is exposed is natural background radiation; the rest comes from man-made sources, most prominently medical X-rays

Exposure to ionizing radiation is linked to development of certain cancers, in particular, leukemias and cancers of the breast, lungs, brain and thyroid

Catastrophic nuclear accident that occurred on 26 April 1986 at the Chernobyl Nuclear Power Plant in Ukraine

Over 1019 Becquerel (Bq) of radioactive isotopes released, including 5.2x1018 Bq of beta-emitting isotopes of iodine that concentrate in thryoid gland

Fallout from Chernobyl affected millions of people living within a few hundred kilometers of reactor and caused a 30-100 fold increase in incidence of thyroid cancer, especially in children

Case: Chernobyl

Strong epidemiologic relationship to squamous cell carcinoma, basal cell carcinoma, and melanoma in fair skinned people

Causes formation of pyrimidine dimers in DNA leading to mutations

This type of DNA damage is repaired by the nucleotide excision repair pathway

With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results

Individuals with defects in enzymes that mediate DNA excision-repair are especially susceptible

UV light

Risk factors for cancer Lifestyle

Tobacco use, overweight/obesity, physical inactivity, alcohol consumption all contribute to risk of cancer

Diet Heterocyclic amines produced during cooking of meat are

carcinogens

Long-term exposure to food additives such as nitrite preservatives and azo dyes has been associated with induction of carcinogenesis

Bisphenol from plastic food containers can migrate into food and may increase risk of breast and prostate cancers

Saturated fatty acids, trans fatty acids, and refined sugars and flour present in most foods have also been associated with various cancers

(continued)




Lifestyle and diet make up ~66% of cancer cases in North America


Infectious agents

Viral

Herpesvirus B Kaposi sarcoma (45,000 cases worldwide per year)

Cancer that causes patches of abnormal tissue to grow under skin, in lining of mouth, nose, and throat or in other organs

Patches are usually red or purple and are made of cancer cells and blood cells)

(continued)


Infectious agents

Viral

Epstein-Barr virus Non-Hodgkins lymphoma (9000 cases)

Cancer of lymphoid tissue, which includes lymph nodes, spleen, and other organs of immune system

Human papillomavirus (HPV) cervical cancer (360,000 cases)

Hepatitis C virus hepatocellular cancer (110,000 cases)

Hepatitis B virus - hepatocellular cancer (230,000 cases)

(continued)

Bacterial

Helicobacter pylori (H. pylori) gastric cancer (350,000 cases worldwide per year)

2 to 4-fold increase in risk of gastric cancer upon infection

Spiral, flagellated bacteria that colonizes in human GI tract (grows in mucus layer that coats inside of human stomach)

To survive in harsh, acidic environment of stomach, H. pylori secretes an enzyme called urease, which converts chemical urea to ammonia

The production of ammonia around H. pylori neutralizes acidity of stomach, making it more hospitable for bacterium

Discovery of H. pylori and recognition of its place in the pathogenesis of peptic ulcer disease are chiefly due to Barry Marshall, who swallowed a solution of the organism and developed acute gastritis 1 week later

Helminths (parasitic worms)

Schistosoma haematobium (S. haematobium) bladder cancer (10,000 cases per year)

Parasitic blood flukes or flatworms

Liver flukes cholangiocarcinoma (1000 cases worldwide per year)

Cholangiocarcinoma = cancerous tumors associated with bile duct

Flukes migrate to biliary tree and mature in intrahepatic bile ducts

5-fold increase in risk of cholangiocarcinoma

Documents

BISC 313 - Carcinogenesis