PAPER III

UNIT-1

NATURE OF CANCER

Content

UNIT

CONTENT
NORMAL CELL BIOLOGY

BIOLOGY OF CANCER CELLS

1
PATHOLOGICAL & PATHOPHYSIOLOGICAL CHANGES
IN CANCEROUS TISSUE

STRUCTURE OF SOLID TUMOUR

PRODUCTS PRODUCED BY TUMOUR CELLS

GENERAL OBJECTIVES
At the end of the class doctoral student will be able to Expain about nature of
cancer and develop desirable skills while practising in clinical area.

SPECIFIC OBJECTIVES
At end of this chapter doctoral student will be able to
Explain about normal cell biology
Brief about biology of cancer cells.
Discuss about pathological and pathophysiological changes in cancerous
tissue
Enumerate about structure of solid tumour
Enlist about products produced by tumour cells

1.NORMAL CELL BIOLOGY

1.1Cell Division:
All cells are derived from pre existing cells (Cell Theory)
Cell division is the process by which cells produce new cells

 Cell division differs in prokaryotes (bacteria) and eukaryotes (protists,

xfungi, plants, & animals)
Some tissues must be repaired often such as the lining of gut, white blood
cells, skin cells with a short lifespan
Other cells do not divide at all after birth such as muscle & nerve 1
Reasons for Cell Division:
Cell growth
Repair & replacement of damaged cell parts
Reproduction of the species
Copying DNA:
Since the instructions for making cell parts are encoded in the DNA, each
new cell must get a complete set of the DNA molecules
This requires that the DNA be copied (replicated, duplicated) before cell
division1

FIGURE1:STRUCURE OF DNA
1.2Chromosomes & Their Structure:
The plans for making cells are coded in DNA
DNA, deoxyribose nucleic acid, is a long thin molecule that stores
genetic information
DNA in a human cell is estimated to consist of six billion pairs
of nucleotides
DNA is organized into giant molecules called chromosomes
Chromosomes are made of protein & a long, single, tightly-coiled
DNA molecule visible only when the cell divides

When a cell is not dividing the DNA is less visible & is called chromatin

 DNA in eukaryotic cells wraps tightly around proteins called histones to

help pack the DNA during cell division
Non histone proteins help control the activity of specific DNA genes
Kinetochore proteins bind to centromere and attach chromosome to the
spindle in mitosis
Centromeres hold duplicated chromosomes together before they are
separated in mitosis
Telomeres are the ends of chromosomes which are important in cell aging
When DNA makes copies of itself before cell division, each half of the
chromosome is called a sister chromatid 1

FIGURE2:CHROMATID

DNA of prokaryotes (bacteria) is one, circular chromosome attached to

the inside of the cell membrane

1.3Chromosome Numbers:
Humans somatic or body cells have 23 pairs of chromosomes or 46
chromosomes (diploid or 2n number)
The 2 chromatids of a chromosome pair are called homologues (have
genes for the same trait at the same location)

FIGURE3 :Homologs
Human reproductive cells or gametes (sperms & eggs) have one set or 23
chromosomes (haploid or n number)
Every organism has a specific chromosome number1

Organism
Human
Fruit fly
Lettuce
Goldfish

Chromosome
Number (2n)
46
8
14
94

TABLE1: NUMBER OF CHROMOSOME

 Fertilization, joining of the egg & sperm, restores the diploid

chromosome number in the zygote (fertilized egg cell)
Sex chromosomes, either X or Y, determine the sex of the organism
Two X chromosomes, XX, will be female and XY will be male
All other chromosomes, except X & Y, are called autosomes
Chromosomes from a cell may be arranged in pairs by size starting with
the longest pair and ending with the sex chromosomes to make
a karyotype
A human karyotype has 22 pairs of autosomes and 1 pair of sex
chromosomes (23 total)

FIGURE4 :Human Male Karyotype

Genes:
A section of DNA which codes for a protein is called a gene
Each gene codes for one protein
Humans have approximately 50,000 genes or 2000 per chromosome
About 95% of the DNA in chromosome is "junk" that does not code for
any proteins1
1.4CELL CYCLE:
Cells go through phases or a cell cycle during their life before they divide
to form new cells
The cell cycle includes 2 main parts --- interphase, and cell division

\
FIGURE5: CELL CYCLE

 Cell division includes mitosis (nuclear division) and cytokinesis (division

of the cytoplasm)
Interphase is the longest part of a cell's life cycle and is called the "resting
stage" because the cell isn't dividing
Cells grow, develop, & carry on all their normal metabolic
functions during interphase
Interphase consists of 3 parts --- G1, S, & G2phases
Interphase:
G1 or 1st Growth Phase occurs after a cell has undergone cell division
Cells mature & increase in size by making more cytoplasm & organelles
while carrying normal metabolic activities in G1
S or Synthesis Phase follows G1 and the genetic material of the
cell (DNA) is copied or replicated
G2 or 2nd Growth Phase occurs after S Phase and the cell makes all
the structures needed to divide1
1.5Cell division in Prokaryotes:
Prokaryotes such as bacteria do not have a nucleus
Prokaryotes divide into two identical new cells by the process of binary
fission
Binary fission is an asexual method of reproduction

 In binary fission, the chromosome, attached to cell membrane, makes a

copy of itself and the cell grows to about twice its normal size
Next, a cell wall forms between the chromosomes & the parent cell
splits into 2 new identical daughter cells (clones)

FIGURE6: Cell division in Prokaryotes

1.6Cell Division in Eukaryotes:

Eukaryotes have a nucleus & membrane-bound organelles which must be
copied exactly so the 2 new cells formed from division will be exactly
alike
The original parent cell & 2 new daughter cells must
have identical chromosomes

