Introduction

• A tumor is a pathologic disturbance of cell growth, characterized by

excessive and abnormal proliferation of cells.
• Tumors are abnormal mass of tissue which may be solid or fluid
filled.
• When the growth of tumor cells confined to the site of origin and
are of normal physicality they are concluded as benign tumors.
When the cells are abnormal and can grow uncontrollably, they are
concluded as cancerous cells i.e. malignant tumor.
• To determine whether a tumor is benign or cancerous, a doctor can
take a sample of the cells with a biopsy procedure. Then the biopsy
is analyzed under a microscope by a pathologist
• Tumours: Benign and Malignant
• Non-malignant or benign tumours are much more common
than malignant tumours.
• A benign tumour is a limited growth of cells that seems to
be under some sort of control. Although there is no
apparent purpose in the growth, the cells are more mature
and closely resemble the cells from which they developed.
Once the growth reaches a certain size, it usually slows or
stops, such as a mole on the skin.
• All the cells of a benign tumour stay together as a lump or
swelling that is usually confined by a capsule or lining of
fibrous tissue. They do not spread to other parts of the
body and are generally easily removed by surgery
 Benign Tumors: Noncancerous
• If the cells are non-cancerous, the tumor is concluded as benign.
• It won’t invade nearby tissues or spread to other areas of the body (metastasize).
• A benign tumor is less harmful unless it is present nearby any important organs, tissues, nerves,
or blood vessels and causing damage.
• Fibroids in the uterus and breast, polyps of colon and moles are some examples of benign
tumors.
• Benign tumors can be removed by surgery. They can grow very large, sometimes weighing
pounds. They can be dangerous, such as when they occur in the brain and crowd the normal
structures in the enclosed space of the skull.
• The growth of benign tumors produces a "mass effect" that can compress tissues and may cause
nerve damage, reduction of blood to an area of the body (ischaemia), tissue death (necrosis)
and organ damage.
• The health effects of the tumor may be more prominent if the tumor is within an enclosed space
such as the cranium, respiratory tract, sinus or inside bones. T
• tumors of endocrine tissues may overproduce certain hormones, especially when the cells are
well differentiated. Examples include thyroid adenomas and adrenocortical adenomas.
• They can press on vital organs or block channels. Also, some types of benign tumors such as
intestinal polyps are considered as precancerous and are removed immediately to prevent them
becoming malignant.
• Benign tumors usually don’t reoccur once removed, but if they do it is usually in the same place.
• Although most benign tumors are not life-threatening, many types of benign
tumors have the potential to become cancerous (malignant) through a
process known as tumor progression.
• For this reason and other possible negative health effects, some benign
tumors are removed by surgery
• Benign neoplasms are typically but not always composed of cells which bear
a strong resemblance to a normal cell type in their organ of origin.
• These tumors are named for the cell or tissue type from which they
originate, followed by the suffix "-oma" (but not -carcinoma, -sarcoma, or -
blastoma, which are generally cancers).
• For example, a lipoma is a common benign tumor of fat cells (lipocytes), and
a chondroma is a benign tumor of cartilage-forming cells (chondrocytes).
• Adenomas are benign tumors of gland-forming cells, and are usually
specified further by their cell or organ of origin, as in hepatic adenoma (a
benign tumor of hepatocytes, or liver cells).
• Teratomas contain many cell types such as skin, nerve, brain and thyroid,
among others, because they are derived from germ cells
• There are a few cancers with 'benign-sounding' names which have been
retained for historical reasons, including melanoma (a cancer of pigmented
skin cells, or melanocytes)
 Malignant tumors
• A malignant tumor contrasts with a non-cancerous benign tumor in that a
malignancy is not self-limited in its growth, is capable of invading into
adjacent tissues, and may be capable of spreading to distant tissues. A
benign tumor has none of those properties.

• Malignancy in cancers is characterized by anaplasia, invasiveness, and

metastasis.
• Malignant tumors are also characterized by genome instability, so that
cancers, as assessed by whole genome sequencing, frequently have
between 10,000 and 100,000 mutations in their entire genomes.
• Cancers usually show tumour heterogeneity, containing multiple
subclones.
• They also frequently have reduced expression of DNA repair enzymes due
to epigenetic methylation of DNA repair genes or altered microRNAs that
control DNA repair gene expression.
• Malignant means that the tumor is made of cancer cells and it can
invade nearby tissues. Some cancer cells can move into the
bloodstream or lymph nodes, where they can spread to other
tissues within the body—this is called metastasis.
• Cancer can occur anywhere in the body including the breast, lungs,
intestines, reproductive organs, blood, or skin. For example, breast
cancer begins in the breast tissue and may spread to lymph nodes
in the armpit if it’s not caught early enough and treated.
• Once breast cancer has spread to the lymph nodes, the cancer cells
can travel to other areas of the body, like the bones or liver. The
breast cancer cells can then form tumors in those locations referred
as secondary tumor.
• A biopsy of these tumors might show characteristics of the original
breast cancer tumor
 Differences Between Benign and
Malignant Tumors
• There are many important differences between benign and
malignant tumors which are as follows:
• i. On the Basis of Growth rate: Generally malignant tumors grow
more rapidly than benign tumors, although there are slow-growing
and fast-growing tumors in either category.
• ii. On the basis of Ability to invade locally: Malignant tumors use to
invade the tissues around them. One of the most prominent
hallmarks of cancer is penetration of the basal membrane that
surrounds normal tissues.
• iii. On the Basis of Ability to spread at distance: Malignant tumors
may spread to other parts of the body using the bloodstream or the
lymphatic system. Malignant tumors may also invade nearby tissues
and send out fingers into them, while benign tumors don’t. Benign
tumors only grow in size at the place of their origin.
• On the Basis of Recurrence: Benign tumors can be removed completely by surgery
as they have clearer boundaries, and as a result, they are less likely to reoccur. If
they do reoccur, it is only at the original site.
• Malignant tumors may spread to other parts of body. They are more likely to
reoccur such as breast cancer recurring in the lungs or bones.
• v. On the Basis of Cellular Appearance: When a pathologist looks at tumor cells
under a microscope, it is very easy to determine whether they are normal, benign
cells or cancerous cells as Cancer cells often have abnormal chromosomes and
DNA, making their nuclei larger and darker. They also often have different shapes
than normal cells.
• However, sometimes the difference is subtle.
• vi. On the Basis of Systemic effects: There are some benign tumors that secrete
hormones, such as benign pheochromocytomas, malignant tumors are more likely
to do so.
• Malignant tumors can secrete substances that cause effects throughout the body,
such as fatigue and weight loss. This is known as paraneoplastic syndrome.
• vii. On the Basis of Treatments: A benign tumor can
usually be completely treated with surgery, although
some may be treated with radiation therapy or
chemotherapy.
• Some benign tumors are not treated as they are not
posing any health risk.
