Cancer

Pathology
Dr. Sidra Batool
Pharm.D, M.Phil. Pharmacology
Senior Lecturer, SICP
Difference in terms
Hyperplasia
Hypertrophy
Dysplasia
Neoplasm
Tumor
Cancer
HYPERPLASIA
The enlargement of an organ or tissue caused by an
increase in the reproduction rate of its cells is called
HYPERPLASIA.

 It is a normal physiological response to demand

placed on a tissue.
HYPERPLASIA

For example, in a guitar

player, the basal cells of
the epidermis in the
fingertips can proliferate to
produce hard pads of
keratin by repeated
contact with the strings.
Hypertrophy
The increase in the size of
the cells (Not number) is
called Hypertrophy.

Its also one of the body’s

adaptive response
Dysplasia
If cell division becomes poorly regulated, cells may lose some of their
morphological characteristics and/or functions.

The tissue becomes disordered in appearance, often with an increase

in the numbers of immature cells, and greater variability between cells.
This appearance is called dysplasia.
 What is Cancer?
Cancer is a group of diseases in which
cells are aggressive, invasive, and
sometimes metastatic
OR
a class of diseases or disorders
characterized by uncontrolled division of
cells and the ability of these to spread,
either by direct growth into adjacent tissue
through invasion, or by implantation into
distant sites by metastasis.
Tumor

A tumor is an abnormal mass of tissue that results when

cells divide more than they should or do not die when they
should. Tumors may be benign (not cancer), or malignant
(cancer). Also called neoplasm.
Tumor and cancers
Tumors and cancers are different.

 A tumor develops when a lesion or lump is formed in your body due to

abnormal cellular growth.

Therefore, satisfactory definition of a neoplasm or tumour is a mass of

tissue formed as a result of abnormal, excessive, uncoordinated,
autonomous and purposeless proliferation of cells even after cessation of
stimulus for growth which caused it.

In the case of cancer, this cellular growth is uncontrollable and it spreads in the
body.
Tumor and cancers
Not all tumors are cancerous and not all cancers are tumors

Tumors may be benign or malignant

Tumors when spread over other body parts becomes a cancer.

Tumor Mass and Tumor Nodule
“Mass" is often used when the lesion has a maximal diameter of at
least 20 millimeters (mm) in greatest direction,

while the term "nodule" is usually used when the size of the lesion is
less than 20 mm in its greatest dimension

 (25.4 mm = 1 inch).
Neoplasia
• “Cancer is a “Neoplastic developmental disorder”

• Plasia = development & growth by cellular multiplication

• Neoplasia means “new growth,” and a new growth is called a neoplasm.

Definition

• Neoplasia is the uncontrolled, disorderly proliferation of cells, resulting in a benign or

malignant growth known as a neoplasm (in ancient Greek, “neo” means “new” and
plasma means “creation”).
Component of neoplasia
• Parenchyma proliferation neoplastic cell are involve

• Stroma  non-neoplastic cells like connecting tissue and blood vessels

 Norma\ vs. cancerous ce\
Is
Basal polarity Loss of basal
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No Pleomorphism
pleomorphism
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 Typical characteristics
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Types of neoplasia
• Neoplasia are of two types
• Benign neoplasm
• Malignant neoplasm
Benign tumor
• Benign tumors are usually well differentiated and closely resemble the tissue of origin.

• They grow slowly and do not metastasize. If their growth compresses adjacent tissues,
they can be harmful.

• For example, benign intracranial tumors can be more lethal than some malignant skin
tumors.

• Suffix “oma” to the cell type from which the tumor arises e.g. fibroma (benign tumor
arising in fibrous tissue) and chondroma (a benign cartilaginous tumor), adenoma,
papilloma
Papilloma
• Benign neoplasm most often arises from surface epithelium,
such as squamous epithelium of the skin, larynx, or tongue.

• It may also develop from transitional epithelium of the urinary

bladder, ureter, or renal pelvis.

• The tumor consists of delicate fingerlike epithelial processes

overlying a core of connective tissue stroma that contains
blood vessels.
Adenoma
• This benign neoplasm of glandular epithelium includes these variants:

a. Papillary cystadenoma is characterized by adenomatous papillary processes that extend

into cystic spaces, as in cystadenoma of the ovary.

b. fibroadenoma is marked by proliferation of connective tissue surrounding glandular

epithelium; for example, fibroadenoma of the breast.

Benign tumors of mesenchymal origin

• These are most often named by the tissue of origin (e.g., leiomyoma, rhabdomyoma,
lipoma, fibroma, chondroma).