 DNA is copied in the S phase of the cell cycle & organelles, found in the
cytoplasm, are copied in the Growth phases
Both the nucleus (mitosis) and the cytoplasm (cytokinesis) must be
divided during cell division in eukaryotes
1.7 Stages of Mitosis:
Division of the nucleus or mitosis occurs first
Mitosis is an asexual method of reproduction
Mitosis consists of 4 stages --- Prophase, Metaphase, anaphase, &
Telophase1

FIGURE 7:Stages of Mitosis

Prophase:
o Chromosomes become visible when they condense into sister
chromatids

o Sister chromatids attach to each other by the centromere

o Centrioles in animal cells move to opposite ends of cell
o Spindle forms from centriole (animals) or microtubules (plants)
o Kinetochore fibers of spindle attach to centromere
o Polar fibers of spindle extend across cell from pole to pole
o Nuclear membrane dissolves
o Nucleolus disintegrates
Metaphase:
o Chromosomes line up in center or equator of the cell attached to
kinetochore fibers of the spindle
Anaphase:
o Kinetochore fibers attached to the centromere pull the sister
chromatids apart
o Chromosomes move toward opposite ends of cell
Telophase:
o Nuclear membrane forms at each end of the cell around the
chromosomes
o Nucleolus reform

o Chromosomes become less tightly coiled & appear as chromatin

again
o Cytokinesis begins1

1.8 Summary of Mitosis:

Interphase

Early Prophase

1. Cell matures & carries on normal

1. Chromosomes condense &

activities
2. DNA copied & appears as
chromatin

become visible
2. Centrioles separate &
spindle starts forming

3. Nucleolus visible

Late Prophase

Metaphase

1. Spindle forms with aster at each

pole

1. Chromosomes line up at the

2. Nuclear membrane &

nucleolusdisintegrate
3. Centromere of chromosomes

equator of the cell attached

to kinetochore fibers of
spindle

attaches to spindle fibers

Telophase/Cytokinesis
Anaphase

1. Nuclear membrane &

nucleolus reform

1. Centromeres split apart

2. Cell pinches into 2 cells in
2. Homologs move to opposite poles

animals

of the cell
3. In plants, a cell plate
separates the 2 new cells
FIGURE 8:MITOSIS
1.9 Cancer is Uncontrolled Mitosis:
Mitosis must be controlled, otherwise growth will occur without limit
(cancer)
Control is by special proteins produced by oncogenes

 Mutations in control proteins can cause cancer.1

2.BIOLOGY OF CANCER CELLS
The abnormalities in cancer cells usually result from mutations in proteinencoding genes that regulate cell division. Over time more genes become
mutated. This is often because the genes that make the proteins that normally
repair DNA damage are themselves not functioning normally because they are
also mutated. Consequently, mutations begin to increase in the cell, causing
further abnormalities in that cell and the daughter cells. Some of these mutated
cells die, but other alterations may give the abnormal cell a selective advantage
that allows it to multiply much more rapidly than the normal cells. This
enhanced growth describes most cancer cells, which have gained functions
repressed in the normal, healthy cells. As long as these cells remain in their
original location, they are considered benign; if they become invasive, they are
considered malignant. Cancer cells in malignant tumors can often metastasize,
sending cancer cells to distant sites in the body where new tumors may form. 4
2.1Genetics of Cancer

Only a small number of the approximately 35,000

genes in the human genome have been associated with cancer. Alterations in the
same gene often are associated with different forms of cancer. These
malfunctioning genes can be broadly classified into three groups.
The first group, called proto-oncogenes, produces protein products that
normally enhance cell division or inhibit normal cell death. The mutated
forms of these genes are called oncogenes.
The second group, called tumor suppressors, makes proteins that
normally prevent cell division or cause cell death.
The third group contains DNA repair genes, which help prevent
mutations that lead to cancer.

Proto-oncogenes and tumor suppressor genes work much like the accelerator
and brakes of a car, respectively. The normal speed of a car can be maintained
by controlled use of both the accelerator and the brake. Similarly, controlled cell
growth is maintained by regulation of proto-oncogenes, which accelerate
growth, and tumor suppressor genes, which slow cell growth. Mutations that
produce oncogenes accelerate growth while those that affect tumor suppressors
prevent the normal inhibition of growth. In either case, uncontrolled
cell growth 4

2.2 Oncogenes and Signal Transduction

In normal cells, proto-oncogenes code for the proteins that send a signal to the
nucleus to stimulate cell division. These signaling proteins act in a series of
steps called signal transduction cascade or pathway . This cascade includes a
membrane receptor for the signal molecule, intermediary proteins that carry the
signal through the cytoplasm, and transcription factors in the nucleus that
activate the genes for cell division. In each step of the pathway, one factor or
protein activates the next; however, some factors can activate more than one
protein in the cell. Oncogenes are altered versions of the proto-oncogenes that
code for these signaling molecules. The oncogenes activate the signaling
cascade continuously, resulting in an increased production of factors that
stimulate growth. For instance, MYC is a proto-oncogene that codes for a
transcription factor. Mutations in MYC convert it into an oncogene associated
with seventy percent of cancers. RAS is another oncogene that normally
functions as an on-off switch in the signal cascade. Mutations in RAS cause
the signaling pathway to remain on, leading to uncontrolled cell growth.