• Malignant tumors may require chemotherapy,
radiation therapy, or immunotherapy medications to
eliminate a tumor cell that still remains after treatment
or to treat secondary tumors present at other parts of
the body (Figure )
 Tumors arise from many specialized
cell types throughout the body
• The majority of human tumors arise from epithelial tissues.
• Epithelia are sheets of cells that line the walls of cavities and channels or, in the
case of skin, serve as the outside covering of the body.
• By the first decades of the twentieth century, detailed histological analyses had
revealed that normal tissues containing epithelia are all structured similarly.
• Thus, beneath the epithelial cell layers in each of these tissues lies a basement
membrane (sometimes called a basal lamina); it separates the epithelial cells from
the underlying layer of supporting connective tissue cells, termed the stroma
• The basement membrane is a specialized type of extracellular matrix (ECM) and is
assembled from proteins secreted largely by the epithelial cells.
• Another type of basement membrane separates endothelial cells, which form the
inner linings of capillaries and larger vessels, from an outer layer of specialized
smooth muscle cells.
• In all cases, these basement membranes serve as a structural scaffolding of the
tissue
• Epithelia are of special interest, because they spawn the most common human
cancers—the carcinomas.
• Carcinoma: These tumors are responsible for
more than 80% of the cancer-related deaths in
the Western world.
• Included among the carcinomas are tumors
arising from the epithelial cell layers of the
gastrointestinal tract—which includes mouth,
esophagus, stomach, and small and large
intestines—as well as the skin, mammary gland,
pancreas, lung, liver, ovary, uterus, prostate,
gallbladder, and urinary bladder.
• This group of tissues encompasses cell types that arise from all
three of the primitive cell layers in the early vertebrate embryo.
• Thus, the epithelia of the lungs, liver, gallbladder, pancreas,
esophagus, stomach, and intestines all derive from the inner cell
layer, the endoderm.
• Skin arises from the outer embryonic cell layer, termed the
ectoderm, while the ovaries originate embryologically from the
middle layer, the mesoderm.
• Therefore, in the case of carcinomas, histopathological
classification is not informed by the developmental history of the
tissue of origin.
• The epithelial and stromal cells of these various tissues collaborate
in forming and maintaining the epithelial sheets.
• Most carcinomas fall into two major categories that
reflect the two major biological functions associated
with epithelia (Table ).
• Some epithelial sheets serve largely to seal the cavity
or channel that they line and to protect the underlying
cell populations
• Tumors that arise from epithelial cells forming these
protective cell layers are termed squamous cell
carcinomas.
• For example, the epithelial cells lining the skin
(keratinocytes) and most of the oral cavity spawn
tumors of this type.
• Many epithelia also contain specialized cells that secrete substances
into the ducts orcavities that they line. This class of epithelial cells
generates adenocarcinomas. Often these secreted products are
used to protect the epithelial cell layers from the contents of the
cavities (lumina) that they surround
• Thus, some epithelial cells lining the lung and stomach secrete
mucus layers that protect them, respectively, from the air (and
airborne particles) and from the corrosive effects of high
concentrations of acid.
• The epithelia in some organs such as the lung, uterus, and cervix
have the
capacity to give rise to pure adenocarcinomas or pure squamous cell
carcinomas .quite frequently, however, tumors in these organs are
found in which both types of carcinoma cells coexist.
Normal squamous cells are often flattened and function to protect the epithelium
and underlying tissue from the contents of the lumen or, in the case of skin, from
the outside world
In this carcinoma of the esophagus, large tongues of malignant squamous
epithelial cells are invading the underlying stromal/mesenchymal
tissue.
 sarcoma
• The remainder of malignant tumors arise from nonepithelial tissues throughout
the body.
• The first major class of nonepithelial cancers derive from the various connective
tissues, all of which share a common origin in the mesoderm of the embryo
• These tumors, the sarcomas, constitute only about 1% of the tumors encountered
• . Sarcomas derive from a variety of mesenchymal cell types.
• Included among these are fibroblasts and related connective tissue cell types that
secrete collagen, the major structural component of the extracellular matrix of
tendons and skin; adipocytes, which store fat in their cytoplasm; osteoblasts,
which assemble calcium phosphate crystals within matrices of collagen to form
bone; and myocytes, which assemble to form muscle
• Hemangiomas, which are relatively common in children, arise from precursors of
the endothelial cells. The stromal layers of epithelial tissues include some of these
mesenchymal cell types
• Classification
• Sarcomas are typically divided into two major
groups: bone sarcomas and soft tissue sarcomas,
each of which has multiple subtypes.
• Subtypes of bone sarcoma:
• Osteosarcoma
• Chondrosarcoma
• Poorly differentiated round/spindle cell tumors
(includes Ewing sarcoma)
• Hemangioendothelioma
• Angiosarcoma
• Fibrosarcoma/myofibrosarcoma
• Chordoma
• Adamantinoma
• Subtypes of soft tissue sarcoma:

• Liposarcoma (includes the following varieties: well-

differentiated, not otherwise specified, de-
differentiated, myxoid/round cell, and pleomorphic)
• Atypical lipomatous tumor
• Dermatofibrosarcoma protuberans (includes
fibrosarcomatous and pigmented varieties)
• Giant cell tumor of soft tissues
• Leiomyosarcoma
• Symptoms of bone sarcomas typically include bone pain, especially at
night, and swelling around the site of the tumor.
• Symptoms of soft tissue sarcomas vary, but often present as firm, painless
lumps or nodules. Gastrointestinal stromal tumors often are
asymptomatic, but can be associated with vague complaints of abdominal
pain, a feeling of fullness, or other signs of intestinal obstruction.
• Causes and risk factors
• The cause of most bone sarcomas is not known, but several factors are
associated with an increased risk of developing bone sarcoma.
• Previous exposure to ionizing radiation (such as prior radiation therapy) is
one such risk factor.
• Exposure to alkylating agents, such as those found in certain cancer
chemotherapeutic medicines, also increases the risk of bone sarcoma.
Certain inherited genetic syndromes, including Li-Fraumeni syndrome,
heritable RB1 gene mutations, and Paget's disease of bone, are associated
with an increased risk of developing bone sarcomas
 Hematopoietic cancers
• The second group of nonepithelial cancers arise from the various cell types that constitute the
blood-forming (hematopoietic) tissues, including the cells of the immune system these cells also
derive from the embryonic mesoderm.
• Among them are cells destined to form erythrocytes (red blood cells), antibody- secreting (plasma)
cells, as well as T and B lymphocytes.
• The term leukemia (literally “white blood”) refers to malignant derivatives of several of these
hematopoietic cell lineages that move freely through the circulation and, unlike the red blood cells,
are nonpigmented.
• Lymphomas include tumors of the lymphoid lineages (B and T lymphocytes) that aggregate to form
solid tumor masses, most frequently found in lymph nodes, rather than the dispersed, single-cell
populations of tumor cells seen in leukemias.
