Cancer

INTRODUCTION
• Borrowed from Latin cancer (“crab”), and Greek (karkínos, “crab”);
applied to cancerous tumors because ‘it sticks to the part stubbornly
like a crab’.
• Cancer is an umbrella term for a large group of diseases caused when
abnormal cells divide rapidly, and spread to other tissue and organs.
Cancer is one of the leading causes of death in the world.
• Normally some cells proliferate throughout life (labile cells), some
have limited proliferation (stable cells), while others do not replicate
(permanent cells). On the other hand, cancerous cells lose control and
regulation of replication and form an abnormal mass of tissue.

DIFFERENCE BETWEEN BENIGN AND
METASTATIC TUMORS
• In a healthy body, the trillions of cells it’s made of grow and divide, as
the body needs them to function daily. Healthy cells have a specific
life cycle, reproducing and dying off in a way that is determined by the
type of cell.
• New cells take the place of old or damaged cells as they die. Cancer
disrupts this process and leads to abnormal growth in cells. It’s caused
by changes or mutations in DNA.
• DNA exists in the individual genes of every cell. It has instructions
that tell the cell what functions to perform and how to grow and
divide. Mutations occur frequently in DNA, but usually cells correct
these mistakes. When a mistake is not corrected, a cell can become
cancerous.

• Mutations can cause cells that should be replaced to survive instead of
die, and new cells to form when they’re not needed. These extra cells
can divide uncontrollably, causing growths called tumors to form.
Tumors can cause a variety of health problems, depending on where
they grow in the body.
• But not all tumors are cancerous. Benign tumors are noncancerous
and do not spread to nearby tissues. Sometimes, they can grow large
and cause problems when they press against neighboring organs and
tissue. Malignant tumors are cancerous and can invade other parts of
the body.
• Some cancer cells can also migrate through the bloodstream or
lymphatic system to distant areas of the body. This process is called
metastasis. Cancers that have metastasized are considered more
advanced than those that have not. Metastatic cancers tend to be harder
to treat and more fatal.

•All tumours, benign as well as malignant, have 2
basic components:
Parenchyma comprised by proliferating tumour
cells; parenchyma determines the nature and
evolution of the tumour.
Supportive stroma composed of fibrous
connective tissue and blood vessels; it provides
the framework on which the parenchymal tumour
cells grow.

NOMENCLATURE OF CANCERS
• The tumours derive their nomenclature on the basis of the
parenchymal component comprising them.
• The suffix ‘-oma’ is added to denote benign tumours.
• Cancers are named for the area in which they begin and the type of
cell they are made of, even if they spread to other parts of the body.
For example, a cancer that begins in the lungs and spreads to the liver
is still called lung cancer. Carcinoma is a cancer that starts in the
skin(epithelial) or the tissues that line other organs.
• Sarcoma is a cancer of connective tissues such as bones, muscles,
cartilage, and blood vessels.
• Leukemia is a cancer of bone marrow, which creates blood cells.
• Lymphoma and myeloma are cancers of the immune system.

• With the exclusion of hair, teeth and nails, almost any group
of cells in the body might become a site for cancer. In order
to distinguish cancers, tumours are classified according to the
tissue in which they develop.
• The human body is composed of two major classes of tissue:
parenchymal or epithelial tissues and mesenchymal tissues,
comprising connective tissues, muscle and blood vessel.
• Benign tumours of most tissues are usually simply designated
the suffix (-oma).
• Malignant tumours of the parenchyma are designated the
term carcinoma, while malignant tumours of mesenchymal
tissues are designated the term (sarcoma).

DIFFERENCES
BETWEEN BENIGN
AND MALIGNANT
TUMORS

HISTOLOGICAL EXAMINATION OF CANCER
• When the diagnosis of cancer is suspected on clinical examination and on other
investigations, it must be confirmed. The most certain and reliable method which
has stood the test of time is the histological examination of biopsy.
• These methods are most valuable in arriving at the accurate diagnosis.
• These are based on microscopic examination of excised tumour mass or
open/needle biopsy from the mass supported with complete clinical and
investigative data.
• The tissue must be fixed in 10% formalin for light microscopic examination and in
glutaraldehyde for electron microscopic studies.
These methods are:
• Paraffin-embedding technique In this, 10% formalin fixed tissue is used. The
representative tissue piece from larger tumour mass or biopsy is processed through
a tissue processor having an overnight cycle, embedded in molten paraffin wax for
making tissue blocks. These blocks are trimmed followed by fine-sectioning into
3-4 µm sections using rotary microtome for which either fixed knife or disposable
blades are used for cutting. These sections are then stained with haematoxylin and
eosin (H & E) and examined microscopically.

WHAT IS AN UNFIXED TISSUE AND FIXED
TISSUES?
• Chemical fixatives are used to preserve tissue from
degradation, and to maintain the structure of the cell
and of sub-cellular components such as cell
organelles(e.g., nucleus, endoplasmic reticulum,
mitochondria).
• Before mounting the tissue onto the microscope, it
must be fixated.
• The most common fixative for light microscopy is
10% neutral buffered formalin and for electron
microscopy the most commonly used fixative is
glutaraldehyde.