About thirty percent of tumors including lung, colon, thyroid, and pancreatic
carcinomas have a mutation in RAS.4
Signal transduction pathway.
A signal (in this example, a growth factor) binds to a tyrosine kinase receptor
on the outside of the cell. This activates the membrane protein (through the
addition of phosphate groups), which in turn activates proteins, such as kinases,
in the cytoplasm. Several other proteins may be involved in the cascade,
ultimately activating one or more transcription factors. The activated
transcription factors enter the nucleus where they stimulate the expression of the
genes that are under the control of that factor. This is an example of the RAS
pathway, which results in cell division.
The conversion of a proto-oncogene to an oncogene may occur by mutation of
the proto-oncogene, by rearrangement of genes in the chromosome that moves
the proto-oncogene to a new location, or by an increase in the number of copies
of the normal proto-oncogene. Sometimes a virus inserts its DNA in or near the
proto-oncogene, causing it to become an oncogene. The result of any of these
events is an altered form of the gene, which contributes to cancer. mutations that
convert protooncogenes into oncogenes result in an accelerator stuck to the
floor, producing uncontrolled cell growth.4
Most oncogenes are dominant mutations; a single copy of this gene is sufficient
for expression of the growth trait. This is also a gain of function mutation
because the cells with the mutant form of the protein have gained a new
function not present in cells with the normal gene. If your car had two
accelerators and one were stuck to the floor, the car would still go too fast, even
if there were a second, perfectly functional accelerator. Similarly, one copy of
an oncogene is sufficient to cause alterations in cell growth. The presence of an

oncogene in a germ line cell (egg or sperm) results in an inherited

predisposition for tumors in the offspring. However, a single oncogene is not
usually sufficient to cause cancer, so inheritance of an oncogene does not
necessarily result in cancer.
2.3Tumor Suppressor Genes The proteins made by tumor suppressor genes
normally inhibit cell growth, preventing tumor formation. Mutations in these
genes result in cells that no longer show normal inhibition of cell growth and
division. The products of tumor suppressor genes may act at the cell membrane,
in the cytoplasm, or in the nucleus. Mutations in these genes result in a loss of
function (that is, the ability to inhibit cell growth) so they are usually recessive.
This means that the trait is not expressed unless both copies of the normal gene
are mutated. Using the analogy to a car, a mutation in a tumor suppressor gene
acts much like a defective brake: if your car had two brakes and only one was
defective, you could still stop the car
How is it that both genes can become mutated? In some cases, the first mutation
is already present in a germ line cell (egg or sperm); thus, all the cells in the
individual inherit it. Because the mutation is recessive, the trait is not expressed.
Later a mutation occurs in the second copy of the gene in a somatic cell. In that
cell both copies of the gene are mutated and the cell develops uncontrolled
growth. An example of this is hereditary retinoblastoma, a serious cancer of the
retina that occurs in early childhood. When one parent carries a mutation in one
copy of the RB tumor suppressor gene, it is transmitted to offspring with a fifty
percent probability. About ninety percent of the offspring who receive the one
mutated RB gene from a parent also develop a mutation in the second copy of
RB, usually very early in life. These individuals then develop retinoblastoma.
Not all cases of retinoblastoma are hereditary: it can also occur by mutation of
both copies of RB in the somatic cell of the individual. Because retinoblasts are
rapidly dividing cells and there are thousands of them, there is a high incidence

of a mutation in the second copy of RB in individuals who inherited one

mutated copy. This disease afflicts only young children because only individuals
younger than about eight years old. have retinoblasts. In adults, however,
mutations in RB may lead to a predisposition to several other forms of cancer. 4
Three other cancers associated with defects in tumor suppressor genes include
familial adenomatous polyposis of the colon (FPC), which results from
mutations to both copies of the APC gene; hereditary breast cancer, resulting
from mutations to both copies of BRCA2; and hereditary breast and ovarian
cancer, resulting from mutations to both copies of BRCA1. While these
examples suggest that heredity is an important factor in cancer, the majority of
cancers are sporadic with no indication of a hereditary component. Cancers
involving tumor suppressor genes are often hereditary because a parent may
provide a germ line mutation in one copy of the gene. This may lead to a higher
frequency of loss of both genes in the individual who inherits the mutated copy
than in the general population. However, mutations in both copies of a tumor
suppressor gene can occur in a somatic cell, so these cancers are not always
hereditary. Somatic mutations that lead to loss of function of one or both copies
of a tumor suppressor gene may be caused by environmental factors, so even
these familial cancers may have an environmental component. DNA Repair
Genes A third type of gene associated with cancer is the group involved in DNA
repair and maintenance of chromosome structure. Environmental factors, such
asionizing radiation, UV light, and chemicals, can damage DNA. Errors in DNA
replication can also lead to mutations. Certain gene products repair damage to
chromosomes, thereby minimizing mutations in the cell. When a DNA repair
gene is mutated its product is no longer made, preventing DNA repair and
allowing further mutations to accumulate in the cell. These mutations can
increase the Cell Biology and Cancer 5 Table 1. Some Genes Associated4

2.4DNA Repair Genes A third type of gene associated with cancer is the group
involved in DNA repair and maintenance of chromosome structure.
Environmental factors, such asionizing radiation, UV light, and chemicals, can
damage DNA. Errors in DNA replication can also lead to mutations. Certain
gene products repair damage to chromosomes, thereby minimizing mutations in
the cell. When a DNA repair gene is mutated its product is no longer made,
preventing DNA repair and allowing further mutations to accumulate in the cell.
These mutations can increase the frequency of cancerous changes in a cell. A
defect in a DNA repair gene called XP (Xeroderma pigmentosum) results in
individuals who are very sensitive to UV light and have a thousand-fold
increase in the incidence of all types of skin cancer. There are seven XP genes,
whose products remove DNA damage caused by UV light and other
carcinogens. Another example of a disease that is associated with loss of DNA
repair is Bloom syndrome, an inherited disorder that leads to increased risk of
cancer, lung disease, and diabetes. The mutated gene in Bloom syndrome, BLM,
is required for maintaining the stable structure of chromosomes. Individuals
with Bloom syndrome have a high frequency of chromosome breaks and
interchanges, which can result in the activation of oncogenes.
Cancer cells do not stop dividing, so what stops a normal cell from dividing? In
terms of cell division, normal cells differ from cancer cells in at least four ways.
Normal cells require external growth factors to divide. When synthesis of
these growth factors is inhibited by normal cell regulation, the cells stop
dividing. Cancer cells have lost the need for positive growth factors, so they
divide whether or not these factors are present. Consequently, they do not
behave as part of the tissue they have become independent cells.
Normal cells show contact inhibition; that is, they respond to contact with
other cells by ceasing cell division. Therefore, cells can divide to fill in a gap,