• This class of tumors is responsible for ~7% of cancer-associated mortality in the United States.
• Hematological malignancies may derive from either of the two major blood cell lineages: myeloid
and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes,
thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma
cells.
• Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and
chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are
myeloid in origin.
• The third and last major grouping of nonepithelial
tumors arises from cells that form various components
of the central and peripheral nervous systems
• These are often termed neuroectodermal tumors to
reflect their origins in the outer cell layer of the early
embryo. Included here are gliomas, glioblastomas,
neuroblastomas, schwannomas, and
medulloblastomas
• . They comprise only 1.3% of all diagnosed cancers,
these are responsible for about 2.5% of cancer-related
deaths.
 CHARACTERISTIC PROPERTIES OF
CANCERS AND CANCER CELLS
• In spite of their diversity, human cancers share several fundamental properties
• these properties may be acquired step by step and become evident at various stages
during the progression of a cancer.
• the combination of uncontrolled cell proliferation, altered differentiation and
metabolism, genomic instability, and invasiveness with eventual metastasis is unique to
and defines cancer.
• Increased and autonomous cell proliferation: The
most obvious property of tumors is growth
beyond normal measures. In fact, the term
‘tumor’ when used in a broader sense designates
every abnormally large structure in the human
body, also including swellings or fluid-filled cysts
• The borderlines between hyperplasia, benign
tumors, and cancer are often evident from
microscopic or even macroscopic inspection, but
in some cases additional criteria or markers have
to be employed to make the distinction.
• Hyperproliferation in cancers is brought about by
an altered response to exogenous growth
regulatory signals
• Insufficient apoptosis: Cell proliferation in cancers may be caused by a
combination of three factors:
• (1) The rate of cell proliferation is enhanced by an increase in the
proportion of cells with an active cell cycle, i.e., a higher ‘proliferative
fraction’, and/or by a more rapid transit through the cell cycle, together
resulting in increased DNA synthesis and mitosis.
• (2) The rate of cell death is often decreased by relatively diminished
apoptosis.
• In some cancers, this is in fact the driving force for increased proliferation.
• In others, the rate of apoptosis is enhanced compared to normal tissue;
but not sufficiently so as to compensate for the increase in mitotic activity.
• (3) In normal tissues, successive stages of differentiation are typically
associated with progressively decreased proliferative capacity and/or with
apoptotic death of the fully differentiated cells
• a block to differentiation is in some cases sufficient to confer an increased
proliferation rate.
• Altered differentiation: Many cancers consist of cells which resemble
precursor cells of their tissue of origin and have not embarked on the
normal course of differentiation, whereas others show properties of
cells at intermediate stages of differentiation.
• Some cancers, however, do consist of cells with markers of full
differentiation, with the crucial difference that they continue to
proliferate. In these cancers, it is not difficult to identify the cell of
origin, which is important for diagnosis.
• Most cancers, however, express markers that do not occur in their
tissue of origin
• Frequently, cancer cells express proteins which are otherwise only
found in fetal cells. Such proteins, e.g. carcinoembryonic antigen in
colon carcinoma or alpha-fetoprotein in liver cancer are called
‘oncofetal’ markers. Other proteins expressed in cancers are never
synthesized in the original cell type, e.g. ‘cancer testis antigens’ in
melanoma and various peptide hormones in small cell lung cancer.
• This phenomenon is called ‘ectopic’ expression. Some cancers
change their phenotype to resemble cells from a different tissue in a
process called ‘metaplasia’.
• Two such ‘generic’ cell types are a small epithelial-like cell with a large nucleus to
cytoplasm ratio and a spindle-shaped cell resembling a mesenchymal fibroblast.
• These cell types are end points of cancer progression in some carcinoma cases,
typically found in aggressive cases and therefore also in metastases.
• altered differentiation confers properties to cancer cells that are otherwise found
in tissue precursor cells, fetal cells or cells of other tissues.
• Moreover, altered differentiation is also related to increased proliferation., the
control of proliferation and differentiation are intimately linked in normal tissues.
• The final stages of differentiation of many normal tissues are associated with an
irreversible loss of replicative potential or even with cell death This process is
therefore called ‘terminal differentiation’
• For instance, differentiated cells in keratinizing epithelia crosslink with each other,
dissolve their nuclei, and become filled with structural proteins.
• This way, a steady state between cell generation and loss is maintained which
breaks down, if differentiation fails in a cancer
• Altered metabolism: Cell proliferation, whether normal or abnormal,
requires according changes in cell metabolism.
• Most evidently, DNA synthesis requires deoxynucleotides, so enzymes
required for nucleotide biosynthesis, and specifically of deoxynucleotide
biosynthesis, are induced and activated in proliferating cells.
• Further cell components such as membranes and organelles also need to be
duplicated. For this reason, lipid biosynthesis is increased in cancer cells,
likely because they cannot obtain enough fatty acids, phospholipids and
cholesterol from lipoproteins supplied by the gut and liver.
• Thus, expression and activity of key enzymes like fatty acid synthase and
hydroxymethylglutaryl-coenzyme A reductase are increased in cancer cells.
• Porphyrin biosynthesis is also often increased.
• Warburg noted in the 1930’s, many tumor cells switch from
• aerobic to an aerobic glucose metabolism.
• A key requirement for cell growth is increased protein synthesis, which is
apparent at several levels by enhanced size and number of nucleoli,
increased expression of transcription initiation factors and enhanced
phosphorylation of ribosomal proteins.
• A particularly strong boost in protein synthesis may be required during
invasion and metastasis
• cancer growth poses an enhanced energy demand on the patient,
which increases with the tumor load
• cancers release the waste products of their metabolism, such as
lactate, with which the body has to cope. These are, unfortunately,
only some of the systemic effects of cancers.
• Cancers also secrete enzymes and hormones that act on the host,
some of which are toxic. In particular, cytokines like tumor necrosis
factor 􀁄 can elicit a general break-down of metabolic function with
visible wasting, termed ‘cachexia’, and suppression of the immune
system, thereby facilitating ‘opportunistic’ infections.
• Other tumor products, such as FAS ligand can damage sensitive
organs such as the liver, and ectopically produced hormones can
interfere with homeostasis.
• Calcitonin production by small cell lung cancers may cause life-
threatening variations in calcium levels.
• indirect disturbances of the body homeostasis by cancers, designated
as ‘paraneoplastic’ symptoms, can be as problematic for the well-
being and survival of a patient as the malignant growth per se.
• Genomic instability: A clear distinction between cancerous and non-
cancerous cell proliferation lies in genomic instability. Cancer cells as a rule
contain multiple genetic and epigenetic alterations
• Polyploidy, an increase in the number of genomes per cell, can be
ascertained by measuring cellular DNA content. Aneuploidy, i.e. a change in
the number and structure of individual chromosomes, is revealed by
cytogenetic methods.
