This document discusses fundamentals of cancer including what cancer is, causes of cancer, types of cancer, and hallmarks of cancer. Specifically, it states that cancer is caused by changes in gene expression leading to uncontrolled cell growth and proliferation. The main causes of cancer discussed are physical carcinogens like radiation, chemical carcinogens, and viral infections. The two main types of cancer are leukemias/lymphomas and solid tumors which can be carcinomas or sarcomas. Hallmarks of cancer include self-sufficient growth signals, evading cell death, unlimited replication, induced angiogenesis, and metastasis.

1. Fundamentals of Cancer
Dr. Rama Rao Malla
Head, Dept. of Biochemistry
Institute of Science
GITAM University

2. What is cancer ? Cancer is an abnormal growth of
cells caused by multiple changes in
gene expression
leading to
deregulation of cell
proliferation and cell death
Evolving cell population can invade
adjacent tissues and metastasize to
distant sites
promote the growth of new
blood vessels from which
the cells derive
nutrients.
Causing significant morbidity and,
if untreated, death of the host

3. Cancer are usually derived from a
single abnormal cell
Cancerous (malignant) cells can
develop from any tissue within the
body
Cancerous cells grow and multiply,
form a mass of cancerous tissue—
called a tumor
Tumors can be cancerous or
noncancerous.
Cancerous cells from the primary
(initial) site can spread throughout
the body (metastasize).
Over view

4. General Etiology and
Pathogenesis

5. Cancer is a complex group of diseases
with many possible causes.
Etiology is the study of causes of a
disease
It is suggested that every living
organism has some inactive cancer-
causing genes called proto-oncogenes.
A number of physical, chemical or
biological agents are known to mutate
and activate these proto-oncogenes into
active and cancer causing oncogenes.
Due to altered gene activity, normal
control mechanism is lost and the
abnormal cell growth and cell division
take place.
The physical, chemical and biological
agents, which induce cancer growth, are
called carcinogens.
Etiology of Cancer or
Causes of cancer

6. Ionising radiations like X-rays,
gamma-rays and particulate
radiations from radioactive
substances are known to break DNA
strands and induce mutations to
cause cancers
e.g., excessive exposure to sunlight
stimulate the development of skin
cancer
The evidence of carcinogenic effect of
X-rays is the incidence of leukemia
in radiologists
Japanese people are exposed to
radiations during World War II
nuclear explosions and showed the
incidence of leukemia.
Carcinogens:
Physical agents

7. Ultraviolet light (UV) (non-ionizing
radiation).
Two nucleotide bases in DNA—
cytosine and thymine—are most
vulnerable to radiation that can
change their properties.
UV light can induce
adjacent pyrimidine bases in a DNA
strand to become covalently joined as
a pyrimidine dimer.
UV radiation, in particular longer-
wave UVA, can also cause oxidative
damage to DNA

8. Chemical agents like caffein, polycyclic
hydrocarbons, heavy metallic ions etc.
are also carcinogenic.
Hormones like testosterone and
estrogens are known to cause prostate
and breast cancer respectively.
Chewing of beetles is known to cause
mouth cancer.
Cigarette and cigar tobacco smoking
causes lip, mouth and lung cancers due
to presence of a carcinogenic agent,
benzpyrene and N-nitroso-dimethylene.
Dye workers have a high rate of bladder
cancer.
Recently high carbohydrate foods like
potato chips and French fries are
reported to cause cacner due to
formation of carcinogenic chemical,
called acrylamide by heating
Carcinogens:
chemical agents

9. Direct-acting
Direct-acting carcinogens are already
electrophilic
Electrophilic (electron-seeking)
molecules will bind to nucleophilic
(electron-rich) macromolecules in the
cell
DNA, RNA. Proteins
e.g. Nitrogen mustard,
Nitrosomethylurea
Benzyl chloride
Indirect-acting carcinogens are
metabolically activated into
electrophilic species
e.g. Polycyclic aromatic hydrocarbons
(PAH)
Produced by incomplete combustion of
organic materials
Present in chimney soot, charcoal-
grilled meats, auto exhaust, cigarette
smoke
Carcinogens:
Types of chemical carcinogens