but they stop dividing as soon as there are enough cells to fill the gap. This
characteristic is lost in cancer cells, which continue to grow after they touch
other cells, causing a large mass of cells to form.
Normal cells age and die, and are replaced in a controlled and orderly manner
by new cells. Apoptosis is the normal, programmed death of cells. Normal cells
can divide only about fifty times before they die. This is related to their ability
to replicate DNA only a limited number of times. Each time the chromosome
replicates, the ends (telomeres) shorten. In growing cells, the enzyme
telomerase replaces these lost ends. Adult cells lack telomerase, limiting the
number of times the cell can divide. However, telomerase is activated in cancer
cells, allowing an unlimited number of cell divisions.
Normal cells cease to divide and die when there is DNA damage or when cell
division is abnormal. Cancer cells continue to divide, even when there is a large
amount of damage to DNA or when the cells are abnormal. These progeny
cancer cells contain the abnormal DNA; so, as the cancer cells continue to
divide they accumulate even more damaged DNA.
2.5What Causes Cancer? The prevailing model for cancer development is that
mutations in genes for tumor suppressors and oncogenes lead to cancer.
However, some scientists challenge this view as too simple, arguing that it fails
to explain the genetic diversity among cells within a single tumor and does not
adequately explain many chromosomal aberrations typical of cancer cells. An
alternate model suggests that there are master genes controlling cell division.
A mutation in a master gene leads to abnormal replication of chromosomes,
causing whole sections of chromosomes to be missing or duplicated. This leads
to a change in gene dosage, so cells produce too little or too much of a specific
protein. If the chromosomal aberrations affect the amount of one or more
proteins controlling the cell cycle, such as growth factors or tumor suppressors,

the result may be cancer. There is also strong evidence that the excessive
addition of methyl groups to genes involved in the cell cycle, DNA repair, and
apoptosis is characteristic of some cancers. There may be multiple mechanisms
leading to the development of cancer. This further complicates the difficult task
of determining what causes cancer.4
2.6Tumor Biology Cancer cells behave as independent cells, growing without
control to form tumors. Tumors grow in a series of steps.
The first step is hyperplasia, meaning that there are too many cells resulting
from uncontrolled cell division. These cells appear normal, but changes have
occurred that result in some loss of control of growth.
The second step is dysplasia, resulting from further growth, accompanied by
abnormal changes to the cells.
The third step requires additional changes, which result in cells that are even
more abnormal and can now spread over a wider area of tissue
These cells begin to lose their original function; such cells are called anaplastic.
At this stage, because the tumor is still contained within its original location
(called in situ) and is not invasive, it is not considered malignant it is
potentially malignant. The last step occurs when the cells in the tumor
metastasize, which means that they can invade surrounding tissue, including the
bloodstream, and spread to other locations. This is the most serious type of
tumor, but not all tumors progress to this point. Non-invasive tumors are said to
be benign. The type of tumor that forms depends on the type of cell that was
initially altered. There are five types of tumors.
Carcinomas result from altered epithelial cells, which cover the surface of our
skin and internal organs. Most cancers are carcinomas.

 Sarcomas result from changes in muscle, bone, fat, or connective tissue.

Leukemia results from malignant white blood cells.
Lymphoma is a cancer of the lymphatic system cells that derive from bone
marrow.
Myelomas are cancers of specialized white blood cells that make antibodies
2.7Angiogenesis Although tumor cells are no longer dependent on the control
mechanisms that govern normal cells, they still require nutrients and oxygen in
order to grow. All living tissues are amply supplied with capillary vessels,
which bring nutrients and oxygen to every cell. As tumors enlarge, the cells in
the center no longer receive nutrients from the normal blood vessels. To provide
a blood supply for all the cells in the tumor, it must form new blood vessels to
supply the cells in the center with nutrients and oxygen. In a process called
angiogenesis, tumor cells make growth factors which induce formation of new
capillary blood vessels. The cells of the blood vessels that divide to make new
capillary vessels are inactive in normal tissue; however, tumors make
angiogenic factors, which activate these blood vessel cells to divide. Without
the additional blood supplied by angiogenesis, tumors can grow no larger than
about half a millimeter.
Without a blood supply, tumor cells also cannot spread, or metastasize, to new
tissues. Tumor cells can cross through the walls of the capillary blood vessel at
a rate of about one million cells per day. However, not all cells in a tumor are
angiogenic. Both angiogenic and nonangiogenic cells in a tumor cross into
blood vessels and spread; however, non-angiogenic cells give rise to dormant
tumors when they grow in other locations. In contrast, the angiogenic cells
quickly establish themselves in new locations by growing and producing new
blood vessels, resulting in rapid growth of the tumor.