• These aberrations are often already revealed upon microscopic observation
of tumor tissues by altered size and shape of the nuclei in the cancer cells
and aberrant mitotic figures. Other cancers remain diploid or nearly so, but
contain point mutations and/or altered DNA methylation patterns.
• As cancers progress, the numbers of alterations in their genome tend to
increase. Therefore, cancers, even if outwardly homogeneous, usually
consist of cell clones that differ at least slightly in their genetic constitution.
• The variant clones are continuously selected for those proliferating fastest,
tolerating adverse conditions best, capable of evading immune responses,
etc., with the best-adapted cell clone dominating growth
• This variation becomes particularly evident during tumor treatment by
chemotherapy which exerts a strong selection pressure for those cell clones
carrying alterations that allow them to survive and continue to expand in
spite of therapy.
• Genomic instability in a cancer continuously creates novel clones from the
initial tumor (left). These clones are selected according to their ability to
proliferate in the face of hypoxia and immune responses, and to adapt at
metastatic sites. One (right) or several clones may succeed
• Genomic instability in cancer cells can be derived from several sources,
e.g. from defects in DNA repair and in mechanisms checking genomic
integrity
• Immortalization: Many cancer cells are ‘immortalized’, which means they are
capable of a theoretically infinite number of cell divisions.
• Most human cells can undergo only a finite number of divisions, likely up to
60-80, before they irreversibly lose their ability to proliferate (􀁄 7.4).
• , the cells constituting the germ line are exempt from this restriction and so
are tissue stem cells.
• For instance, hematopoetic stem cells in the bone marrow can be
successively transplanted across several recipients and still remain capable of
reconstituting the entire hematopoetic system, blood and immune cells.
Immortality in stem cells is maintained by specific mechanisms such as
expression of telomerase ), which is also found in cancers.
• , some human cancer cells can be maintained in tissue culture or as
transplants in animals, designated ‘xenografts’, over many generations, as far
as we can tell, infinitely many.
• , it is not certain that all human cancers are immortalized, since many cannot
be grown in tissue culture or as xenografts. Even telomerase expression is
not universal.
• To become life-threatening, however, a cancer does not need to consist of
cells with infinite growth potential.
• Starting out from a single cell, 50 replications would yield up to 249 tumor
cells, which must be compared to something between 1013 and 1014 normal
cells in a human.
• Lethal cancers are much smaller than that.
• Invasion and metastasis: A property more directly evident in human cancers
is their ability for invasion and metastasis.
• Invasion and metastasis are the definitive criteria which distinguish benign
from malignant tumors
• ., invasion and metastasis, with tumor cachexia and immune suppression,
account for most of the lethality of human cancers.
• During invasion, cancers spread from their site of origin into different layers
and parts of the same tissue, eventually growing beyond it and into
neighboring structures.
• Invasion involves multiple steps and often substantial rebuilding of the tissue
structure by the tumor cells, by other cells in the tissue responding to signals
from the tumor cells, and by immune and inflammatory cells. T
• typically, in carcinomas, the basement membrane separating epithelium and
mesenchyme is destroyed and tumor extensions push through the connective
tissue and muscle layers.
• From some cancers, cells separate and migrate through the neighboring
tissues, as single cells, in an Indian file pattern or as small, adherent cell
clusters.
• Invasion is often accompanied by inflammation, so lymphocytes, granulocytes
and macrophages are present in the invaded tissue and in the tumor mass.
• An important component of malignant growth is neoangiogenesis .
• The nutrient and oxygen supply from preexisting blood vessels is usually not
sufficient to support growth of tumors beyond a size of a few mm.
• Therefore, cancers, but also some benign tumors, induce neoangiogenesis,
which comprises the growth of new capillaries, and the rebuilding of existing
blood vessels. Lymph vessels can also be remodeled or newly formed.
• During metastasis, cancer cells separate from the primary tumor and migrate by
the blood or lymph to different organs where they form new tumors.
• Depending on the route, ‘hematogenic’ metastasis, which usually leads to
metastases at distant organ sites, is distinguished from ‘lymphogenic’
metastasis, which leads initially to the formation of metastases in lymph nodes
draining the region from which the cancer emerges. Like invasion, metastasis is
really a multistep process.
• , many more cancer cells enter the blood or lymph than actually form
metastases.
• Important barriers are posed by the necessity to leave the blood stream at
capillaries which carcinoma cells cannot pass (‘extravasation’) and to survive
and resume proliferation in the microenvironment of a different tissue.
• In fact, individual cancer cells or small groups may end up in a different tissue
only to survive over long periods without net growth.
• These ‘micrometastases’ are not detectable by current imaging techniquew,
although they may be biochemically detectable by proteins secreted by the
cancer cells.
• Over time, they may adapt to their new
environment and expand to larger metastases
that threaten the patient’s life.
• This may occur several years after the primary
tumor has been removed.
• Cancers differ in the extent and the sites to which
they metastasize
• Generally, preferred organs for metastasis are
those with extended microcapillary systems such
as liver, lung, and bone.
• Changes in Cell Membrane Structure and Function
• The cell surface membrane (plasma membrane) plays an important role in
the “social” behavior of cells, that is, communication with other cells, cell
movement and migration, adherence to other cells or structures, access to
nutrients in the microenvironment, and recognition by the body's immune
system.
• Alterations of the plasma membrane in malignant cells may be inferred
from a variety of properties that characterize their growth and behavior,
• Eg. , the loss of density-dependent inhibition of growth, decreased
adhesiveness, loss of anchorage dependence, and invasiveness through
normal tissue barriers. In addition, a number of changes in the
biochemical characteristics of malignant cells' surfaces have been
observed. These include appearance of new surface antigens,
proteoglycans, glycolipids, and mucins, and altered cell-cell and cell-
extracellular matrix communication.
• Alterations in Cell Surface Glycolipids, Glycoproteins,
Proteoglycans, and Mucins
• Aberrant glycosylation was first suggested as the basis for the
tumor-associated determinants of glycolipids by the finding of a
accumulation of fucose-containing glycolipids found in human
adenocarcinomas, some of which were identified as
lactofucopentaose-III-ceramide, lactofucopentaose-II-ceramide
(Lewis A blood group glycolipid), and lactodifucohexose and
lactodifucooctose ceramide (Lewis B glycolipid).
• These identifications were confirmed once monoclonal antibodies
were used to identify antigens definitively.
• chemical basis for some of the changes in tumor cell glycoproteins
was attributed to the fact that the N-linked oligosaccharides of
tumor cells contain more multiantennary structures than the
oligosaccharides derived from normal cells.
• Tumor-associated carbohydrate antigens can be classified into three
groups:
• (1) epitopes expressed on both glycolipids and glycoproteins;
• (2) epitopes expressed only on glycolipids;
• (3) epitopes expressed only on glycoproteins.