10. Viral infections account for an
estimated one in seven human cancers
worldwide
Majority of these are due to infection
with two DNA viruses
HBV - linked to hepatocellular
carcinoma
HPV - linked to cervical carcinoma
Very small viruses
Can integrate their viral DNA into host
genome
They code for viral proteins which block
tumor suppressor proteins in cells
Carcinogens:
Viral Carcinogens:

11. It contains 70% of proteins
Diet, physical inactivity, and obesity
are related to approximately 30–
35% of cancer deaths.
Physical inactivity is believed to
contribute to cancer risk not only
through its effect on body weight
but also through negative effects on
immune system and endocrine
system.
Diets that are low in vegetables,
fruits and whole grains, and high
processed or red meats are linked
with a number of cancers.
A high-salt diet is linked to gastric
cancer, aflatoxin B1, a frequent food
contaminate, with liver cancer, and
Betel nut chewing with oral cancer.
Carcinogens:
Diet and exercise:

12. Cancerous tissues (malignancies) can
be divided into two types
Cancer from blood, blood-forming
tissues and cells of the immune system
e.g. leukemias and lymphomas
Leukemias arise from blood-forming
cells and crowd out normal blood cells
in the bone marrow and bloodstream.
Cancer cells from lymphomas expand
lymph nodes, producing large masses
in the armpit, abdomen or chest.
Types of cancer:
leukemias and
lymphomas

13. Solid tumors are solid mass of cells
often termed as cancer
Cancers can be carcinomas or
sarcomas.
Carcinomas are cancers of cells that
line the skin, lungs, digestive tract, and
internal organs.
e.g. skin, lung, colon, stomach, breast,
prostate, and thyroid gland.
Typically, carcinomas occur more often
in older than in younger people.
Types of cancer:
Solid tumors:
Carcinomas:

14. Sarcomas are cancers of mesodermal
cells.
Mesodermal cells normally form
muscles, blood vessels, bone, and
connective tissue.
e.g. Leiomyosarcoma - cancer of smooth
muscle that is found in the wall of
digestive organs and osteosarcoma -
bone cancer.
Typically, sarcomas occur more often in
younger than in older people.
Types of cancer:
Solid tumors:
Sarcomas :

15. Normal cells grow and divide, but
have many controls on that growth.
They only grow when stimulated by
growth factors.
If they are damaged, a molecular
brake stops them from dividing
until they are repaired.
If they can't be repaired, they
commit cell suicide (apoptosis).
They can only divide a limited
number of times.
They are part of a tissue structure,
and remain where they belong.
They need a blood supply to grow.
Hall marks of
cancer:

16. Several mechanisms are required to
transform normal cell to cancer cell.
This occurs in a series of steps, which
Hanahan and Weinberg refer to as
hallmarks.
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Evading apoptosis
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis
Each mechanism is controlled by
several proteins.
These proteins become non-functional
or malfunctioning when the DNA
sequence of their genes is damaged
through acquired or somatic mutations.
Hall marks of
cancer:

17. Normal cells require external growth
signals to grow and divide.
These signals are transmitted through
receptors that pass through the cell
membrane.
When the growth signals are absent,
they stop growing.
Cancer cells can grow and divide
without external growth signals. Some
cancer cells can generate their own
growth signals.
E.g. glioblastomas produce platelet-
derived growth factor and sarcomas can
produce tumor growth factor α (TGF-
α).
Receptors are overexpressed.
E.g. Epidermal growth factor receptor
is overexpressed in stomach, brain and
breast cancers,
HER2 receptor is overexpressed in
stomach and breast cancer.
Hall marks of cancer:
Self-sufficiency in
growth signals

18. Growth of normal cells is controlled by
growth inhibitors present in the
surrounding environment or in the
extracellular matrix or on the surfaces
of neighboring cells.
These inhibitors act on the cell cycle by
interrupting cell division (mitosis) in
the interphase.
The growth inhibitor signals prevents
transition from (G1) to S.
Cancer cells are generally resistant to
growth-preventing signals from their
neighbours.
Hall marks of cancer:
Insensitivity to anti-
growth signals