How do tumors begin to produce angiogenic factors? An oncogene called BCL2

has been shown to greatly increase the production of a potent stimulator of
angiogenesis. It appears, then, that oncogenes in tumor cells may cause an
increased expression of genes that make angiogenic factors. There are at least
fifteen angiogenic factors and production of many of these is increased by a
variety of oncogenes. Therefore, oncogenes in some tumor cells allow those
cells to produce angiogenic factors. The progeny of these tumor cells will also
produce angiogenic factors, so the population of angiogenic cells will increase
as the size of the tumor increases.
2.8Viruses and Cancer
Many viruses infect humans but only a few viruses are known to promote
human cancer. These include both DNA viruses and retroviruses, a type of RNA
virus. (See the HIV and AIDS unit.) Viruses associated with cancer include
human papillomavirus (genital carcinomas), hepatitis B (liver carcinoma),
Epstein-Barr virus (Burkitts lymphoma and nasopharyngeal carcinoma), human
T-cell leukemia virus (T-cell lymphoma); and, probably, a herpes virus called
KSHV (Kaposis sarcoma and some B cell lymphomas). The ability of
retroviruses to promote cancer is associated with the presence of oncogenes in
these viruses. These oncogenes are very similar to protooncogenes in animals.
Retroviruses have acquired the proto-oncogene from infected animal cells. An
example of this is the normal cellular c-SIS proto-oncogene, which makes a cell
growth factor. The viral form of this gene is an oncogene called v-SIS. Cells
infected with the virus that has v-SIS overproduce the growth factor, leading to
high levels of cell growth and possible tumor cells.4
Viruses can also contribute to cancer by inserting their DNA into a chromosome
in a host cell. Insertion of the virus DNA directly into a proto-oncogene may
mutate the gene into an oncogene, resulting in a tumor cell. Insertion of the

virus DNA near a gene in the chromosome that regulates cell growth and
division can increase transcription of that gene, also resulting in a tumor cell.
Using a different mechanism, human papillomavirus makes proteins that bind to
two tumor suppressors, p53 protein and RB protein, transforming these cells
into tumor cells. Remember that these viruses contribute to cancer, they do not
by themselves cause it. Cancer, as we have seen, requires several events.
Environmental Factors Several environmental factors affect ones probability
of acquiring cancer. These factors are considered carcinogenic agents when
there is a consistent correlation between exposure to an agent and the
occurrence of a specific type of cancer. Some of these carcinogenic agents
include X-rays, UV light, viruses, tobacco products, pollutants, and many other
chemicals. X-rays and other sources of radiation, such as radon, are carcinogens
because they are potent mutagens. Marie Curie, who discovered radium, paving
the way for radiation therapy for cancer, died of cancer herself as a result of
radiation exposure in her research. Tobacco smoke contributes to as many as
half of all cancer deaths in the U.S., including cancers of the lung, esophagus,
bladder, and pancreas. UV light is associated with most skin cancers, including
the deadliest form, melanoma. Many industrial chemicals are carcinogenic,
including benzene, other organic solvents, and arsenic. Some cancers associated
with environmental factors are preventable. Simply understanding the danger of
carcinogens and avoiding them can usually minimize an individuals exposure
to these agents. The effect of environmental factors is not independent of cancer
genes. Sunlight alters tumor suppressor genes in skin cells; cigarette smoke
causes changes in lung cells, making them more sensitive to carcinogenic
compounds in smoke. These factors probably act directly or indirectly on the
genes that are already known to be involved in cancer. Individual genetic
differences also affect the susceptibility of an individual to the carcinogenic
affects of environmental agents. About ten percent of the population has an

alteration in a gene, causing them to produce excessive amounts of an enzyme

that breaks down hydrocarbons present in smoke and various air pollutants. The
excess enzyme reacts with these chemicals, turning them into carcinogens.
These individuals are about twenty-five times more likely to develop cancer
from hydrocarbons in the air than others are.4

3.PATHOLOGICAL & PATHOPHYSIOLOGICAL CHANGES IN

CANCEROUS TISSUE
3.1Genetics
Cancer is fundamentally a disease of tissue growth regulation failure. In order
for a normal cell to transform into a cancer cell, the genes that regulate cell
growth and differentiation must be altered.5,6
The affected genes are divided into two broad categories. Oncogenes are genes
that promote cell growth and reproduction. Tumor suppressor genes are genes
that inhibit cell division and survival. Malignant transformation can occur
through the formation of novel oncogenes, the inappropriate over-expression of
normal oncogenes, or by the under-expression or disabling of tumor suppressor
genes. Typically, changes in manygenes are required to transform a normal cell
into a cancer cell.6
Genetic changes can occur at different levels and by different mechanisms. The
gain or loss of an entire chromosome can occur through errors inmitosis. More
common are mutations, which are changes in the nucleotide sequence of
genomic DNA.6

Large-scale mutations involve the deletion or gain of a portion of a

chromosome. Genomic amplification occurs when a cell gains many copies
(often 20 or more) of a small chromosomal locus, usually containing one or
more oncogenes and adjacent genetic material. Translocation occurs when two
separate chromosomal regions become abnormally fused, often at a
characteristic location.Small-scale mutations include point mutations, deletions,
and insertions, which may occur in the promoter region of a gene and affect
its expression, or may occur in the gene's coding sequence and alter the function
or stability of its protein product. Disruption of a single gene may also result
from integration of genomic material from a DNA virus or retrovirus, leading to
the expression of viral oncogenes in the affected cell and its descendants.5,6
Replication of the enormous amount of data contained within the DNA of living
cells will probabilistically result in some errors (mutations). Complex error
correction and prevention is built into the process, and safeguards the cell
against cancer. If significant error occurs, the damaged cell can "self-destruct"
through programmed cell death, termed apoptosis. If the error control processes
fail, then the mutations will survive and be passed along to daughter cells.5,6

Some environments make errors more likely to arise and propagate. Such
environments can include the presence of disruptive substances
calledcarcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.
The errors that cause cancer are self-amplifying and compounding, for example:

A mutation in the error-correcting machinery of a cell might cause that

cell and its children to accumulate errors more rapidly.