Frozen section
• In this technique, unfixed tissue is used and the procedure is
generally carried out when the patient is undergoing surgery
and is still under anaesthesia.
• Here, instead of tissue processor and paraffin-embedding,
cryostat machine is used and fresh unfixed tissue is used.
• The tissue biopsy is quickly frozen to ice at about –25°C that
acts as embedding medium and then sectioned.
• Sections are then ready for rapid H & E(hematoxylin and
eosin) or toluidine blue staining.
• Frozen section is a rapid intraoperative diagnostic procedure
for tissues before proceeding to a major radical surgery or
may be used to know the extent of presence of cancer at the

For histological diagnosis the following methods of sampling is done: • Biopsy- biopsy is a surgical
removal of small piece of tissue For microscopic examination for the presence of cancer cell. There
are three ways tissues can be removed for • Biopsy:- • Endoscopy • Needle biopsy • Surgical biopsy
Endoscopy- in this process , A thin, flexible tube with a tiny camera on the end is inserted into the
body cavity. This allows the doctor to view the abnormal area and shall take a tissue sample if
needed.
Needle biopsy - the doctor takes a small tissue sample by Inserting a needle into abnormal area.
Different types of needles used are-
• Vim Silverman needle for liver biopsy
• Renal biopsy needle for renal tissue
• True cut biopsy needle for prostatic Tissue or breast tissue
Surgical Biopsy:- • There are two types of surgical biopsies.
• An excisional biopsy :it is performed when the doctor removes the entire tumor, often with some
surrounding normal tissue.
• An incisional biopsy: it is performed when the doctor removes just a portion of the tumor. If cancer
is found to be present, the entire tumor may be removed immediately or during another operation.
The processing of tissue and its diagnosis takes a two or three days.

INVASION AND METASTASIS
• Majority of neoplasms can be categorised into benign and malignant on the
basis of certain clinical features, biologic behaviour and morpho logical
characteristics. However, there are exceptions. Therefore, it must be borne
in mind that based characteristics of neoplasms, there is a wide variation in
all the tumours.
• The characteristics of tumours are described under the following headings:
• I. Rate of growth
• II. Cancer phenotype and stem cells
• III. Clinical and gross features
• IV. Microscopic features
• V. Spread of tumours
a. Local invasion or direct spread
b. Metastasis or distant spread.

• One of the cardinal features of malignant tumours is its ability to invade and
destroy adjoining tissues (local invasion or direct spread) and disseminate to
distant sites (metastasis or distant spread).
Modes of spread of MALIGNANT TUMOURS
• Malignant tumours also enlarge by expansion and some well-differentiated
tumours may be partially encapsulated as well e.g. follicular carcinoma thyroid.
• But characteristically, they are distinguished from benign tumours by invasion,
infiltration and destruction of the surrounding tissue, besides spread to distant sites
or metastasis.
• In general, tumours invade via the route of least resistance, though eventually
most cancers recognise no anatomic boundaries. Often, cancers extend through
tissue spaces, permeate lymphatics, blood vessels, perineural spaces and may
penetrate a bone by growing through nutrient foramina.
• More commonly, the tumours invade thin-walled capillaries and veins than thick-
walled arteries. Dense compact collagen, elastic tissue and cartilage are some of
the tissues which are sufficiently resistant to invasion by tumours.

INVASION OR LOCAL SPREAD
• Invasion refers to the direct extension and penetration by cancer cells
into neighbouring tissues.
• The proliferation of transformed cells and the progressive increase in
tumour size eventually leads to a breach in the barriers between
tissues, leading to tumour extension into adjacent tissue.
• Local invasion is also the first stage in the process that leads to the
development of secondary tumours or metastases.

METASTASIS
• Metastasis, from the Greek methistanai, meaning to move to another place,
describes the ability of cancer cells to penetrate into lymphatic and blood vessels,
circulate through these systems and invade normal tissues elsewhere in the body.
This process proceeds in an orderly and predictable manner, sometimes termed the
'metastatic cascade.
• The ability of cancer cells to migrate from a primary site of disease is attributed to
the mutation of genes that regulate the production of proteins that normally tether
cells to their surrounding tissues.
• Decreased synthesis by cancer cells of a number of substances that bind them to
neighbouring cells, together with the abnormal synthesis of enzymes capable of
degrading the bonds between cells and tissues, allow cancer cells to escape the
primary tumour site
• Besides anaplasia, invasiveness and metastasis are the two other most important
features to distinguish malignant from benign tumours. Benign tumours do not
metastasise while all the malignant tumours can metastasise.

ROUTES OF METASTASIS
Cancers may spread to distant sites by following pathways:
1. Lymphatic spread
2. Haematogenous spread
3. Spread along body cavities and natural passages (Transcoelomic
spread, along epithe lium-lined surfaces, spread via cerebrospinal
fluid, implantation).

LYMPHATIC SPREAD
• LYMPHATIC SPREAD In general, carcinomas metastasise by lymphatic
route while sarcomas favour haematogenous route. However, some
sarcomas may also spread by lymphatic pathway.
• The involvement of lymph nodes by malignant cells may be of two forms:
i) Lymphatic permeation The walls of lymphatics are readily invaded by
cancer cells and may form a continuous growth in the lymphatic channels
called lymphatic permeation.
ii) Lymphatic emboli Alternatively, the malignant cells may detach to form
tumour emboli so as to be carried along the lymph to the next draining lymph
node. The tumour emboli enter the lymph node at its convex surface and are
lodged in the subcapsular sinus where they start growing. Later, of course, the
whole lymph node may be replaced and enlarged by the metastatic tumour.

METASTATIC CARCINOMA OF
LYPMH NODES.

HEMATOGENOUS SPREAD
• Blood-borne metastasis is the common route for sarcomas but certain
carcinomas also frequently metastasise by this mode, especially those
of the lung, breast, thyroid, kidney, liver, prostate and ovary.
• The sites where blood-borne metastasis commonly occurs are: the
liver, lungs, brain, bones, kidney and adrenals, all of which provide
‘good soil’ for the growth of ‘good seeds’, i.e. seed-soil theory
postulated by Ewing and Paget a century ago.
• However, a few organs such as the spleen, heart, and skeletal muscle
generally do not allow tumour metastasis to grow.
• Spleen is unfavourable site due to open sinusoidal pattern which does
not permit tumour cells to stay there long enough to produce
metastasis. In general, only a proportion of cancer cells are capable of
clonal proliferation in the proper environment; others die without
establishing a metastasis.