19. Apoptosis is a form of programmed cell
death, the mechanism by which cells
are programmed to die
By apoptotic mechanism mutant cells
are continually removed.
The apoptotic machinery monitor the
cell for abnormal behavior.
e.g. Survival signals and their receptors
monitor DNA damage, oncogene
overexpression, and low oxygen
(hypoxia).
The p53 tumor suppressor protein
elicits apoptosis in response to DNA
damage, and is a major mechanism of
cancer control.
Cancer cells are characteristically able
to bypass this mechanism.
Hall marks of cancer:
Evading apoptosis

20. Non-cancer cells die after a certain
number of divisions.
Cells have an intrinsic program,
which limits division to 60–70
doublings and reach senescence.
The counting device for cell doublings
is the telomere, which decreases in
size (loses nucleotides at the ends of
chromosomes) during each cell cycle.
Most tumor cells are immortalized.
Cancer cells escape this limit,
indefinitely grow and divide.
This limit can be overcome by
disabling p53 tumor suppressor
proteins
Many cancers involve the
upregulation of telomerase, the
enzyme that maintains telomeres.
Hall marks of cancer:
Limitless replicative
potential

21. Angiogenesis is the process by which
new blood vessels are formed.
Angiogenesis is involved in the growth
of cervix, breast and melanoma
tumors.
In order to progress, they must
develop a blood supply.
New blood vessels continuously
supply of oxygen and other nutrients.
Angiogenesis is balanced by inducers
and inhibitors.
Inducers include vascular endothelial
growth factor (VEGF) and acetic and
basic fibroblast growth factor (FGF
1/2)
Inhibitor is thrombospondin-1
Hall marks of cancer:
Sustained angiogenesis

22. Cancer cells can break away from
their site or organ of origin to invade
surrounding tissue and spread
(metastasize) to distant body parts.
It involves cell adhesion molecules
(CAMs) , integrins, E-cadherin and
Matrix-degrading proteases.
Specific mutations activate ability of
cells to metastasize
Ex. decreased cell to cell adhesion,
secretion of preteases that digest
surrrounding barriers, and ability to
grow in new locations
Hall marks of cancer:
Tissue invasion and
metastasis

23. Genome instability (also “genetic
instability” or “genomic instability”)
refers to a high frequency of
mutations within the genome of a
cellular lineage.
These mutations can include changes
in nucleic acid sequences,
chromosomal rearrangements or
aneuploidy.
Genome instability is central to
carcinogenesis.
e.g. High frequency of externally
caused DNA damage
Reductions in expression of DNA
repair genes
Endogenous DNA damage is very
frequent, occurring on average more
than 60,000 times in human cells, any
reduced DNA repair is likely an
important source of genome
instability.
Genome instability :
Introduction

24. Chromosomal instability:
It involves chromosome abnormalities
like deletion and duplication of
chromosomes or chromosome parts,
chromosome rearrangements and
mitotic recombination
Microsatillite instability :
It is characterized by increased rate
of small scale genetic changes
Several colorectal and gastric cancer
syndromes are known to have defects
in the replication of short tandem
repeat sequences (microsatellite
sequences), known
as microsatellite instability.
Mechanism of genomic instability is
related to cell cycle regulation, DNA
damage and repair. Cell aging and
telomere function
Genome instability (GI) :
Types

25. Genomic instability is caused by
cellular metabolism
routine errors in DNA
replication
recombination.
In addition, exogenous genotoxic
agents, such as
ultraviolet light,
oxidative stress
chemical mutagens, can lead
to a range of nucleotide modifications
and DNA breaks.
Genome instability (GI) :
Factors affecting
genomic instability
Telomere dysfunction and
genomic instability
One of the important source of genomic instability is telomere shortenin

26. Base and nucleotide excision repair
Excise & Repair abnormal bases or
nucleotides, such as UV radiation
induced pyrimidine dimers
Mutations in components of these pathways : Cause genomic instability
Genomic instability (GI)
:
Main pathways
Mismatch repair (MMR)
during DNA replication
Loss of function of MSH2 and MLH1, which are required for mismatch repair,
results in hypermutation and microsatellite instability

27. DNA replication
Deregulated DNA replication
Deregulation can occur through oncogene activation , loss of certain tumour
suppressors, DNA polymerase inhibition , replication stress
Double-strand break repair (DSBR)
Homologous recombination repair of double-strand breaks (DSBs) uses
the sister DNA molecule as a template to repair the break
Defect in recombination leads to
chromosomal instability