A further mutation in an oncogene might cause the cell to reproduce more

rapidly and more frequently than its normal counterparts.

A further mutation may cause loss of a tumor suppressor gene, disrupting

the apoptosis signalling pathway and resulting in the cell becoming
immortal.

A further mutation in signaling machinery of the cell might send errorcausing signals to nearby cells5,6

FIGURE9:CELL MUTATION
3.2 Epigenetics
Epigenetic alterations refer to functionally relevant modifications to the genome
that do not involve a change in the nucleotide sequence. Examples of such
modifications are changes in DNA methylation (hypermethylation and
hypomethylation) and histone modification and changes in chromosomal
architecture (caused by inappropriate expression of proteins such
as HMGA2 or HMGA1). Each of these epigenetic alterations serves to regulate

gene expression without altering the underlying DNA sequence. These changes
may remain through cell divisions, last for multiple generations, and can be
considered to be epimutations (equivalent to mutations).6
Epigenetic alterations occur frequently in cancers. As an example,
Schnekenburger and Diederich listed protein coding genes that were frequently
altered in their methylation in association with colon cancer. These included 147
hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes,
10 were hypermethylated in 100% of colon cancers, and many others were
hypermethylated in more than 50% of colon cancers.6
While large numbers of epigenetic alterations are found in cancers, the
epigenetic alterations in DNA repair genes, causing reduced expression of DNA
repair proteins, may be of particular importance. Such alterations are thought to
occur early in progression to cancer and to be a likely cause of
the genetic instability characteristic of cancers.6
Reduced expression of DNA repair genes causes deficient DNA repair. This is
shown in the figure at the 4th level from the top. (In the figure, red wording
indicates the central role of DNA damage and defects in DNA repair in
progression to cancer.) When DNA repair is deficient DNA damages remain in
cells at a higher than usual level (5th level from the top in figure), and these
excess damages cause increased frequencies of mutation and/or epimutation
(6th level from top of figure). Mutation rates increase substantially in cells
defective in DNA mismatch repair or in homologous recombinational repair
(HRR). Chromosomal rearrangements and aneuploidy also increase in HRR
defective cells.
Higher levels of DNA damage not only cause increased mutation (right side of
figure), but also cause increased epimutation. During repair of DNA double

strand breaks, or repair of other DNA damages, incompletely cleared sites of

repair can cause epigenetic gene silencing.
Deficient expression of DNA repair proteins due to an inherited mutation can
cause an increased risk of cancer. Individuals with an inherited impairment in
any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have
an increased risk of cancer, with some defects causing up to a 100% lifetime
chance of cancer (e.g. p53 mutations). Germ line DNA repair mutations are
noted in a box on the left side of the figure, with an arrow indicating their
contribution to DNA repair deficiency. However, such germline mutations
(which cause highly penetrant cancer syndromes) are the cause of only about 1
percent of cancers.6
In sporadic cancers, deficiencies in DNA repair are occasionally caused by a
mutation in a DNA repair gene, but are much more frequently caused by
epigenetic alterations that reduce or silence expression of DNA repair genes.
This is indicated in the figure at the 3rd level from the top. Many studies of
heavy metal-induced carcinogenesis show that such heavy metals cause
reduction in expression of DNA repair enzymes, some through epigenetic
mechanisms. In some cases, DNA repair inhibition is proposed to be a
predominant mechanism in heavy metal-induced carcinogenicity. In addition,
there are frequent epigenetic alterations of the DNA sequences coding for small
RNAs calledmicroRNAs (or miRNAs). MiRNAs do not code for proteins, but
can "target" protein-coding genes and reduce their expression.6
Cancers usually arise from an assemblage of mutations and epimutations that
confer a selective advantage leading to clonal expansion (see Field defects in
progression to cancer). Mutations, however, may not be as frequent in cancers
as epigenetic alterations. An average cancer of the breast or colon can have

about 60 to 70 protein-altering mutations, of which about three or four may be

"driver" mutations, and the remaining ones may be "passenger" mutations.[81]
As pointed out above under genetic alterations, cancer is caused by failure to
regulate tissue growth, when the genes that regulate cell growth and
differentiation are altered. It has become clear that these alterations are caused
by both DNA sequence mutation in oncogenes and tumor suppressor genes as
well as by epigenetic alterations. The epigenetic deficiencies in expression of
DNA repair genes, in particular, likely cause an increased frequency of
mutations, some of which then occur in oncogenes and tumor suppressor genes.6

FIGURE10:PROGRESSION TO CANCER

3.3Metastasis
Metastasis is the spread of cancer to other locations in the body. The new
tumors are called metastatic tumors, while the original is called the primary
tumor. Almost all cancers can metastasize.5,6 Most cancer deaths are due to
cancer that has spread from its primary site to other organs (metastasized).