• They include the most common neoplasm in women, the uterine leiomyoma, or fibroid
tumor.
Choristoma

• This is a small non-neoplastic area of normal tissue misplaced within another organ, such
as pancreatic tissue within the stomach wall.

Hamartoma

• This is a non-neoplastic, disorganized, tumorlike overgrowth of cell types regularly found

within an affected organ; hemangioma, an irregular accumulation of blood vessels, is an
example.
 Malignant tumors (cancer)
• Invasion (spread of the neoplasm into adjacent structures) and metastasis (implantation of the
neoplasm into noncontiguous sites) are characteristic.
• Metastasis is the most important defining characteristic of malignancy, although there are
some malignant tumors, such as basal cell carcinoma of the skin, that rarely metastasize.
• Malignant tumors are usually less differentiated than benign tumors.
• anaplasia, in which tumor cells are very poorly differentiated and exhibit pleomorphism,
hyperchromatism (dark-staining nuclei), an increased nuclear-cytoplasmic ratio, abnormal
mitoses, cellular dyspolarity, and often prominent nucleoli, is a common feature.
• In general, highly anaplastic tumors are very aggressive, and well-differentiated tumors are
less aggressive.
• Paradoxically, the most aggressive tumors often respond well to chemotherapy and
radiotherapy, because these modalities are most effective with rapidly dividing cells
 Carcinoma
i. Squamous cell carcinoma originates from stratified squamous epithelium of, for example,
the skin, mouth, esophagus, and vagina, as well as from areas of squamous metaplasia, as in
the bronchi or the squamocolumnar junction of the uterine cervix. It is marked by the
production of keratin.

ii. Transitional cell carcinoma arises from the transitional cell epithelium of the urinary tract.

iii. Adenocarcinoma is carcinoma of glandular epithelium and includes malignant tumors of

the gastrointestinal mucosa, endometrium, and pancreas. It is often associated with
desmoplasia, tumor-induced proliferation of non-neoplastic fibrous connective tissue,
particularly in adenocarcinoma of the breast, pancreas, and prostate.
• Sarcoma is a malignant tumor of mesenchymal origin. It is often used with a prefix that
denotes the tissue of origin of the tumor, as in osteosarcoma (bone), rhabdomyosarcoma
(skeletal muscle), leiomyosarcoma (smooth muscle), and liposarcoma (fatty tissue).

• Eponymically named tumors include Burkitt lymphoma, Hodgkin disease, and Wilms
tumor. Note that we no longer use the possessive apostrophe and ―s‖ after these tumors
(e.g., it is not ―Burkitt‘s lymphoma).

• Teratoma is a neoplasm derived from all three germ cell layers, which may contain
structures such as skin, bone, cartilage, teeth, and intestinal epithelium. It may be either
malignant or benign and usually arises in the ovaries or testes
 Mixed tumors
 When two types of tumours are combined in the same tumour, it is called a
mixed tumour.
 Adenosquamous carcinoma is the combination of adenocarcinoma and
squamous cell \ carcinoma in the endometrium.
 Mixed tumors

o Collision tumour is a term used for morphologically two different

cancers in same organ which do not mix.
o Mixed tumour of salivary gland (or pleomorphic adenoma) is a term
used for a benign tumour having a combination of both epithelial
and mesenchymal tissue elements.
 Teratomas
o Majority of neoplasms, even mixed tumors, are composed of

cells from a single germ layer.

o An exception is a tumor called a teratoma, which contains

recognizable mature or immature cells or tissues belonging to
more than one germ cell layer (and sometimes all three).
 Teratomas
o Most common sites for teratomas are ovaries and
testis (gonadal teratomas).

o Teratomas may be benign or mature (most of the ovarian

teratomas) or malignant or immature (most of the testicular
teratomas).
Characteristics of tumors

• The characteristics of tumors are described under the following headings:

• Differentiation & anaplasia

• Rate of growth

• Local invasion

• Metastasis
Differentiation and anaplasia
• Differentiation refers to the extent to which parenchymal cells resemble comparable
normal cells both morphologically and functionally.

• Well-differentiated tumors cells resemble mature normal cells of tissue of origin

• Poorly differentiated or undifferentiated tumors have primitive appearing, unspecialized

cells.

• In general, benign neoplasms are well differentiated.

