Download Carcinogenesis - UMF IASI 2015

Carcinogenesis
Characteristics of Cancer
Disorder of altered cell differentiation and growth
 Results in neoplasia (“new growth”)
Growth is uncoordinated and relatively
autonomous
 Lacks normal regulatory controls over cell
growth and division
 Tends to increase in size and grow after
stimulus ceases or needs of organism are met
Determination and
Differentiation
The Cell Cycle
Definition: The interval between each cell
division
Genetic information is duplicated

Duplicated chromosomes are appropriately aligned
for distribution between two genetically identical
daughter cells
Checkpoints in cycle provide opportunities for
monitoring the accuracy of deoxyribonucleic acid
(DNA) replication

Edited and repaired defects ensure full complement
of genetic information to each daughter cell
Control of Cell Cycle
Control of Cell Cycle
The cell cycle is controlled by many proteins from
inside & outside the cell.
Intracellular cyclins and cyclin dependent kinases
(CDKs) control the checkpoints.
Extracellular proteins from other cells called Growth
Factors signal the target cell to divide.
Binding of growth factors to membrane receptor
proteins of the target cell triggers a molecular
signaling pathway - a series of proteins which allows
the cell to pass the checkpoints of the cell cycle.
Cell Cycle is controlled by genes.
Tumor Suppressor Proteins Inhibit Cell
Division & Prevent Cancer
Tumor suppressor proteins are proteins that bind to
checkpoint proteins to stop the cell cycle & prevent cell
division.
An important function of tumor suppressor proteins is to
stop the division of mutated cells until mistakes in DNA
are repaired by enzymes.
TS proteins keep most mutations from being passed on
to daughter cells & developing into cancer.
If the genes for TS proteins mutate or are deleted
cancers may result.
Two important TS proteins are the p53 protein & the RB
protein.
Cell Proliferation
Definition

The process by which cells divide and
reproduce
Regulation

Regulated in normal tissue, so the number of
cells actively dividing equal the number of
cells dying or being shed
Two Major Categories of Cells
Existing in Humans
Gametes (ovum and sperm)


Haploid (containing one set of chromosomes
from one parent)
Designed for sexual fusion forming a diploid
cell (containing both sets of chromosomes)
Somatic cell

The diploid cell that forms the rest of the
body
Categories of Cell Types of the
Body
Well-differentiated neurons and cells of skeletal
and cardiac muscle unable to divide and
reproduce
Parent or progenitor cells that continue to divide
and reproduce
 Blood cells, skin cells, liver cells
Undifferentiated stem cells that can be triggered
to enter cell cycle and produce large numbers of
progenitor cells when needed
Types of Tumors
Adenoma: benign tumor of glandular epithelial
tissue
Adenocarcinoma: malignant tumor of glandular
epithelial tissue
Carcinoma: malignant tumor of epithelial tissue
Osteoma: benign tumor of bone tissue
Sarcoma: malignant tumors of mesenchymal
origin
Papillomas: benign microscopic or macroscopic
fingerlike projections growing on a surface
Factors differentiating Benign
and Malignant Neoplasms
Cell characteristics
Manner of growth
Rate of growth
Potential for metastasizing or spreading
Ability to produce generalized effects
Tendency to cause tissue destruction
Capacity to cause death
Characteristics of Benign
Neoplasms
A slow, progressive rate of growth that may
come to a standstill or regress
An expansive manner of growth
Inability to metastasize to distant sites
Composed of well-differentiated cells that
resemble the cells of the tissue of origin
Characteristics of Malignant
Neoplasms
Tend to grow rapidly and spread widely
Have the potential to kill regardless of their
original location
Tend to compress blood vessels and outgrow
their blood supply, causing ischemia and tissue
necrosis
Rob normal tissues of essential nutrients
Liberate enzymes and toxins that destroy tumor
tissue and normal tissue
Methods by which Cancer
Spreads
Direct invasion and extension
Seeding of cancer cells in body cavities
Metastatic spread through the blood or lymph
pathways
Factors Affecting Tumor Growth
The number of cells that are actively dividing or
moving through the cell cycle
The duration of the cell cycle
The number of cells that are being lost
compared with the number of new cells being
produced
Carcinogenesis
Hypotheses of the Origin of Neoplasia
1. Oncogenes and Tumor Suppresor Genes
2. Viral Oncogene Hypothesis
3. Epigenetic Hypothesis
4. Failure of Immune Surveillance
1. Oncogenes and Tumor Suppresor
Genes
Genes that Control Cell Growth and Replication
Genes control cell division by cytokines.
Three classes of regulatory genes.
1.
2.
3.
Promotors – Proto-oncogenes
Inhibitors – Cancer-suppressor genes – p53
DNA stability genes.
Non-lethal Genetic damage lies at the
center of carcinogenesis.
Loss/damage to suppressor genes,
Duplication of promotor genes
Loss/damage of DNA stability genes.
Alterations of Specific Cellular
Functions in Cancer
Tumor Suppressor
Genes
Oncogenes
Inactivation
Activation
Differentiation
Apoptosis/Proliferation
CANCER
Proto-oncogenes
Oncogenes:

Viral proteins which interact with the cellular controll
mechanisms to overcome the strict regulation of
proliferation (v-ras, v-myc, v-abl, ...)
Proto-Oncogenes:

Cellular proteins which correspond to the viral
Oncogenes but which are strictly regulated. Mutations
in this genes could transform a cell into a tumor cell
(c-ras, c-myc, c-abl, ...).
Proto-oncogenes
TYPES OF ONCOGENES
1.
2.
3.
4.
5.
Growth factors
Growth factors receptors
Intracellular signaling transduction factors
Proteins with GTPase activity
Cytoplasmic serine threonine kinases
DNA-binding nuclear proteins
Cell cycle factors
Relationship between gene products
of proto oncogene
Growth factors eg IGF
Growth factor receptors
Eg erb-2, ret
Signal transducing
factors
Eg cytoplasmic
kinases
cell cycle
proteins eg
cyclin D
DNA binding
proteins
concerned with
transcription
Proto-oncogenes
FUNCTION OF ONCOGENES
•
•
Cancers have characteristics that indicate, at cellular
level, loss of the normal function of oncogene products
consistent with a role in the control of cellular
proliferation and differentiation in the process known as
signal transduction. It is a complex multistep pathway
from the cell membrane, through the cytoplasm to the
nucleus.
Proto oncogenes have been highly conserved during
evolution, and the protein products they encode are
likely to have essential biological functions.
Oncogenes Are Mutated
Proto-oncogenes
A cell can acquire a cancer causing oncogene from
 A virus
 A mutation in a proto-oncogene
Oncogenes still code for the proteins needed for
cell division but they cause cancer by producing
 Increased In growth factor
 Increased In growth factor receptors
 Increased in signal transduction
 Increase in activation of transcription
Cancer causing Mutations
Proto-oncogenes form oncogenes by
• being misplaced (e.g. by translocation) to a site where the
gene is continually expressed resulting in overproduction
of a protein that stimulates cell division (e.g. in CML*)
• By mutating to a form that is over expressed.
Mutations in Tumor Suppressor genes cause cancer by
inactivating the genes.
Tumor-suppressor genes
BIOLOGICAL FUNCTIONS OF TUMOR
SUPPRESSOR GENES
1. Growth Inhibitors (e.g., TGF-β; glucocortocoids)
2. Growth Inhibitor Receptors
3. Signal Transduction Protein Inhibitors
4. Transcription Factors of Growth Inhibitors
Tumor-suppressor genes
Geneproducts which are normaly responsible for
negative controll of transcription and proliferation
Examples:
 pRb inhibits transcription factors of the E2F-family,
which are needed to get into the S-Phase of the cell
cycle (Restriction Point)
 p53 induces transcription of the CDK-inhibitor (CDI)
p21 which causes a cell cycle arrest (one function)
 p53 is found upregulated in cells with a high level of
DNA damage
Tumor-suppressor genes
RETINOBLASTOMA
•
•
Retinoblastoma (Rb) is a relatively rare, highly
malignant childhood cancer of the developing retinal
cells of the eye that usually occurs before the age of 5
years.
Rb can occur either sporadically (non-hereditary form,
ussually involve only one eye), or be familial
(hereditary form, more commonly bilateral), which is
inherited in an AD manner, and also tend to present
at an earlier age.
Retinoblastoma
The p53 Tumor Suppressor
Protein
The p53 tumor suppressor protein is activated when DNA
is damaged. The p53 gene is called the “guardian angel
of the genome”
P53 activates genes
for proteins that
 Prevent cell
entering S phase
 Repair DNA
 Cause apoptosis
(if DNA is
irreparable)
DNA Stability Genes
Monitor and maintain the integrity of the
DNA.
Loss of function promotes mutations
Detection of DNA lesions decreased
 Repair of damage decreased or improper
 Decreased apoptosis