Metastasis is very common in the late stages of cancer, and it can occur via the
blood or the lymphatic system or both. The typical steps in metastasis are local
invasion,intravasation into the blood or lymph, circulation through the
body, extravasation into the new tissue, proliferation, and angiogenesis.
Different types of cancers tend to metastasize to particular organs, but overall
the most common places for metastases to occur are the lungs, liver, brain, and
the bones.5,6
3.4 Pathology
The tissue diagnosis given by the pathologist indicates the type of cell that is
proliferating, its histological grade, genetic abnormalities, and other features of
the tumor. Cytogenetics and immunohistochemistry are other types of testing
that the pathologist may perform on the tissue specimen. These tests may
provide information about the molecular changes (such as mutations, fusion
genes, and numericalchromosome changes) that have happened in the cancer
cells, and may thus also indicate the future behavior of the cancer (prognosis)
and best treatment.
4.SOLID TUMOURS
INTRODUCTION SOLID TUMORS -Solid tumors are abnormal mass of
tissue that usually does not contain cysts or liquid areas. Solid tumors may be
benign (not cancerous), or malignant (cancerous). Different types of solid
tumors are named for the type of cells that form them. Examples of solid tumors
are sarcomas, carcinomas, and lymphomas. The word tumor does not always
imply cancer. In discussing tumors that are malignant (cancerous), however, the
term solid tumor is used to distinguish between a localized mass of tissue and
leukemia. Leukemia is a type of tumor that takes on the fluid properties of the
organ it affects e.g. the blood.

Modeling of Solid Tumor Growth The biology of cancer is a complex interplay

of many underlying processes, taking place at different scales both in space and
time..
4.1Classification of localized solid tumors: Different kinds of solid tumors are
named for the type of cells of which they are composed:
Sarcomas -- Cancers arising from connective or supporting tissues, such as
bone or muscle.
Carcinomas -- Cancers arising from the bodys glandular cells and epithelial
cells, which line body tissues.
Lymphomas -- Cancers of the lymphoid organs such as the lymph nodes,
spleen, and thymus, which produce and store infection-fighting cells. These
cells also occur in almost all tissues of the body, and lymphomas therefore may
develop in a wide variety of organs.
Kinds of Solid Tumors
Lymphomas
Lymphomas are cancers of the lymphatic tissues, which make up the bodys
lymphatic system. Lymphomas have been broadly divided into Hodgkins
disease and non-Hodgkins lymphomas, which include a number of diseases.
a) Hodgkins disease It tends to involve peripheral lymph nodes (those near the
surface of the body), where the first sign of disease may be a painless swelling
in the neck, armpit, or groin. Hodgkins disease occurs most commonly in
patients in their twenties and thirties and occasionally in adolescents; it is rare in
younger children.

b) Non-Hodgkins lymphomas - In children, non-Hodgkins lymphomas most

frequently occur in the bowel, particularly in the region adjacent to the
appendix, and in the upper midsection of the chest. An initial sign of disease in
non-Hodgkins lymphoma may be abdominal pain or swelling, breathing
difficulties and sometimes difficulty in swallowing, or swelling of the face and
neck. Non-Hodgkins lymphomas may also occur in other organs, including the
liver, spleen, bone marrow, lymph nodes, central nervous system, and bones.
Brain Tumors are the second most common cancers of childhood.
Symptoms include seizures, morning headaches, vomiting, irritability,
behavior problems, and changes in eating or sleeping habits, lethargy, or
clumsiness. Diagnosis is often difficult, because these symptoms can and
frequently do indicate any number of other problems, either physical or
emotional.
Neuroblastoma arises from very young nerve cells that develop
abnormally. More than half of these tumors occur in the adrenal glands,
which are located in the abdominal area near the kidneys. Symptoms
include a mass, listlessness, persistent diarrhoea, and pain in the abdomen
or elsewhere.
Wilms tumor is a cancer that originates in the cells of the kidney. It
occurs in children from infancy to age 15.It is very different from adult
kidney cancers. It may rarely be hereditary, and about 5 percent of the
cases involve both kidneys. Imaging plays a crucial role in the evaluation
of the primary tumor and regional and metastatic disease . Slight swelling
or a lump in abdomen is its first most detectable symptom. Symptoms
such as blood in the urine, weakness, fever, loss of appetite, or abdominal
pain may or may not be present.3
Retinoblastoma is cancer of the eye. It may be hereditary, and one-third
of the cases involve both eyes. If diagnosed early, it is possible to destroy
the tumor with radiation therapy and preserve normal vision. If the tumor

is so large that there is no hope of maintaining useful vision using

radiation, the eye is removed. In cases where both eyes are involved, an
attempt is made to preserve vision in both eyes through treatment with
radiation. When advanced disease is found in both eyes, an attempt is
made to preserve vision in at least one eye. Whenever there is any
possibility of useful vision, all efforts are made to preserve it.
Chemotherapy, radiation, or both may also be used to treat metastases.

Rhabdomyosarcoma, also called rhabdosarcoma, is a type of soft

tissue sarcoma arising from muscle cells. It occurs slightly more
frequently in males. Although it can occur in any muscle tissue, it is
generally found in the head and neck area, the pelvis, or in the
extremities. A noticeable lump or swelling is present in almost all cases.
Other symptoms depend on the location; if the growth is near the eyes,
for example, a vision problem may develop. If the neck is involved, there
may be hoarseness or difficulty in swallowing.
Osteogenic Sarcoma It arises in the ends of the bones. The bones most
frequently involved are the large bones of the upper arm (humerus) and
the leg (femur and tibia). Osteogenic sarcoma usually occurs between the

ages of 10 and 25 and is more common among males than females.3

Ewings Sarcoma -differs from osteosarcoma in that it affects a different
part of the bone. It tends to be found in bones other than the long bones of
the arm and leg, such as the ribs. Like osteogenic sarcoma, it usually
occurs between the ages of 10 and 25, is seen more often in males, and
frequently spreads to other bones and the lungs. Young people with this
type of cancer usually have more general signs-fever, chills, and
weakness-than is present in osteogenic sarcoma.3