• A few features of hematogenous metastasis are as under:
i) Systemic veins drain blood into vena cavae from limbs,
head and neck and pelvis. Therefore, cancers of these sites
more often metastasise to the lungs.
ii) Portal veins drain blood from the bowel, spleen and
pancreas into the liver. Thus, tumours of these organs
frequently have secondaries in the liver.
iii) Pulmonary veins provide another route of spread of not
only primary lung cancer but also metastatic growths in the
lungs. Blood in the pulmonary veins carrying cancer cells
from the lungs reaches left side of the heart and then into
systemic circulation and thus may form secondary masses
elsewhere in the body.

i) Arterial spread of tumours is less likely because they are
thick-walled and contain elastic tissue which is resistant to
invasion. Nevertheless, arterial spread may occur when
tumour cells pass through pulmonary capillary bed or
through pulmonary arterial branches which have thin walls.
However, cancers of the kidneys, adrenals, bones, limbs
and uterus, which are drained by systemic veins, spread to
the lungs via pulmonary artery.
ii) Retrograde spread by blood route may occur at unusual
sites due to retrograde spread after venous obstruction, just
as with lymphatic metastases. Important examples are
vertebral.

SPREAD ALONG BODY CAVITIES AND
NATURAL PASSAGES.
• Uncommon routes of spread of some cancers are by seeding across body cavities
and natural passages as under:
i) Transcoelomic spread Certain cancers invade through the serosal wall of the
coelomic cavity so that tumour fragments or clusters of tumour cells break off
to be carried in the coelomic fluid and are implanted elsewhere in the body
cavity.
Peritoneal cavity is involved most often, but occasionally pleural and pericardial
cavities are also affected.
• A few examples of transcoelomic spread are as follows:
a) Carcinoma of the stomach seeding to both ovaries (Krukenberg tumour).
b) Carcinoma of the ovary spreading to the entire peritoneal cavity without
infiltrating the underlying organs.
c) Pseudomyxoma peritonei is the gelatinous coating of the peritoneum from mucin-
secreting carcinoma of the ovary or apppendix.
d) Carcinoma of the bronchus and breast seeding to the pleura and pericardium.

ii) Spread along epithelium-lined surfaces It is unusual for a malignant
tumour to spread along the epithelium-lined surfaces because intact
epithelium and mucus coat are quite resistant to penetration by tumour
cells. However, exceptionally a malignant tumour may spread through:
a) the fallopian tube from the endometrium to the ovaries or vice-versa;
b) through the bronchus into alveoli; and c) through the ureters from the
kidneys into lower urinary tract.
iii) Spread via cerebrospinal fluid Malignant tumour of the ependyma
and leptomeninges may spread by release of tumour fragments and
tumour cells into the CSF and produce metastases at other sites in the
central nervous system.
iv) Implantation There are isolated and rare case reports of spread of
some cancers by implantation by surgeon’s scalpel, needles, sutures, and
direct prolonged contact of cancer of the lower lip causing its
implantation to the apposing upper lip.

DISTURBANCES IN CELL GROWTH-
WHAT IS NORMAL CELL PROLIFERATION?
• Cells form the basic structural and functional units of an organism. All cells
contain a cell membrane, cytoplasm and nucleus. Situated in the nucleus is
the genetic material or deoxyribonucleic acid (DNA), which is the
fundamental building block for life. DNA is made up of subunits called
genes. Each gene is coded for a specific product such as a protein or
enzyme.
• Genes are contained in chromosomes and only the genes required are
switched on. Some important genes in the context of cellular proliferation
include:
• PROTO-ONCOGENES: a gene involved in normal cell growth. Mutations
(changes) in a proto-oncogene may cause it to become an oncogene, in
which it becomes overactive and can cause the growth of cancer cells
• TUMOUR SUPPRESSOR GENES: a type of gene that makes a protein
called a tumour suppressor protein that helps control cell growth. Mutations
(changes in DNA) in tumour suppressor genes may lead to cancer.

• Each tissue and organ in the body is composed of vast populations of
cells, totaling more than 1014 (100 000 000 000 000). An astonishing
1012 (1 000 000 000 000) cells die or are shed in the normal course of
each day and must be replaced to sustain life.
• The process by which cells grow and divide to replenish lost cells is
termed cell proliferation. This is a highly regulated activity in normal,
healthy tissue. The synthesis of new cells is balanced against cell loss
so that the total number of cells composing all tissues and organs in
the body remains essentially unchanged.
• Cell growth, the replication of genetic material and cell division are all
governed by the cell cycle, a highly-ordered series of events that
culminates in mitosis (the division of a cell, giving rise to two
daughter cells). Progression through the cell cycle depends on
successful passage through a number of critical phases, known as
checkpoints, which function to ensure the synthesis of fully
functioning daughter cells

WHAT IS ABNORMAL CELL PROLIFERATION?
• While some cell types, such as those that compose the skin and
bone marrow, continue to proliferate throughout life, other types
including bone and muscle cells cease active proliferation when a
human reaches adulthood.
• Most normal cells remain in a non-proliferative state unless they
are stimulated to divide to replace lost cells.
• Abnormal regulation of the cell cycle can lead to the over
proliferation of cells and an accumulation of abnormal cell
numbers.
• Cancer cells arise from one cell that becomes damaged, and
when divided, the damage is passed on to the daughter cell and
again to the granddaughter cells and so on. Such uncontrolled,
abnormal growth of cells is a defining characteristic of cancer.