• To the first group belongs the lacto series structure that is found in
the most common human cancers, such as lung, breast, colorectal,
liver, and pancreatic cancers. The common backbone structure for
these epitopes is Ga1β1→3G1cNAcβ1→3Ga1 (type 1 blood group) or
Ga1β1→4G1cNacβ1→3Ga1 (type 2 blood group)
• The second group of epitopes, expressed exclusively on glycolipids, is
mostly on the ganglio or globo series structures. This series of
epitopes are expressed abundantly only on certain types of human
cancers, such as melanoma, neuroblastoma, small-cell lung
carcinoma, and Burkitt lymphoma.
• The third group of epitopes, seen only on glycoproteins, is the
multiantennary branches of N-linked carbohydrates and the
alterations of O-linked carbohydrate chains seen in some mucins.
• Tumor-associated carbohydrate antigens can also
be classified by the cell types expressing them as
• (1) those expressed on only certain types of
normal cells (often only in certain developmental
stages) and greatly accumulated in tumor cells;
• (2) expressed only on tumor cells, for example,
altered blood group antigens or mucins; and
• (3) expressed commonly on normal cells but
present in much higher concentrations on tumor
cells, for example, the GM3ganglioside in
melanoma and Lex in gastrointestinal cancer.
• A variety of chemical changes in tumor cells have been
identified that can explain altered glycosylation
patterns. These result from three kinds of altered
processes:
• (1) incomplete synthesis and/or processing of normally
existing carbohydrate chains and accumulation of the
resulting precursor form;
• (2) “neosynthesis” resulting from activation of
glycosyltransferases that are absent or have low
activity in normal cells; and
• (3) organizational rearrangement of tumor cell
membrane glycolipids.
• Mucins
• Mucins are a type of highly glycosylated glycoproteins that a variety of
secretory epithelial cells produce.
• They are 50%; to 80%; carbohydrate by weight and function to lubricate and
protect ductal epithelial cells. They contain O-linked glycans (serine- and
threonine-linked) of various lengths and structures, depending on the tissue
type in which they are produced.
• They are made in a wide variety of tissues, including the gastrointestinal
tract, lung, breast, pancreas, and ovary, and tumors arising in these organs
may have an altered glycosylation pattern that distinguishes them from the
normal mucins and renders them immunogenic.
• Total expression of the mucins is increased in many cancers and upregulated
in some normal tissues under different physiologic states (eg, lactating
mammary gland).
• Increased expression of muc1 has been observed in most adenocarcinomas
of the breast, lung, stomach, pancreas, prostate, and ovary
• Focal aberrant expression of muc2 and muc3has been frequently observed
in a variety of adenocarcinomas.
• , in general, mucin genes appear to be independently regulated and their
expression is organ and cell-type specific
• There is evidence for host immune recognition of the breast cancer
mucin, in that cytotoxic T lymphocytes isolated from breast cancer
patients recognize a mucin epitope expressed on the breast cancer
cells.
• The immune-recognized epitope involves the core protein that
appears to be selectively exposed on breast, ovarian, and other
carcinomas.
• It has also been demonstrated that patients can produce antibodies
to cancer mucins
• Some mucin antigens are shed from tumor cells and can be
detected in the sera of patients with pancreatic, ovarian, breast,
and colon cancers. These include CA19-9, CA125, CA15-3, SPan-1,
and DuPan-2 that are currently being used as tumor markers.
• Proteoglycans
• The proteoglycans are high-molecular-weight glycoproteins that have a protein
core to which are covalently attached large numbers of side chains of sulfated
glycosaminoglycans as well as N-linked and/or O-linked oligosaccharides.
• They are categorized on the basis of their glycosaminoglycans into several types,
including heparan sulfate, chondroitin sulfate, dermatan sulfate, and keratan
sulfate.
• The glycosaminoglycans have different repetitive disaccharide units bound to the
core protein through a common glycosaminoglycan linkage region:
G1cNAcβ1→3Ga1β1→3Ga1β1→4Xy1β1-O-Ser.
• Proteoglycans interact via their multiple binding domains with many other
structural macromolecules, giving them the capacity “to function as a multipurpose
‘glue’ in cellular interactions.”
• They bind together extracellular matrix (ECM) components, such as hyaluronic acid,
collagen, laminin, and fibronectin; mediate binding of cells to the ECM; act as a
reservoir for growth factors; and “present” growth factors to growth factor
receptors on cells.
• The proteoglycans also act as cell adhesion factors by promoting organization of
actin filaments in the cell's cytoskeleton. Proteoglycans have been shown to
undergo both quantitative and qualitative changes during malignant
transformation, and alterations have been reported in breast, colon, and liver
carcinomas, in glioma cells, and in transformed murine mammary cells and 3T3
fibroblasts
• Two putative tumor-suppressor genes are
glycosyl transferases required for the biosynthesis
of the proteoglycan heparan sulfate.
• Mutations of these genes, called ext1 and ext2,
have been associated with the development of
skeletal dysplasias, and these findings suggest
that alterations in the synthesis of heparan
sulfate precursor polysaccharide are involved in
dysregulation of heparan sulfate production and
function in tumor formation.
 Angiogenesis in Cancer
• Cancer has the ability to spread to adjacent or distant organs, which
makes it life threatening.
• Tumor cells can penetrate blood or lymphatic vessels, circulate
through the intravascular stream, and then proliferate at another
site: metastasis .
• For the metastatic spread of cancer tissue, growth of the vascular
network is important.
• The processes whereby new blood and lymphatic vessels form are
called angiogenesis and lymphangiogenesis, respectively.
• Both have an essential role in the formation of a new vascular
network to supply nutrients, oxygen and immune cells, and also to
remove waste products
• Tumor growth and metastasis depend on angiogenesis and
lymphangiogenesis triggered by chemical signals from tumor cells in
a phase of rapid growth
• In the absence of vascular support, tumors may become necrotic or
even apoptotic
• Therefore, angiogenesis is an important factor in the
progression of cancer. Neovascularization, including
tumor angiogenesis, is basically a four-step process.
• First, the basement membrane in tissues is injured
locally. There is immediate destruction and hypoxia.
• Second, endothelial cells activated by angiogenic factors
migrate.
• Third, endothelial cells proliferate and stabilize.
• Fourth, angiogenic factors continue to influence the
angiogenic process.
• Vascular endothelial cells divide only about every 1000
days on average.
• Angiogenesis is stimulated when tumor tissues require
nutrients and oxygen.
• Angiogenesis is regulated by both activator
and inhibitor molecules.
• However, up-regulation of the activity of
angiogenic factors is itself not sufficient for
angiogenesis of the neoplasm. Negative
regulators or inhibitors of vessel growth need
to also be down-regulated
 Endogenous angiogenic factors
• More than a dozen different proteins have been identified as
angiogenic activators, including vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (bFGF),
angiogenin, transforming growth factor (TGF)-α, TGF-β,
tumor necrosis factor (TNF)-α, platelet-derived endothelial
growth factor, granulocyte colony-stimulating factor,
placental growth factor, etc.,
• The VEGF family and their receptors (VEGFR) are receiving
increasingly more attention in the field of neoplastic
vascularization.