5.PRODUCTS PRODUCED BY TOMOUR CELLS

Tumor antigen is an antigenic substance produced in tumor cells, i.e., it

triggers an immune response in the host. Tumor antigens are useful tumor
markers in identifying tumor cells with diagnostic tests and are potential
candidates for use in cancer therapy.
5.1 MECHNISM OF TUMOR ANTIGENESIS
Normal proteins in the body are not antigenic because of self-tolerance, a
process in which self-reacting cytotoxic T lymphocytes (CTLs)
and autoantibody-producing B lymphocytes are culled "centrally" in primary
lymphatic tissue (BM) and "peripherally" in secondary lymphatic tissue
(mostly thymus for T-cells and spleen/lymph nodes for B cells). Thus any
protein that is not exposed to the immune system triggers an immune response.
This may include normal proteins that are well sequestered from the immune
system, proteins that are normally produced in extremely small quantities,
proteins that are normally produced only in certain stages of development, or
proteins whose structure is modified due to mutation.
5.2 CLASSIFICATION OF TUMOR ANTIGENS
Initially tumor antigens were broadly classified into two categories based on
their pattern of expression:
Tumor-Specific Antigens (TSA), which are present only on tumor cells and not
on any other cell
Tumor-Associated Antigens (TAA), which are present on some tumor cells and
also some normal cells.
This classification, however, is imperfect because many antigens thought to
be tumor-specific turned out to be expressed on some normal cells as well. The

modern classification of tumor antigens is based on their molecular structure

and source.
Accordingly they can be classified as

Products of Mutated Oncogenes and Tumor Suppressor Genes

Products of Other Mutated Genes

Overexpressed or Aberrantly Expressed Cellular Proteins

Tumor Antigens Produced by Oncogenic Viruses

Oncofetal Antigens

Altered Cell Surface Glycolipids and Glycoproteins

Cell Type-Specific Differentiation Antigens

Types
Any protein produced in a tumor cell that has an abnormal structure due
to mutation can act as a tumor antigen. Such abnormal proteins are produced
due to mutation of the concerned gene. Mutation of protooncogenes and tumor
suppressors which lead to abnormal protein production are the cause of the
tumor and thus such abnormal proteins are called tumor-specific antigens.
Examples of tumor-specific antigens include the abnormal products
of ras and p53 genes. In contrast, mutation of other genes unrelated to the tumor
formation may lead to synthesis of abnormal proteins which are called tumorassociated antigens.

Other examples include tissue differentiation antigens, mutant protein antigens,

oncogenic viral antigens, cancer-testis antigens and vascular or stromal specific
antigens. Tissue differentiation antigens are those that are specific to a certain
type of tissue. Mutant protein antigens are likely to be much more specific to
cancer cells because normal cells shouldn't contain these proteins. Normal cells
will display the normal protein antigen on their MHC molecules, whereas
cancer cells will display the mutant version. Some viral proteins are implicated
in forming cancer (oncogenesis), and some viral antigens are also cancer
antigens. Cancer-testis antigens are antigens expressed primarily in the germ
cells of the testes, but also in fetal ovaries and the trophoblast. Some cancer
cells aberrantly express these proteins and therefore present these antigens,
allowing attack by T-cells specific to these antigens. Example antigens of this
type are CTAG1B and MAGEA1.[1]
Proteins that are normally produced in very low quantities but whose production
is dramatically increased in tumor cells, trigger an immune response. An
example of such a protein is the enzyme tyrosinase, which is required
for melanin production. Normally tyrosinase is produced in minute quantities
but its levels are very much elevated inmelanoma cells.
Oncofetal antigens are another important class of tumor antigens. Examples
are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These
proteins are normally produced in the early stages of embryonic development
and disappear by the time the immune system is fully developed. Thus selftolerance does not develop against these antigens.
Abnormal proteins are also produced by cells infected with oncoviruses,
e.g. EBV and HPV. Cells infected by these viruses contain latent
viral DNA which is transcribed and the resulting protein produces an immune
response In addition to proteins, other substances like cells

surface glycolipids and glycoproteins may also have an abnormal structure in

tumor cells and could thus be targets of the immune system.2
5.2 IMPORTANCE OF TUMOR ANTIGENS
Tumor antigens, because of their relative abundance in tumor cells are useful in
identifying specific tumor cells. Certain tumors have certain tumor antigens in
abundance.
Certain tumor antigens are thus used as tumor markers. More importantly,
tumor antigens can be used in cancer therapy as tumor antigen vaccines2

Tumor antigen

Tumor in which

Remarks

it is found
Germ cell tumors

Alphafetoprotein (AFP)

Hepatocellular
carcinoma

Carcinoembryonic
antigen (CEA)

bowel cancers

CA-125

Ovarian cancer

MUC-1

breast cancer

Epithelial tumor
antigen (ETA)

Breast cancer

Occasional lung or breast

cancer

Tyrosinase

Malignant
melanoma

normally present in minute

quantities; greatly elevated
levels in melanoma

Melanoma-associated

malignant

Also normally present in

antigen (MAGE)

melanoma

the testis

abnormal products
of ras, p53

Various tumors

TABLE2: tumor antigens

REFERENCE
1.Molecular Biology of the Cell, Fourth Edition, Bruce Alberts, Alexander
Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walte
2.Coulie PG, Hanagiri T, Takanoyama M: From Tumor Antigens to
Immunotherapy. Int J Clin Oncol 6:163, 2001
3. Gavhane Y. N. et al. / International Journal of Pharma Sciences and Research
(IJPSR) Vol.2(1), 2011, 1-12
4,Gibbs, W. Wayt. 2003. Untangling the roots of cancer. Scientific American,
July, 5765. New evidence challenges old theories of how cancer develops.
5. Lahtz C, Pfeifer GP (February 2011). "Epigenetic changes of DNA repair
genes in cancer". J Mol Cell Biol 3 (1): 518.
6. Varricchio, Claudette G. (2004). A cancer source book for nurses. Boston:
Jones and Bartlett Publishers. p. 229