Carcinogenesis

Patricia Jakel, RN,MN,OCN

What Is Cancer?

What is cancer?

A series of cellular, genetic aberrations that cause abnormal cell proliferation.

Unchecked local growth (tumor formation) and invasion of surrounding tissue.

Ability to metastasize (e.g. spread in a contiguous fashion to form secondary sites).

Changing Approach and Outcomes

Cancer as disease change from acute to chronic

20th Century Model: “Seek and Destroy”

21st Century Model : “Target and Control”

Essential Aberrations of Malignancy Proliferation Evading Apoptosis-avoiding

programmed cell death Cellular Differentiation Motility and Invasion Recruitment of Blood Vessels and

Angiogenesis Metastatic Spread Cancer cells must compete

successfully at each event to go forward.

Mechanism of Cancer

Apoptosis- is programmed cell death-that is, it is an active process controlled by cellular signaling. It may be triggered by the absence of a required growth factor:intercellular signals that indicate DNA damage or other injury to the cell; harmful external agents; or other intra- and extracellular events.

Mechanism of Cancer Angiogenesis- or the formation of new blood

vessels, critical step in tumor growth. Without tumors must obtain oxygen and nutrients by diffusion and therefore cannot grow larger.

The tumor remains dormant until it can stimulate blood vessel growth from nearby capillaries.

Malignant cells can release growth factors and enzymes that stimulate rapid formation of blood vessels. These chemical include VEGF- Targeted therapy.

Carcinogenesis

Refers to the process by which cancer arises. Likely involves a series of multiple steps or cellular changes over time. This three-stage theory is the most widely used explanation of the process by which a normal cell is transformed into a cancer cell.

Pathology-cancer arsies due to cumulative alteration in a

cell’s genes

1. Proto-oncogenes- the genetic portion of the DNA that regulates normal cell growth and repair: mutation may allow cell to proliferate beyond normal body needs.

Pathology

2.Tumor suppressor gene- the genetic portion of the DNA that stops cell division; mutation may allow cells to proliferate beyond normal body needs.

3. Oncogenes- abnormal, mutated genes responsible for the transformation of a normal cell into a cancer cell. May arise from mutations in proto-oncogenes, tumor suppressor genes, or other genes.

3. Oncogenes continued-

Different types of oncogenes may act together to induce cancers. 1.p53 tumor suppressor gene-normally

functions to stop cell proliferation, which allows DNA damage to be repaired.

When mutated, p53 restraint on cell proliferation is lost.

p53 mutations occur in about half of all human cancers: most common in colorectal, lung, and breast cancer.

3. Oncogene continued

2. Ras family of proto-oncogens-normally function to promote cellular growth

When mutated ras oncognes may allow cells to proliferate unrestrainted.

Ras oncogene are the most frequently detected oncogenes in human cancers; most common in pancreatic, colorectal, and thyroid cancers

Clinical Implications

Presence of certain oncogenes may have diagnostic and prognostic value.

Prevention of gene mutation is one focus of chemoprevention clinical trails.

Understanding of genetic changes may result in new targets for treatment

Genes and Cancer

Proto-Oncogenes- normal genes that participate in in normal tissue repair. Molecular “bucket brigade.”

Oncogenes- mutated proto-oncogenes. Excessively active

Secreted growth factor Cell-surface growth-factor receptors Membrane associated G protein

Tumor-Suppressor Genes- normal tell the cell to stop growing, role in cell cycle activity, helps with apoptosis

Relationship between genes and cancer

Cancer is a disease if genes gone awry. Genes that control the orderly replication of cells become damaged, allowing the cell to reproduce without restraint and eventually to spread into neighboring tissues and set up growths throughout the body.

Cancer Tends to Involve Multiple Mutations

Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites

More mutations, more genetic instability, metastatic disease

Proto-oncogenes mutate to oncogenes

Mutations inactivate DNA repair genes

Cells proliferate

Mutation inactivates suppressor gene

Benign tumor cells grow only locally and cannot spread by invasion or metastasis

Time

Cancer and Genetics

All cancer is genetic, in that it is triggered by altered genes. However, just a small portion of cancer is inherited: a mutation carried in reproductive cells, passed on from one generation to the next, and present in cells throughout the body.

Cancer and Genetics

Most cancer is random mutations that develop in body cells division during one’s lifetime- either as a mistake when cells are going through cell division or in response to injuries from environmental agents such as radiation or chemicals.

1. Initiation

A cancer causing agent damages the DNA, this gene may then: Undergo repair Become permanently changed

(mutated)but not cause cancer unless exposed to threshold levels of cancer promotors.

Become mutated and produce a cancer cell line.

Promotion- a process by which carcinogens are subsequently introduced, resulting in one of the following changes: Reversible damage to the

proliferation mechanism of the cell; the effects of the promoting factors may be inhibited: Cancer-reversing agent. Host Characteristics Time and dose limits.

Promotion continued.

Irreversible damage to the proliferation mechanism, resulting in cancer cell transformation.

Progression

Invasion -cells continue to divide; increase in bulk, pressure, and secretion of enzymes result in local spread and invasion of surrounding structures.

Neovascularization-formation of new blood vessels.

Metastasis-the production of secondary tumors at distant

sites. Routes of metastasis Sites Clinical Implication

Metastasis is the major cause of death from cancer.

Most tumors have begun to metastasize at the time of detection.