• VEGF is a powerful angiogenic agent in neoplastic tissues, as
well as in normal tissues.
• Under the influence of certain cytokines and other growth
factors, the VEGF family appears in cancerous tissue and the
adjacent stroma, and plays an important role in
neovascularization
• Some angiogenic phenotypes can be triggered by
hypoxia resulting from the increasing distance between
the growing tumor cells and the capillaries or from the
inefficiency of new vessels.
• Hypoxia induces the expression of VEGF and its receptor
via hypoxia-inducible factor-1α (HIF-1α)
• Tumor cells feed on the new blood vessels by producing
VEGF and then secreting it into the surrounding tissue.
When the tumor cells encounter endothelial cells, they
bind to receptors on the outer surface of the endothelial
cell.
• The binding of VEGF to its receptor activates relay
proteins that transmit a signal into the nucleus of the
endothelial cell.
• The nuclear signal prompts a group of genes to make
products needed for new endothelial cell growth.
• Table 1
• Endogenous regulators of angiogenesis

• Activators Inhibitors
• Growth factors
• Vascular endothelial growth factor family
• Acidic and basic fibroblast growth factor
• Angiogenin
• Angiostatin
• Transforming growth factor
• Tumor necrosis factor-α
• Plated-delivered endothelial growth factor
• Hepatocyte growth factor
• Epidermal growth factor
• Placental growth factor
• Granulocyto colony stimulating factor
• Cytokines
• Interleukin-1
• Interleukin-6 Interleukin-10
• Interleukin-8 Interleukin-12
• Proteases and protease inhibitors
• Cathepsin Tissue inhibitor metalloprotease
• Gelatinase A, B Prasminogen activator-inhibitor-1
• Stromelysin
• Urokinase-type plasminogen activator
• Trace elements
• Copper Zinc
• Oncogenes
• c-myc ras p53 Rb
• c-src v-raf
• c-jun
• Endogenous modulators
• Alpha 5 Beta 3 integrin Angiopoietin-2
• Angiopoitin-1 Angiotensin
• Angiostatin II (AT1 receptor) Angiostatin II (AT2 receptor)
• Endothelin Caveolin-1, -2
• Erythropoietin Endostatin
• Hypoxia Interferon-alpha
• Nitric oxide synthase Isoflsvones
• Plated-activating factor Platerat factor 4
• Prostaglandin E
• Prolactin (16 kd fragment)
• Abbreviations: AT1, angiotensin-1; AT2, angiotensin-2.
• Endothelial cells activated by VEGF produce matrix
metalloproteinases (MMPs).
• The MMPs break down the extracellular matrix which fills the
spaces between cells and is made of protein and
polysaccharides.
• This matrix permits the migration of endothelial cells. The
endothelial cells begin to divide as they migrate into the
surrounding tissues.
• Soon they organize into hollow tubes that evolve gradually
into a mature network of blood vessels with the help of an
adhesion factor, such as integrin α or β
• Newly formed blood vessels need to stabilize or mature.
Angiotensin-1, -2, and their receptor Tie-2 can stabilize and
govern vascular growth.
• Newly formed blood vessels need to stabilize or mature.
Angiotensin-1, -2, and their receptor Tie-2 can stabilize and
govern vascular growth
• Among the VEGF family, VEGF-A, VEGF-B, VEGF-C
and VEGF-E acting on their respective receptors
cause proliferation of blood vessels, while VEGF-C
and VEGFD are involved in lymphangiogenesis ,
• Vascular endothelial growth factor-A is also known
as VEGF/vascular permeability factor (VPF) . The
human VEGF-A gene has been mapped to 6q21.3
• Vascular endothelial growth factor-A is a heparin-
binding glycoprotein that occurs in at least six
molecular isoforms, which consist of 121, 145, 165,
183, 189, and 206 amino acids and are the result of
alternative splicing of the mRNA
• VEGF-A is a potent and very specific mitogen for vascular
endothelial cells and stimulates the full cascade of events
required for angiogenesis and is overexpressed in a variety
of tumors.
• VEGF-B exists as two protein isoforms, VEGF-B167 and
VEGF-B186, resulting from different spliced mRNA and
binds specifically to VEGFR-1. However, VEGF-B forms a
heterodimer with VEGF-A, which may alter its interaction
with its biological receptors and modify its normal
physiological effects.
• VEGF-B levels increase both throughout development and
after birth, closely correlating with the progression of
cardiac angiogenesis
• VEGF-C has a mature form that consists of a VEGF homology
domain, which contains receptor-binding sites and is 30%
identical in amino-acid sequence of VEGF165
• Unlike VEGF-A, the expression of VEGF-C does not appear to be
regulated by hypoxia.
• The expression of VEGF-C appears to be restricted to early
development and certain pathological settings such as tumor
angiogenesis and lymphangiogenesis.
• VEGF-D is known as c-FOS-induced growth factor (FIGF), and the
mature form has 61% identical aminoacid sequence with VEGF-C,
and both of these growth factors bind to the same receptors on
human endothelial cells, namely VEGFR-2 and -3.
• VEGF-C and VEGF-D bind and activate VEGFR-3, regulating
lymphangiogenesis as well as angiogenesis in the mid-stages of
embryogenesis
• VEGF-E is encoded by the parapoxvirus or Orf virus.
• The interaction of VEGF-E with its receptor seems to promote
endothelial cell growth.
• There is a significant overlap between the binding pocket of VEGF-A
and VEGF-E on VEGFR-2 which may suggest alliance of the two
molecules in final response or alternatively an antagonistic
relationship between these two factors
 Inhibitors of angiogenesis
• Up-regulation of the activity of angiogenic factors is in itself not enough to
initiate blood vessel growth, and the functions of negative regulators or
inhibitors of vessel growth may need to be down-regulated.
• There are many naturally occurring proteins that can inhibit angiogenesis,
including angiostatin, endostatin, interferon, platelet factor 4,
thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of
metalloproteinase-1, -2, and -3 .
• Angiostatin is composed of one or more fragments of plasminogen .
• It induces apoptosis in endothelial cells and tumor cells, and inhibits
migration and the formation of tubules in endothelial cells.
• Immunohistochemical examination of angiostatin-treated tumors indicated a
decrease in the expression of mRNA for VEGF and bFGF .
• Endostatin is a 20 kDa C-terminal fragment of type XVIII collagen, a
component of the basement membrane
• It binds to the α5β1/αvβ3 integrin, the major fibronectin receptor in
endothelial cells and may block endothelial cell focal adhesions .
• Endostatin also inhibits the growth factor (eg, bFGF and VEGF-A), and
induces proliferation and migration of endothelial cells in vitro and in vivo
 Angiogenesis and the prognosis of
cancer
• Several studies have indicated that angiogenic activators play an
important part in the growth and spread of tumors.