• Malignant neoplasms in contrast, range from well differentiated, moderately differentiated

to poorly differentiate types.
• Anaplasia: lack of differentiation and is a characteristic feature of most malignant tumors

• Loss of polarity  loss of basal polarity (nuclei of epithelial cells are oriented along the
basement membrane which is termed as basal polarity)
• Pleomorphism  variation in size and shape of the tumour cells

• N:C ratio 

• Hyperchromatism

• Nucleolar changes

• Mitotic figures

• Functional (Cytoplasmic) changes

• Chromosomal abnormalities
Rate of growth
• Tumor cells generally proliferate more rapidly than the normal cells

• Benign tumors  grow slowly

• most malignant tumors  grow rapidly sometimes

• Some benign tumors for example uterine leiomyoma increase in size during pregnancy due
to probably steroidal effects (estrogen) and regress in menopause.

• The rate at which the tumor enlarges depends upon 2 main factors:

1. Rate of cell production, growth fraction and rate of cell loss

2. Degree of differentiation of the tumor

• Examples include renal cell carcinoma, malignant melanoma, and choriocarcinoma.

Local invasion
Benign tumor Malignant tumor
• Localized • invasion, infiltration and destruction of
• Non-metastasize the surrounding tissue
• Slow growth • Poorly demarcated
• Form fibrous capsule • Surgical resection is deficient
Metastasis (Distant Spread)
• Metastasis (meta = transformation, stasis = residence)

• spread of tumor by invasion in such a way that discontinuous secondary tumor

mass/masses are formed at the site of lodgment.

• benign tumors do not metastasize

• malignant tumors with a few exceptions like gliomas of the central nervous system and
basal cell carcinoma of the skin, can metastasize
Routes of Metastasis
• Cancers may spread to distant sites by following pathways:

1. Lymphatic spread  carcinomas metastasize by lymphatic route

2. Hematogenous spread  Blood-borne metastasis is the common route for sarcomas but
certain carcinomas also frequently metastasize by this mode

3. Spread along body cavities and natural passages  spread by seeding across body cavities
and natural passages
i. Transcoelomic spread (Specific mechanism of cancer metastasis, where cancer cells spread
across the surfaces of body cavities lined by the peritoneum, pleura, or pericardium)

ii. Spread along epithelium-lined surfaces

iii. Spread via cerebrospinal fluid

iv. Implantation
Grading and staging of cancer
• Grading is defined as the gross and microscopic degree of differentiation of the tumor,
• Grading of a cancer is based on;
• the degree of differentiation of tumor cells
• the number of mitoses within the tumor and presumably correlates to aggressive
character of the neoplasm
• Cancers are classified into grades I to IV with increasing anaplasia. Criteria for individual
grades vary with each form of neoplasm
• Grade I: Well-differentiated (less than 25% anaplastic cells).
• Grade II: Moderately-differentiated (25-50% anaplastic cells).
• Grade III: Moderately differentiated (50-75% anaplastic cells).
• Grade IV: Poorly-differentiated or anaplastic (more than 75% anaplastic cells)
• Staging means extent of spread of the tumor within the patient.

• The staging of cancers is based on;

• the size of primary lesions,

• its extent of spread to regional lymph nodes

• the presence or absence of blood born metastases

• Two major staging systems are currently in use are Union International Center Cancer
(UICC) which utilizes the so-called TNM system
• T for primary tumor

• N for regional lymph node involvement

• M for metastasis
TNM staging
• With increasing size, the primary lesion is characterized as T to T4 to be added to indicate
an in-situ lesion (localized, non-invasive: early-stage cancer that has not spread to neighboring
tissues).

• No for no nodal involvement whereas, N1 -N3 wound denote involvement of an

increasing number and range of nodes

• Mo signifies no distant metastasis whereas M1 or sometimes M2 indicates the presence of

blood born metastasis
American joint committee (AJC) staging

• divides all cancers into stages 0 to IV incorporating within each of these stages the
size of the primary lesion as well as the presence of nodal spread and the distant
metastasis

• The staging of neoplastic disease has assumed great importance in the selection of
the best form of therapy for the patient.

• Indeed, staging has proved to be of greater clinical value than grading.

American joint committee (AJC) staging
• Stage Grouping:
• The AJCC system groups cancers into Stages 0 through IV, based on
the combination of the T, N, and M values. These stages are used to
describe the progression of the cancer:
• Stage 0: Known as carcinoma in situ, where cancer is localized and has not
spread to surrounding tissues.
• Stage I: Early-stage cancer, usually a small tumor that hasn't spread to lymph
nodes or distant sites.
• Stage II and III: Larger tumors or tumors that have spread to nearby lymph
nodes, but not to distant sites. The exact criteria for II and III can vary depending
on the type of cancer.
• Stage IV: Advanced cancer with distant metastasis, meaning the cancer has
spread to other parts of the body.
Carcinogenesis
• Carcinogenesis or oncogenesis or tumorigenesis means the mechanism of induction of
tumors (pathogenesis of cancer); agents that can induce tumors are called carcinogens
(etiology of cancer).