• The total number of cells composing the human body is
determined not only by the rate of proliferation of cells
but also by the rate of cell loss.
• Excess cells and those that are aged or have sustained
damage that impairs normal functioning are eliminated to
prevent accumulation of abnormal numbers of cells.
• The mechanism for regulating the removal of excess
and impaired cells is known as apoptosis. Also referred
to as cell suicide or programmed cell death, apoptosis is
an orderly process during which internal cellular
structures are progressively dismantled, the impaired cell
shrinks and finally is rapidly destroyed by immune cells.

Role of key genes TP53 and RB1
• A number of key genes, proteins and enzymes that regulate the cell cycle and the process
of apoptosis have been identified.
• The TP53 gene and the regulatory protein it is responsible for producing, p53, together
with the RB1 gene and its related protein, pRB, act to inhibit cell proliferation.
• In addition, the role of a group of proteins (cyclins and enzymes) known as cyclin-
dependent kinases (CDKs) that act to stimulate a cell to progress through the cell cycle
have also been identified.
• It is now understood that mutations of these key genes affect the action of regulating
proteins and enzymes and lead to the loss of regulation of cell proliferation that is seen in
cancer.
• Mutations of the TP53 gene are also implicated in disturbances in apoptosis. Cells with
mutated TP53 genes evade the apoptosis mechanisms normally responsible for
eliminating impaired cells.
DNA mutations may result from:
• artificial sources (pesticides, organic chemicals, alkylating agents)
• naturally occurring sources (plant toxins, viruses)
• radiation

DISTURBANCES IN CELL GROWTH IN
CANCER
• The tumour cells generally proliferate more rapidly
than the normal cells. In general, benign tumours grow
slowly and malignant tumours rapidly.
• The rate at which the tumour enlarges depends upon 2
main factors: 1. Rate of cell production, growth
fraction and rate of cell loss
2. Degree of differentiation of the tumour.

Rate of cell production, growth fraction and rate of cell loss Rate of growth
of a tumour depends upon 3 important parameters:
i) doubling time of tumour cells,
ii) number of cells remaining in proliferative pool (growth fraction),
and iii) rate of loss of tumour cells by cell shedding.
• In general, malignant tumour cells have increased mitotic rate (doubling
time) and slower death rate i.e. the cancer cells do not follow normal
controls in cell cycle and are immortal.
• tumours grow relentlessly, they do so because a larger proportion of tumour
cells remain in replicative pool but due to lack of availability of adequate
nourishment, these tumour cells are either lost by shedding or leave the cell
cycle to enter into G0 (resting phase) or G1 phase.
• While dead tumour cells appear as ‘apoptotic figures’ the dividing cells of
tumours are seen as normal and abnormal ‘mitotic figures’. Ultimately,
malignant tumours grow in size because the cell production exceeds the cell
loss. 2. Degree of differentiation Secondly, the rate of growth

2. Degree of differentiation Secondly, the rate of growth of
malignant tumour is directly proportionate to the degree of
differentiation.
• Poorly differentiated tumours show aggressive growth pattern
as compared to better differentiated tumours.
• Some tumours, after a period of slow growth, may suddenly
show spurt(INCREASE) in their growth due to development
of an aggressive clone of malignant cells.
• On the other hand, some tumours may cease to grow after
sometime.
• The regulation of tumour growth is under the control of
growth factors secreted by the tumour cells.

• Out of various growth factors, important ones modulating
tumour biology are listed below and discussed later:
i) Epidermal growth factor (EGF)
ii) Fibroblast growth factor (FGF)
iii) Platelet-derived growth factor (PDGF)
iv) Colony stimulating factor (CSF)
v) Transforming growth factors-b (TGF-b)
vi) Interleukins 1 and 6 (IL-1, IL-6)
vii)Vascular endothelial growth factor (VEGF)
viii)Hepatocyte growth factor (HGF)

• Thus, normal cells are socially desirable. However, cancer cells
exhibit anti-social behaviour as under:
i) Cancer cells disobey the growth controlling signals in the body and
thus proliferate rapidly.
ii) Cancer cells escape death signals and achieve immortality.
iii) Imbalance between cell proliferation and cell death in cancer causes
excessive growth.
iv) Cancer cells lose properties of differentiation and thus perform little
or no function.
v) Due to loss of growth controls, cancer cells are genetically unstable
and develop newer mutations.
vi) Cancer cells overrun their neighbouring tissue and invade locally.
vii) Cancer cells have the ability to travel from the site of origin to other
sites in the body where they colonise and establish distant
metastasis.

GENERAL BIOLOGY OF TUMORS
• The neoplastic cell is characterised by morphologic and functional
alterations, the most significant of which are ‘differentiation’ and
‘anaplasia’. Differentiation is defined as the extent of morphological and
functional resemblance of parenchymal tumour cells
• to corresponding normal cells. If the deviation of neoplastic cell in structure
and function is minimal as compared to normal cell, the tumour is described
as ‘well-differentiated’ such as most benign and low-grade malignant
tumours. ‘Poorly differentiated’, ‘undifferentiated’ or ‘dedifferentiated’ are
synonymous terms for poor structural and functional resemblance to
corresponding normal cell.
• Anaplasia is lack of differentiation and is a characteristic feature of most
malignant tumours. Depending upon the degree of differentiation, the extent
of anaplasia is also variable i.e. poorly differentiated malignant tumours
have high degree of anaplasia. As a result of anaplasia, noticeable
morphological and functional alterations in the neoplastic cells are observed
which are best appreciated under higher magnification of the microscope.

•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.
As a result of anaplasia, noticeable morphological and
functional alterations in the neoplastic cells are observed
which are best appreciated under higher magnification of the
microscope.