• On immunohistochemical examination, the VEGF family and their
receptors were found to be expressed in about half of the human
cancers investigated
• These factors are known to affect the prognosis of adenocarcinomas
that have developed in the uterine cervix, endometrium, ovary and
stomach.
• In addition, a significant correlation between the expression of VEGF
and prognosis has been described in colorectal cancer breast cancer
and lung cancer, head and neck squamous cell carcinoma , Kaposi
sarcoma, and malignant mesothelioma.
• These studies also indicated that the levels of angiogenic factors in
tissue reflect the aggressiveness with which tumor cells spread, and
thus have predictive value in the identification of the high-risk
patients with poor prognosis.
 Causes of cancer
• the most important question in cancer biology is what causes the
cellular alterations that produce a cancer
• If the actual cause of these alterations were known, the elimination
of factors that produce cancer and the development of better
treatment modalities would likely follow. Cancer prevention might
become a reality.
• The incidence rates of various cancers are strongly related to
environmental factors and lifestyle, and cancers have certain
growth characteristics, among which are the abilities to grow in an
uncontrolled manner, invade surrounding tissues, and metastasize.
• In most cases cancer is a disease of aging. The average age at
diagnosis is over 65 and malignant cancers arise from a lifetime
accumulation of ‘‘hits’’ on a person’s DNA.
• These hits may result from genetic susceptibility to environmental
agents such as chemicals; radiation; or viral, bacterial, or parasitic
infections; or from endogenously generated agents such as oxygen
radicals.
• There is frequently a long latent period, in some cases 20
years or more, between the initiating insult and the
appearance of a clinically detectable tumor.
• with the exception of childhood malignancies such as
leukemias and sarcomas that occur in children, cancer
incidence increases with age. Most of the common adult
solid tumors begin to increase after age 45 and go up
logarithmically with age after that, as shown for colorectal
cancer
• This has led to the idea that it takes multiple cellular hits to
explain the age-related incidence of malignancy
• Most of these hits are thought to be mutational in origin and
to result from chromosomal damage or base changes in
DNA.
• The number of hits needed to produce the initiation of a
malignant event may vary from one to six or more.
• However, progression to a full-blown invasive metastatic
cancer almost always requires multiple hits
• 0 20 40 60 80 100
• In chronic myleogenous leukemia (CML), there is an inciting
chromosomal translocation that involves a piece of chromosome 22
being lost.
• This was first observed by Nowell and Hungerford, who named this
small chromosome the Philadelphia chromosome.
• It was shown by Rowley that this was a reciprocal translocation
between chromosomes 9 and 22 (Fig. 2), which produces a chimeric
protein called Bcr/Abl that is a constitutively active tyrosine kinase
promoting cell proliferation
• , CML appears to be triggered by this one-hit event and is probably
the reason why the drug Gleevec, which targets this kinase, is
effective as a single agent in CML
• the chromosomal translocation generating the two altered
chromosomes (9q+,22q–) is reciprocal (for example, involving
a loss and a gain by both), the sizes of the exchanged
chromosomal arms are unequal, leading to the greatly
truncated Chromosome 22 (for example, 22q–)
• A second example is retinoblastoma. There are two
forms of this disease, hereditary and spontaneous.
• Both forms appear to require two initiating genetic
events, leading Knudson, who studied this disease in
detail, to postulate the two-hit hypothesis.
• In the hereditary form, one genetic mutation is
inherited at birth and a second one occurs later.
• This must be the case, since every cell in the eye
contains the hereditary mutation, but only three to
four tumors on average develop in a retinal cell
population of several million cells in affected
individuals.
• Most adult solid cancers (e.g., colon, lung, breast,
prostate) likely require several hits to achieve a full
malignant state.
• The best example of this is colon cancer, for which at
least five hits appear to be required to produce an
invasive carcinoma (Fig. 3).
• Because of genetic instability, a characteristic of most
solid cancers, many more genetic alterations are
frequently seen in later stages of cancer progression.
• This has been ascribed to a ‘‘mutator phenotype’’
observed in many cancers
• Non–small cell carcinoma of the lung, showing
abnormalities of both number and structure. The
arrows indicate aberrant chromosomes.
 CHEMICAL CARCINOGENESIS
• Carcinogenic chemicals and irradiation (ionizing and ultraviolet) are
known to affect DNA and to be mutagenic under certain conditions.
• Evidence that chemicals can induce cancer in humans has been
accumulating since the sixteenth Century
• In 1567, Paracelsus described a ‘‘wasting disease of miners’’ and
proposed that exposure to something in the mined ores caused the
condition
• Later in the eighteenth century, the first direct observation associating
chemicals was made by John Hill, who in 1761 noted that nasal cancer
occurred in people who used snuff excessively.
• In 1775, Percival Pott reported a high incidence of scrotal skin cancer
among men who had spent their childhood as chimney sweeps.
• A hundred years later, von Volkman, in Germany, and Bell, in Scotland,
observed skin cancer in workers whose skin was in continuous contact
with tar and paraffin oils, which we now know contain polycyclic aromatic
hydrocarbons.
• In 1895, Rehn reported the development of
urinary bladder cancer in aniline dye workers
in Germany.
• Similar observations were later made in a
number of countries and established a
relationship between heavy exposure to 2-
naphthylamine, benzidine, or 4-
aminobiphenyl and bladder cancer
• the reactions of carcinogens with cellular macromolecules resulted from
covalent bond formation between an electrophilic form of the carcinogen
and the nucleophilic sites in proteins (e.g., sulfur, oxygen, and nitrogen
atoms in cysteine, tyrosine, and histidine, respectively) and nucleic acids
(e.g., purine or pyrimidine ring nitrogens and oxygen
• Frequently, the parent compound itself did not interact in vitro with
macromolecules until it had been incubated with liver homogenates or liver
microsomal fractions.
• These studies led to the realization that metabolic activation of certain
carcinogenic agents is necessary to produce the ‘‘ultimate carcinogen’’ that
actually reacts with crucial molecules in target cells.
• With the exception of the very chemically reactive alkylating agents, which
are activated in aqueous solution at physiologic pH (e.g., N-methyl-
Nnitrosourea), and the agents that intercalate into the DNA double helix by
forming tight noncovalent bonds (e.g., daunorubicin),
• most of the known chemical carcinogens undergo some metabolic
conversions that appear to be required for their carcinogenic action
• The original, unmodified compounds that were introduced into laboratory
animals came to be called procarcinogens to indicate their ability to become
converted into actively carcinogenic compounds, which were labeled
ultimate carcinogens
• PAHs that affect cancer initiation are typically first chemically modified by
enzymes into metabolites that react with DNA, leading to mutations. When
the DNA sequence is altered in genes that regulate cell replication, cancer
can result.