Invasion and Metastasis

3Cancer cells reinvade and grow at new location

1Cancer cells invade surrounding tissues and blood vessels

2Cancer cells are transported by the circulatory system to distant sites

Carcinoma in Situ

Milddysplasia

Carcinoma in situ (severe dysplasia)

Cancer(invasive)

Normal Hyperplasia

Neoplasm vs Tumor

Interchangeable terms Refers to abnormal growth of tissue that

serves no function and continues to grow unchecked.

Can be benign or malignant Cancer- common term for all malignancies

Tumor Nomenclature

Hematologic Malignancies Lymphomas

Malignancies of the lymphocyte Subclassified as:

Hodgkin's Non-Hodgkin's

Multiple myeloma-arises from the plasma cell (B lymphocyte) line.

Tumor Nomenclature

Hematologic Malignancies Leukemias

Arises from hematopoietic cells Classified according to cell type and maturity. Lympho-denotes leukemia of lymphoid origin. Myleo-denotes leukemia of myeloid origin

Different Kinds of Cancer

Lung

Breast (women)

Colon

BladderProstate (men)

Some common sarcomas:Fat

Bone

Muscle

Lymphomas:Lymph nodes

Leukemias:Bloodstream

Some common carcinomas:

Naming Cancers

Prefix Meaning

adeno- gland

chondro- cartilage

erythro- red blood cell

hemangio- blood vessels

hepato- liver

lipo- fat

lympho- lymphocyte

melano- pigment cell

myelo- bone marrow

myo- muscle

osteo- bone

Cancer Prefixes Point to Location

Why Cancer Is Potentially Dangerous

Melanoma cells travel through bloodstream

Melanoma(initial tumor)

Brain

Liver

Tumor Grading

General Relationship Between Tumor Grade and Prognosis

PatientSurvival

Rate

Years

High grade

Low grade

100%

1 2 3 4 5

Tumor Staging

Five-Year Survival Rates forPatients with Melanoma (by stage)

Stage at Time of Initial Diagnosis

100%

50%

I II III

What Causes Cancer?Some viruses or bacteria

HeredityDiet

Hormones

RadiationSome chemicals

Population-Based Studies

CANADA:Leukemia

Regions of Highest Incidence

BRAZIL:Cervicalcancer

U.S.:Coloncancer

AUSTRALIA:Skincancer

CHINA:Livercancer

U.K.:Lungcancer

JAPAN:Stomachcancer

Heredity? Behaviors? Other Factors?

100

50

50

Stomach Cancer(Number of new cases

per 100,000 people)

U.S.Japan Japanese familiesin U.S.

100

70

7

0

Colon Cancer(Number of new cases

per 100,000 people)

U.S.Japan Japanese familiesin U.S.

Tobacco Use and CancerSome Cancer-Causing Chemicals in Tobacco Smoke

Low-Strength Radiation

Annual Sunshine(UV radiation)

SkinCancer

Incidence

Most

Dallas

Pittsburgh

High

Detroit

LowLeast

High-Strength Radiation

Most

High

LowLeast

Leukemia Incidence

X-ray Dose(atomic radiation)

Ultraviolet radiation-a complete carcinogen

Sources of UVR Sunlight Tanning salons Industrial sources-welding arcs

Viruses-

Infect DNA, resulting in proto-oncogene changes and cell mutation.

Effects modified by: Age Immunocompetence

Viruses

Virus inserts and changes genes forcell growth

Cancer-linked virus

Examples of Human Cancer Viruses

Some Viruses Associated with Human Cancers

AIDS and Kaposi’s Sarcoma

Kaposi’ssarcoma

Withoutdisease

Depressedimmunesystem

HIV infection

KSHV infection

Bacteria and Stomach Cancer

H. pyloriPatient’s tissue sample

Heredity Can Affect Many Types of Cancer

Inherited Conditions That Increase Risk for Cancer

Mutations and Cancer

Genes Implicated in Cancer

What causes cancer???

Exposure to carcinogens-chemical, or viral, or physical or familial Exposure to radiation-cellular DNA

damage by physical release of energy. Ionizing radiation

Damage to the cell by this source; Is usually repaired and no mutation

results. May give rise to a malignancy when

damage affects proto-oncogenes or tumor suppressor genes.

Depends on numerous factors.

Cancer Prevention

Cancer viruses or bacteria

Carcinogenic radiation

Carcinogenic chemicals

Avoid Tobacco

15x

10x

5x

Non-smokerCigarettes Smoked per Day

Lung Cancer Risk Increases with Cigarette Consumption

Lung Cancer Risk

0 15 30

Protect Yourself From Excessive Sunlight

Skin cancers most common with UVR

Melanoma Basal cell carcinoma Squamous cell carcinoma

Avoid Cancer Viruses

Noninfected women

HPV Infection Increases Risk for Cervical Cancer

Cervical Cancer

Risk

Low

High

Women infected with

HPV

Chemical Carcinogens

Chemical substances that alter DNA

Avoid Carcinogens at Work

Some Carcinogens in the Workplace

Examples of ionizing radiation

Most exposure is natural and unavoidable. Diagnostic radiographs, radiation therapy,

radioisotopes used in imaging. Cosmic rays. Radioactive ground minerals and gases-

radon, radium, uranium. Cancers linked to ionizing radiation.

Compromised Immune System

Immune surveillance against cancer Surveillance occurs via recognition of

tumor-associated antigens Immune response may fail .

Age Tumor burden Shed substances Outside factors

Microscopic Appearance of Cancer Cells

Staging of Cancer

TNM T-extent or size of the tumor N-absence or presence and extent of regional

lymph node metastasis M-absence or presence of distant metastases.