TUMOR ANGIOGENESIS AND STROMA
• TUMOUR ANGIOGENESIS In order to provide nourishment to
growing tumour, new blood vessels are formed from pre-existing ones
(angiogenesis). Its mechanism and the role of angiogenic factors
elaborated by tumour cells (e.g. vascular endothelium growth factor or
VEGF).
• Microvascular density The new capillaries add to the vascular density
of the tumour which has been used as a marker to assess the rate of
growth of tumours and hence grade the tumours. This is done by
counting microvascular density in the section of the tumour.
• Central necrosis However, if the tumour outgrows its blood supply as
occurs in rapidly growing tumours or tumour angiogenesis fails, its
core undergoes ischaemic necrosis.

• TUMOUR STROMA The collagenous tissue in the stroma
may be scanty or excessive. In the former case, the tumour is
soft and fleshy (e.g. in sarcomas, lymphomas), while in the
latter case the tumour is hard and gritty (e.g. infiltrating duct
carcinoma breast). Growth of fibrous tissue in tumour is
stimulated by basic fibroblast growth factor (bFGF)
elaborated by tumour cells.
• If the epithelial tumour is almost entirely composed of
parenchymal cells, it is called medullary e.g. medullary
carcinoma of the breast medullary carcinoma of the thyroid.
• If there is excessive connective tissue stroma in the epithelial
tumour, it is referred to as desmoplasia and the tumour is
hard or scirrhous e.g. infiltrating duct carcinoma breast.

MECHANISM AND BIOLOGY OF
INVASION AND METASTASIS
• The process of local invasion and distant spread by lymphatic and
haematogenous routes (together called lymphovascular spread)
involves passage through barriers before gaining access to the vascular
lumen.
• This includes making the passage by the cancer cells by dissolution of
extracellular matrix (ECM) at three levels—at the basement membrane
of tumour itself, at the level of interstitial connective tissue, and at the
basement membrane of microvasculature.

STEPS INVOLVED IN METASTASIS
1. Aggressive clonal proliferation and angiogenesis The first step in
the spread of cancer cells is the development of rapidly proliferating
clone of cancer cells. This is explained on the basis of tumour
heterogeneity, i.e. in the population of monoclonal tumour cells, a sub
population or clone of tumour cells has the right biologic characteristics
to complete the steps involved in the development of metastasis.
Tumour angiogenesis plays a very significant role in metastasis since
the new vessels formed as part of growing tumour are more vulnerable
to invasion because these evolving vessels are directly in contact with
cancer cells.
2. Tumour cell loosening Normal cells remain glued to each other due
to presence of cell adhesion molecules (CAMs) i.e. E (epithelial)-
cadherin. In epithelial cancers, there is either loss or inactivation of E-
cadherin and also other CAMs of immunoglobulin superfamily, all of
which results in loosening of cancer cells.

3. Tumour cell-ECM interaction Loosened cancer cells are now attached to
ECM proteins, mainly laminin and fibronectin. This attachment is facilitated
due to profoundness of receptors on the cancer cells for both these proteins.
There is also loss of integrins, the transmembrane receptors, further favouring
invasion.
4. Degradation of ECM Tumour cells overexpress proteases and matrix-
degrading enzymes, metalloproteinases (e.g. collagenases and gelatinase),
while the inhibitors of metalloproteinases are decreased. Another protease,
cathepsin D, is also increased in certain cancers. These enzymes bring cell
chemotaxis, growth promotion and angiogenesis in the cancer. After the
malignant cells have migrated through the breached basement membrane,
these cells enter the lumen of lymphatic and capillary channels.
6. Thrombus formation The tumour cells protruding in the lumen of the
capillary are now covered with constituents of the circulating blood and form
the thrombus. Thrombus provides nourishment to the tumour cells and also
protects them from the immune attack by the circulating host cells. In fact,
normally a large number of tumour cells are released into circulation but they
are attacked by the host immune cells. Actually a very small proportion of
malignant cells (less than 0.1%) in the blood stream survive to develop into
metastasis.

7. Extravasation of tumour cells Tumour cells in the circulation
(capillaries, venules, lymphatics) may mechanically block these
vascular channels and attach to vascular endothelium and then
extravasate to the extravascular space. In this way, the sequence similar
to local invasion is repeated and the basement membrane is exposed.
8. Survival and growth of metastatic deposit The extravasated
malignant cells on lodgement in the right environment grow further
under the influence of growth factors produced by host tissues, tumour
cells and by cleavage products of matrix components. Some of the
growth promoting factors are: PDGF, FGF, TGF-b and VEGF. The
metastatic deposits grow further if the host immune defense mechanism
fails to eliminate it. Metastatic deposits may further metastasise to the
same organ or to other sites by forming emboli.

ETIOLOGY OF CANCER
A) Predisposing epidemiologic factors or
cofactors which include a number of
endogenous host factors and exogenous
environmental factors.
B) Chronic non-neoplastic (pre-malignant)
conditions.
C) Role of hormones in cancer.

A. PREDISPOSING FACTORS
1. FAMILIALAND GENETIC FACTORS It has long been
suspected that familial predisposition and heredity play a
role in the development of cancers. In general, the risk of
developing cancer in relatives of a known cancer patient is
almost three times higher as compared to control subjects.
Some of the cancers with familial occurrence are colon,
breast, ovary, brain and melanoma. Familial cancers occur
at a relatively early age, appear at multiple sites and occur
in 2 or more first-degree blood relatives. The overall
estimates suggest that genetic cancers comprise about 5%
of all cancers.

• RACIALAND GEOGRAPHIC FACTORS Differences in
racial incidence of some cancers may be partly attributed to
the role of genetic composition but are largely due to
influence of the environment and geo graphic differences
affecting the whole population such as climate, soil, water,
diet, habits, customs etc. Some of the examples of racial and
geographic variations in various cancers are as under:
i) White Europeans and Americans develop most commonly
malignancies of the prostate, lung, breast and colorectal
region. Liver cancer is uncommon in these races.
ii) Black Africans, on the other hand, have more commonly
cancers of the skin, penis, cervix and liver.