• Mutagenic metabolites of PAHs include diol epoxides, quinones,
and radical PAH cations.These metabolites can bind to DNA at specific sites,
forming bulky complexes called DNA adducts that can be stable or unstable.
• Stable adducts may lead to DNA replication errors, while unstable adducts
react with the DNA strand, removing a purine base
(either adenine or guanine). Such mutations, if they are not repaired, can
transform genes encoding for normal cell signaling proteins into cancer-
causing oncogenes.
• Quinones can also repeatedly generate reactive oxygen speciesthat may
independently damage DNA.
• Enzymes in the cytochrome family (CYP1A1, CYP1A2, CYP1B1) metabolize
PAHs to diol epoxides.
• PAH exposure can increase production of the cytochrome enzymes, allowing
the enzymes to convert PAHs into mutagenic diol epoxides at greater
rates. In this pathway, PAH molecules bind to the aryl hydrocarbon
receptor (AhR) and activate it as a transcription factor that increases
production of the cytochrome enzymes.
• Donors of Simple Alkyl Groups :Included in this group are the
dialkylnitrosamines, dialkylhydrazines, aryldialkyltriasenes,
alkylnitrosamides, and alkylnitrosimides.
• The alkylnitrosamides and alkylnitrosimides do not require
enzymatic activation because they can react directly with water or
cellular nucleophilic groups.
• The alkylnitrosamines, alkylhydrazines, and alkyltriazenes,however,
undergo anenzymemediated activation step to form the reactive
electrophile
• These agents are metabolically dealkylated by the mixed-function
oxidase system in the microsomal fraction (endoplasmic reticulum)
of cells, primarily liver cells.
• The monoalkyl derivatives then undergo a nonenzymatic,
spontaneous conversion to monoalkyldiazonium ions that donate
an alkyl to cellular nucleophilic groups in DNA, RNA, and protein.
• Cytochrome P-450–Mediated Activation
• A number of carcinogenic chemicals are chemically inert nucleophilic agents until
they are converted to active nucleophiles by the cytochrome p-450–dependent
mixed function oxidases, or CYPs So far, 57 genes encoding these enzymes have
been identified in the human genome.
• The CYPs most involved in carcinogen activation are CYP1A1, 1A2, 1B1, 2A6, and
3A4.
• A wide variety of chemical carcinogens such as aromatic and heterocyclic amines,
aminoazo dyes, polycyclic aromatic hydrocarbons, N-nitrosamines, and
halogenated olefins are activated by one or more of these CYPs (Fig. 2–7).
• Some of these compounds are further activated by subsequent steps; for
example, 2-acetylaminofluorene (AAF) is further modified by a sulfotransferase to
form the ultimate DNA-binding moiety.
• Somewhat surprisingly, glutathione-S-transferase (GST), which had been thought
to be involved only in detoxifying carcinogens, has been shown to activate some
industrial chemicals, so GST appears to have a dual role, depending on the
chemical.
 Direct acting carcinogens
• Carcinogens may fall into two categories: activation-dependent and
activation-independent.
• Those which do not require metabolic activation or any molecular
modification in order to induce DNA damage are termed direct-acting
carcinogens
• examples include nitrosamines, ultraviolet (UV), IR and alkylating agents
• These agents have the capability to interact directly with DNA and other
cellular components due to their electrophilic groups.
• These electrophilic groups exhibit an inherent reactivity, allowing them to
interact with nitrogen and oxygen atoms within negatively charged cellular
macromolecules to induce molecular modifications and distortion .
• Alteration of DNA bases causes a disarrangement of the genetic material
and formation of DNA adducts depending on the type of carcinogen.
• Failure within DNA repair mechanisms allows DNA lesions to be inherited
by daughter cells, eventually leading to the accumulation of DNA damage
and potentially the development of cancer.
 Indirect-acting carcinogens
• Indirect-acting carcinogens are relatively unreactive parent compounds that include polycyclic
aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HAAs), N-nitrosamines, mycotoxins
and aristolochic acid (AA).
• These require bioactivation in host cells to transform them into carcinogenic metabolites or
reactive intermediates that are capable of exerting genotoxic effects.
• This is often mediated by phase I and/or II metabolic reactions.
• Phase I reactions include oxidation, reduction or hydrolysis, mainly involving cytochrome P450
(CYP) mixed function oxidase isoforms, commonly referred to as CYPs.
• These enzymes have the ability to activate carcinogens independently or in conjugation with phase
II enzymes such as sulfotransferases and N-acetyltransferase .
• A classic example is the bioactivation process of benzo[a]pyrene (B[a]P), which undergoes a multi-
step process involving CYP1A1 and epoxide hydrolase-mediated conversion to r7,t8-dihydroxy-t-
9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE).
• Bulky chemical adducts are commonly seen as a result of the interaction between activated
carcinogens and DNA, e.g. reactive nitrenium ions formed through the reduction and hydrolysation
of AA, yield bulky purine DNA adducts at the exocyclic amino group of purines
• Procarcinogens are substances that become carcinogenic only after alteration by metabolic
processes
 co-carcinogens
• A co-carcinogen is a chemical that promotes the effects of a carcinogen in the production of cancer.
Usually, the term is used to refer to chemicals that are not carcinogenic on their own, such that an
equivalent amount of the chemical is insufficient to initiate carcinogenesis.[
• A chemical can be co-carcinogenic with other chemicals or with nonchemical carcinogens, such
as UV radiation.
• For example, sodium arsenite can be administered to mice at a low enough concentration that it
does not cause tumors on its own, but it increases the rate of formation and size of tumors formed
after UV exposure.
• A chemical may act as a co-carcinogen even if it does not cause direct DNA damage such
as mutation, as long as it can affect a cancer-related pathway.
• An example of this category includes chemicals within the phorbol ester family, which mimic
a native signalling molecule. This ester is not mutagenic, but can increase the rate of cancer by
promoting cell growth, a traditional hallmark of cancer.
• Co-carcinogens can be a lifestyle like cigarette-smoking, alcohol-drinking or even areca nut tobacco-
chewing] Also, some virus are co-carcinogens like Herpesviruses, Epstein–Barr virus (EBV) and
human herpesvirus 4 (HHV-4) Over intake beta carotene for a long period of time increased the risk
of lung cancer, prostate cancer and many other kind of malignant tumor for cigarette smoker and
worker having high contact with asbestos
 EPIGENETIC MECHANISMS INVOLVED IN CHEMICAL
CARCINOGENESIS
• The most well understood epigenetic mechanisms
involve DNA methylation and histone acetylation,
methylation, and phosphorylation .
• Demethylation of promoter regions at the CpG
sequences can lead to an over-expression of proto-
oncogenes, and silencing of gene expression can
occur as a result of hypermethylation, sometimes
leading to chromosome condensation
• . Interestingly, these epigenetic changes in
chromatin can also alter the sensitivity of DNA
sequences to mutation, thus rendering genes more
susceptible to toxic insult