Routes to Genetic Instability
based on Defective DNA Repair
Carcinogenesis
Hypotheses of the Origin of Neoplasia
2 – Viral Oncogene Hypothesis
 RNA Retrovirus – produces DNA provirus
DNA provirus containing viral oncogene (v-onc) is
introduced, or
 DNA provirus without v-onc is inserted adjacent to
c-onc in host cell DNA
 RNA viruses is thought to have acquired v-onc
sequence by recombinant mechanism from animal
cells


DNA virus
Do not contain viral oncogenes
 Act by blocking suppressor gene products
 Examples – HPV, EBV,HBV

Carcinogenesis
Hypotheses of the Origin of Neoplasia
3 – Epigenetic Hypothesis
 Changes
in the regulation of gene
expression rather than in the genetic
apparatus
 Pattern of gene expressions responsible
for tissue differentiation (ie. epigenetic
mechanism) are thought to be heritable
Carcinogenesis
Hypotheses of the Origin of Neoplasia
4 – Failure of Immune Surveillance
 Concepts
 Neoplastic
changes frequently occur in
cells
 Altered DNA result in production of
neoantigens & tumor-associated antigens
 Immune response (cytotoxic) to
neoantigens as foreign antigens
 Neoplastic cells escaping recognition and
destruction become clinical cancers
Causes of Neoplasia
Environmental causes: (Carcinogens)
Chemicals
Viruses
Radiation
Hereditary causes- Genetic defects.
Combination – common.
Obscure defects
Carcinogenesis:
Chemical Carcinogenesis:
Initiation
 DNA damage eg.Benzpyrene
Promotion
 Histologic change – eg.
Turpentine (co-carcinogens)
Malignant transformation:
 Visible tumor formation –
further DNA damage.
Chemical Carcinogenesis:
Direct Acting Carcinogens:

Alkylating Agents: Cyclophosphamide
Procarcinogenes (needs activation)
Polycyclic hydrocarbons – Benzpyrene
 Aromatic amines, dyes - Benzidine
 Natural products: Aflatoxin
 Others: Vinyl chloride, turpentine etc.

Viral Oncogenesis:
Insertion of viral nucleic acids  mutation
Alterations in Oncogenes, cancer
suppressor genes and genes regulating
DNA repair resulting in up-regulation of cell
division  Carcinogenesis.
Nobel Laureates – Varmus and Bishop
v-fes, v-sis  proto-oncogenes.
 v-sis  sis  PDGF  Brain tumours.

Viral Oncogenesis:
Human Papilloma Virus

Cervical neoplasia – warts, papilloma, ca cx
Epstein-Barr virus –

Burkitts Lymphoma, Nasopharyngeal ca.
Hepatitis B & C virus

Hepatocellular carcinoma.
Radiation Carcinogenesis:
Ionizing radiation  dysjunction 
random fusion  mutation.
Neoplasia
Mutations
X Ray workers – Leukemia
Radio-isotopes – Thyroid carcinoma
Atomic explosion – Skin cancer, Leukemia
Clinical Manifestations of Cancer
Tissue Integrity
 Compressed and eroded blood vessels,
ulceration and necrosis, frank bleeding, and
hemorrhage
Cancer Cachexia
 Weight loss and wasting of body fat and
muscle tissue; profound weakness, anorexia,
and anemia
Paraneoplastic Syndromes
 Manifestations in sites not directly affected by
the disease
Molecular Basis of Neoplasia:
Proto-oncogene
Oncogene
Multiple Genetic Changes
Cause Cancer
Multiple Hits and Multiple Factors

Knudson proposed that carcinogenesis requires 2 hits

1st event – initiation


2nd event – promotion


Agent = promoter
Multiple hits occur – 5 or more


Carcinogen = initiator
Each hit produces a change in the genome which is
transmitted to its progeny (ie. clone)
Lag period


Time between exposure (first hit) and development of clinically
apparent cancer
Altered cell shows no abnormality during lag period
Multiple Genetic Changes
Cause Cancer
Multi-step Theory
Initiation
Promotion
Progression
Overview of Carcinogenesis