• iii) Japanese have five times higher incidence of carci noma
of the stomach than the Americans. Breast cancer is
uncommon in Japanese women than American women.
• iv) South-East Asians, especially of Chinese origin, develop
nasopharyngeal cancer more commonly.
• v) Indians of both sexes have higher incidence of carcinoma
of the oral cavity and upper aerodigestive tract, while in
females carcinoma of uterine cervix and of the breast run
parallel in incidence. Etiologic factor responsible for liver
cancer in India is more often viral hepatitis (HBV and HCV)
and subsequent cirrhosis, while in western populations it is
more often due to alcoholic cirrhosis.

3. ENVIRONMENTAL AND CULTURAL FACTORS It may seem
rather surprising that through out our life we are surrounded by an
environment of carcinogens which we eat, drink, inhale and touch.
These include
• Cigarette smoking
• Alcohol abuse
• Synergistic interaction of alcohol and tobacco
• Cancer of the cervix
• Penile cancer
• Betel nut cancer
• Industrial and environmental substances
• Certain constituents of diet.

4. AGE The most significant risk factor for cancer is age. Generally,
cancers occur in older individuals past 5th decade of life (two-third of
all cancers occur above 65 years of age), though there are variations in
age incidence in different forms of cancers. Higher incidence of cancer
in advanced age could be due to alteration in the cells of the host, longer
exposure to the effect of carcinogen, or decreased ability of the host
immune response.
5. SEX Apart from the malignant tumours of organs peculiar to each
sex, most tumours are generally more common in men than in women
except cancer of the breast, gallbladder, thyroid and hypopharynx.
Although there are geographic and racial variations, cancer of the breast
is the commonest cancer in women throughout the world while lung
cancer is the commonest cancer in men. The differences in incidence of
certain cancers in the two sexes may be related to the presence of
specific sex hormones.

B. CHRONIC PRE-MALIGNANT AND NON-NEOPLASTIC
CONDITIONS
• Premalignant lesions are a group of conditions which predispose
to the subsequent development of cancer. Such conditions are
important to recognise so as to prevent the subsequent occurrence
of an invasive cancer.
1. Dysplasia and carcinoma in situ (intraepithelial neoplasia):
Dysplastic cells confined to epithelial layers above the basement
membrane without invading the basement membrane is called as
carcinoma in situ or intraepithelial neoplasia (CIN). As regards the
behaviour of CIN, it may regress and return to normal or may
develop into invasive cancer. In some instances such as in cervical
cancer, there is a sequential transformation from epithelial
dysplasia, to carcinoma in situ, and eventually to invasive cancer.

2. Some benign tumours Commonly, benign tumours
do not become malignant. However, there are some
exceptions e.g.
i) Multiple adenomas of the large intestine have high
incidence of developing adenocarcinoma.
ii) Neurofibromatosis (von Recklinghausen’s disease)
may develop into sarcoma.
iii) Pleomorphic adenoma (mixed salivary tumour) may
sometimes develop carcinoma (carcinoma ex
pleomophic adenoma).

CARCINOGENS AND CARCINOGENESIS
• Carcinogenesis or oncogenesis or tumorigenesis means
mechanism of induction of tumours (pathogenesis of
cancer); agents causing cancer are called as
Carcinogens.
• Based on implicated causative agents, etiology and
pathogenesis of cancer can be discussed under
following 3 headings:
A. Chemical carcinogens and chemical carcinogenesis
B. Physical carcinogens and radiation carcinogenesis
C. Biologic carcinogens and viral oncogenesis.

A. CHEMICAL CARCINOGENESIS
• The first ever evidence of any cause for neoplasia came from the
observation of Sir Percival Pott in 1775 that there was higher
incidence of cancer of the scrotal skin in boys enganged in sweeping
industrial chimneys in London than in the general population.
• This inspired the law-makers in London to pass a ruling that these
workers should bathe daily and this simple public health measure
lowered the cancer incidence of scrotum in these wokers.
• The first successful experimental induction of cancer was produced
by two Japanese workers (Yamagiwa and Ichikawa) in 1914 in the
rabbit’s skin by repeatedly painting with coal tar.

STAGES IN CHEMICAL CARCINOGENESIS
• The induction of cancer by chemical carcinogens occurs after a delay—
weeks to months in the case of experimental animals, and often several
years in humans.
• Other factors that influence the induction of cancer are the dose and mode
of administration of carcinogenic chemical, individual susceptibility and
various predisposing factors.
• Chemical carcinogenesis occurs by induction of mutation in the proto-
oncogenes and anti-oncogenes. The phenomena of cellular transformation
by chemical carcinogens (as also other carcinogens) is a progressive process
involving 3 sequential stages :
• Initiation
• Promotion
• Progression

Initiation of Carcinogenesis
• It is the first stage in carcinogenesis induced by initiator chemical
carcinogens.
• change can be produced by a single dose of the initiating agent
for a short time, though larger dose for longer duration is more
effective.
• change so induced is sudden, irreversible and permanent
• initiators of carcinogenesis can be grouped into 2 categories
1. Direct-acting carcinogen- can induce cellular transformation
without undergoing any prior metabolic activation.
2. Indirect-acting carcinogens or procarcinogens- require
metabolic conversion within the body to become ‘ultimate’
carcinogens having carcinogenicity.

Steps are involved in transforming ‘the target
cell’ into ‘the initiated cell’
• 1. Metabolic activation- indirect-acting carcinogens are activated
in the liver by the mono-oxygenases of the cytochrome P-450
system in the endoplasmic reticulum.
• 2. Reactive electrophiles- direct-acting carcinogens are
intrinsically electrophilic, indirect-acting substances become
electron-deficient after metabolic activation i.e. they become
reactive electrophiles.
Following this step, both types of chemical carcinogens behave
alike and their reactive electrophiles bind to electron-rich portions
of other molecules of the cell such as DNA, RNA and other
proteins.

• 3. Target molecules- primary target of electro philes is DNA,
producing mutagenesis. The change in DNA may lead to ‘the
initiated cell’ or some form of cellular enzymes may be able to
repair the damage in DNA.
• The classic example of such a situation occurs in xero derma
pigmentosum, a precancerous condition, in which there is
hereditary defect in DNA repair mecha nism of the cell and thus
such patients are prone to develop skin cancer.
• FACT- Any gene may be the target molecule in the DNA for the
chemical carcinogen. However, on the basis of chemically
induced cancers in experimental animals and epidemiologic
studies in human beings, it has been observed that most
frequently affected growth promoter oncogene is RAS gene
mutation and antioncogene (tumour suppressor) is p53 gene
mutation.

•4. The initiated cell- The unrepaired
damage produced in the DNA of the cell
becomes permanent and fixed only if the
altered cell undergoes at least one cycle of
proliferation(growth).
This results in transferring the change to the
next progeny of cells so that the DNA
damage becomes permanent and
irreversible.

Promotion of Carcinogenesis
Promotion is the next sequential stage in the chemical carcinogenesis. Promoters of
carcinogenesis are substances such as phorbol esters, phenols, hormones,
artificial sweeteners and drugs like phenobarbital.
 Promoters are chemical substances which lack the intrinsic carcinogenic potential but
their application subsequent to initiator exposure helps the initiated cell to proliferate
further. These substances include phorbol esters, phenols, certain hormones and drugs.
They differ from initiators in the following respects:
i) They do not produce sudden change.
ii) They require application or administration, as the case may be, following initiator
exposure, for sufficient time and in sufficient dose.
iii) The change induced may be reversible.
iv) They do not damage the DNA per se and are thus not mutagenic but instead enhance the
effect of direct-acting carcinogens or procarcinogens.
v) Tumour promoters act by further clonal proliferation and expansion of initiated (mutated)
cells, and have reduced requirement of growth factor, especially after RAS gene mutation.

Progression of Carcinogenesis
• Progression of cancer is the stage when mutated proliferated cell
shows phenotypic features of malignancy.
• These features pertain to morphology, biochemical composition and
molecular features of malignancy.
• Such phenotypic features appear only when the initiated cell starts to
proliferate rapidly.
• Progeny of cells that develops after such repetitive proliferation
inherits genetic and biochemical characteristics of malignancy.

Sequential stages in chemical carcinogenesis (left) in evolution of cancer (right).

PHYSICAL CARCINOGENESIS
•Physical agents in carcinogenesis are divided
into 2 groups:
1. Radiation, both ultraviolet light and ionising
radiation, is the most important physical agent.
2. Non-radiation physical agents are the various
forms of injury and are less important.

RADIATION CARCINOGENESIS
• Ultraviolet (UV) light and ionising radiation are the two main
forms of radiation carcinogens which can induce cancer in
experimental animals and are implicated in causation of some
forms of human cancers.
• A property common between the two forms of radiation
carcinogens is the appearance of mutations followed by a
long period of latency after initial exposure, often 10-20 years
or even later.
• Also, radiation carcinogens may act to enhance the effect of
another carcinogen (co-carcino gens) and, like chemical
carcinogens, may have sequential stages of initiation,
promotion and progression in their evolution.

1. ULTRAVIOLET LIGHT
• The main source of UV radiation is the sunlight; others are UV lamps
and welder’s arcs. UV light penetrates the skin for a few milli metres
only so that its effect is limited to epidermis.
• The efficiency of UV light as carcinogen depends upon the extent of
light-absorbing protective melanin pigmentation of the skin. In
humans, excessive exposure to UV rays can cause various forms of
skin cancers—squamous cell carcinoma, basal cell carcinoma and
malignant melanoma.
• In support of this is the epidemiological evidence of high incidence of
these skin cancers in fair-skinned Europeans, albinos who do not tan
readily, inhabitants of Australia and New Zealand living close to the
equator who receive more sunlight, and in farmers and outdoor
workers due to the effect of actinic light radiation.

How Does light cause Cancer?
• UV radiation may have various effects on the cells.
• The most important is induction of mutation; others are inhibition of cell
division, inactivation of enzymes and sometimes causing cell death.
• The most important biochemical effect of UV radiation is the formation of
pyrimidine dimers in DNA. Such UV-induced DNA damage in normal
individuals is repaired, while in the predisposed persons who are
excessively exposed to sunlight such damage remain unrepaired.
• The proof in favour of mutagenic effect of UV radiation comes from
following recessive hereditary diseases characterised by a defect in DNA
repair mechanism and associated with high incidence of cancers:
i) Xeroderma pigmentosum is predisposed to skin cancers at younger age
(under 20 years of age).
ii) Ataxia telangiectasia is predisposed to leukaemia.
iii) Bloom’s syndrome is predisposed to all types of cancers.
iv) Fanconi’s anaemia with increased risk to develop cancer.

2. IONISING RADIATION
• Ionising radiation of all kinds like X-rays, a-, b- and g-
rays, radioactive isotopes, protons and neutrons can
cause cancer in animals and in man. Most frequently,
radiation-induced cancers are all forms of leukaemias
(except chronic lymphocytic leukaemia); others are
cancers of the thyroid (most commonly papillary
carcinoma), skin, breast, ovary, uterus, lung, myeloma,
and salivary glands. The risk is increased by higher
dose and with high LET (linear energy transfer) such
as in neutrons and a-rays than with low LET as in X-
rays and g-rays

Mechanism involved
• Mechanism Radiation damages the DNA of the cell by one of the 2
possible mechanisms:
i) It may directly alter the cellular DNA.
ii) It may dislodge ions from water and other molecules of the cell and
result in formation of highly reactive free radicals that may bring about
the damage.
• Damage to the DNA resulting in mutagenesis is the most important
action of ionising radiation.
• It may cause chromosomal breakage, translocation, or point mutation.
The effect depends upon a number of factors such as type of radiation,
dose, dose-rate, frequency and various host factors such as age,
individual susceptibility, immune competence, hormonal influences
and type of cells irradiated.

NON-RADIATION PHYSICAL
CARCINOGENESIS
• Mechanical injury to the tissues or prolonged contact
with certain physical agents has been observed to have
higher incidence of certain cancers but without proven
basis.
• A few rare examples of these uncommon associations
are as under:
i) Stones in the gallbladder and in the urinary tract
having higher incidence of cancers of these organs.
ii) Healed scars following burns or trauma for increased
risk of carcinoma of affected skin.

iii) Occupational exposure to asbestos (asbestosis)
associated with asbestos-associated tumours of the lung
and malignant mesothelioma of the pleura.
iv) Workers engaged in hardwood cutting or engraving
having high incidence of adeno-carcioma of paranasal
sinuses.
v) Surgical implants of inert materials such as plastic,
glass etc in prostheses.
vi) Foreign bodies embedded in the body for prolonged
duration.

BIOLOGIC CARCINOGENESIS
• The epidemiological studies on different types of cancers
indicate the involvement of transmissible biologic agents in
their development, chiefly viruses. Other microbial agents
implicated in carcinogenesis are as follows:
Parasites Schistosoma haematobium infection of the urinary
bladder is associated with high incidence of squamous cell
carcinoma of the urinary bladder in some parts of the world
such as in Egypt.
Clonorchis sinensis, the liver fluke, lives in the hepatic duct
and is implicated in causation of
cholangiocarcinoma.(Cholangiocarcinoma is a cancer that
arises from the cells within the bile ducts; both inside and
outside the liver.)

Fungus Aspergillus flavus grows in stored grains
and liberates aflatoxin; its human consumption,
especially by those with HBV infection, is
associated with development of hepatocellular
carcinoma.
Bacteria Helicobacter pylori, a gram-positive
spiral shaped micro-organism, colonises the
gastric mucosa and has been found in cases of
chronic gastritis and peptic ulcer; its prolonged
infection may lead to gastric lymphoma and
gastric carcinoma

VIRAL CARCINOGENESIS
• It has been estimated that about 20% of all cancers
worldwide are due to persistent virus infection.
• The association of oncogenic viruses with neoplasia
was first observed by an Italian physician Sanarelli in
1889 who noted association between myxomatosis of
rabbits with poxvirus.
• The contagious nature of the common human wart
was first established in 1907. Since then, a number of
viruses capable of inducing tumours (oncogenic
viruses) in experimental animals, and some implicated
in humans, have been identified.

Routes of Transmission
• Most of the common viral infections (including oncogenic
viruses) can be transmitted by one of the 3 routes:
i) Horizontal transmission Commonly, viral infection passes
from one to another by direct contact, by ingestion of
contaminated water or food, or by inhalation as occurs in most
contagious diseases. Most of these infections begin on the
epithelial surfaces, spread into deeper tissues, and then through
haematogenous or lymphatic or neural route disseminate to
other sites in the body.
ii) By parenteral route such as by inoculation as happens in some
viruses by inter-human spread and from animals and insects to
humans.
iii) Vertical transmission, when the infection is genetically
transmitted from infected parents to offsprings.

• Based on their nucleic acid content, oncogenic viruses fall
into 2 broad groups:
1. Those containing deoxyribonucleic acid are called DNA
oncogenic viruses.
2. Those containing ribonucleic acid are termed RNA
oncogenic viruses or retroviruses.
Both types of oncogenic viruses usually have 3 genes and are
abbreviated according to the coding pattern by each gene:
i) gag gene: codes for group antigen.
ii) pol gene: codes for polymerase enzyme.
iii) env gene: codes for envelope protein.

• Natural history of viral infection can be categorised into primary
and persistent:
• Primary viral infections are majority of the common viral
infections in which the infection lasts for a few days to a few
weeks and produces clinical manifestations. Primary viral
infections are generally cleared by body’s innate immunity and
specific immune responses.
• Persistence of viral infection or latent infection in some viruses
may occur by acquiring mutations in viruses which resist
immune attack by the host, or virus per se induces
immunosuppression in the host such as HIV.

How does viruses cause cancer?
• In general, persistence of DNA or RNA viruses may induce mutation
in the target host cell, although persistence of viral infection alone is
not sufficient for oncogenesis but is one step in the multistep process
of cancer development.
• Generally, RNA viruses have very high mutation rate (e.g. HIV,
HCV) than DNA viruses.
• Mechanisms as to how specific DNA and RNA viruses cause mutation
in the host cell are varied, but in general continued presence of DNA
or RNA virus in the cell causes activation of growth-promoting
pathways or inhibition of tumour-suppressor products in the infected
cells.
• Thus, such virus-infected host cells after having undergone genetic
changes enter cell cycle and produce next progeny of transformed
cells which have characteristics of autonomous growth and survival
completing their role as oncogenic viruses.

General mode of oncogenesis by each
group of DNA and RNA oncogenic viruses
• Mode of DNA viral oncogenesis Host cells infected by DNA
oncogenic viruses may have one of the following 2 results
i) Replication The virus may replicate in the host cell with consequent
lysis of the infected cell and release of virions.
ii) Integration The viral DNA may integrate into the host cell DNA.
The latter event (integration) results in inducing mutation and thus
neoplastic transformation of the host cell, while the former
(replication) brings about cell death but no neoplastic trans formation.

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