Mechanism of induction of tumors:

• Chemical carcinogenesis – Mutagens – Chemical carcinogenesis and their metabolism

• Physical carcinogenesis (radiation) – Ultraviolet radiation, Asbestos

• Infectious Pathogens (Viral) – Human T-cell leukemia viruses, DNA viruses, Human
papillomaviruses – Epstein-Barr virus, Hepatitis B virus
Chemical carcinogenesis/ mutagens
• Two-step/ multistep process
• Initiation : causes permanent DNA damage (Mutation)
• Promotion (Proliferation)
1. Initiators
• Direct-acting compounds: Direct-acting carcinogens are bind covalently to cellular
macromolecules. E.g. nitrogen mustard, bis(chloro-methyl) ether, benzyl chloride,
Epoxides
• Indirect acting carcinogen (Procarcinogens): Require metabolic conversion to form
ultimate active carcinogen.
2. Promoters
• Can cause cellular proliferation & induce tumors in initiated cells, e.g. estrogen but
they are non-tumorigenic by themselves.
• Proliferation of a mutated cell may lead to the accumulation of additional mutations.
Examples
for indirect-acting chemical carcinogens (procarcinogens)

• Polycyclic aromatic hydrocarbons  cigarette smoke, lung cancer

• Aflatoxin B1  Fungi Aspergillus flavus (contamination of veg. food, peanuts)  liver

cancer (Africa and Asia regions)

• Aromatic amines and Azo dues  bladder (aniline dye) and liver tumors.

• Nitrosamines: Nitrosamines (nitrosamine, dimethyl nitrosamine) are potent carcinogen,

produce kidney, liver tumor and gastrointestinal cancers.

• Metals: Ni2+, Pb2+, Cd2+, Co2+ and Be2+.

Physical carcinogenesis
Radiation
Ultraviolet light
• Causes: mutation, inhibits cell division and cell death
• MOA: formation of pyrimidine dimer
• Main source of UV light is sunlight, UV lamp and welder’s arcs
• Penetration of UV light protected by melanin pigmentation of the skin.
• Sun light  white race  basal cell carcinoma, squamous carcinoma and malignant
melanoma
• Sun light  darker races  protected by melanin pigment, which absorbs UV radiation
• Lifetime risk of 1 rad of whole-body x-ray or gamma-ray radiation is one excess
cancer death per 10,000 person
Ionizing radiation
• X-rays, α-, β- and γrays, radioactive isotopes, protons and neutrons can cause cancer
 Non-radiation Physical Carcinogenesis
• Asbestos: A fibrous amphibole; used for making fireproof articles
• Inhaling asbestos can cause lung cancer
• Source of inhalation:
• mining and manufacturing of asbestos
• installation of asbestos insulation
• air in the vicinity of asbestos plants
• contaminated air in buildings undergoing repair or demolition
• clothing of asbestos workers
Infectious Pathogens
• Virus Viral infection is responsible for 20% of human cancer worldwide
• RNA retrovirus HTLV-I  T-cell leukemia/ lymphoma (endemic in Japan, Africa,
the Caribbean basin and southeastern United States)
• Human papillomavirus (DNA)  squamous carcinoma of the cervix
• Hepatitis B and C viruses  primary hepatocellular carcinoma
• Epstein-Barr virus (EBV)  lymphoma and nasopharyngeal carcinoma
• Human herpesvirus 8  kaposi sarcoma
• Bacteria  Helicobacter Pylori (Gastric lymphoma, Mucosal Associated Lymphoid
Tumor (MALT) & Gastric carcinoma)
• Fungi  aflatoxins produced by Aspergillus flavus - hepatocellular carcinoma
• Parasites  Schistosoma and Clonorchis sinensis)
Cancer inheritance
• Cancer inheritance: Genetic basis. E.g., Breast cancer (associated genes are BRCA-1 and
BRCA-2
Hallmarks of cancer
• The hallmarks were proposed by Douglas Hanahan & Robert Weinberg
• The hallmarks of cancer provide a logical framework for understanding the remarkable
diversity of neoplastic diseases. As normal cells evolve progressively to a neoplastic state,
they acquire these hallmark capabilities.
• There are 8 hallmarks;
• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory signals
• Altered cellular metabolism
• Evasion of apoptosis
• Limitless replicative potential (immortality)
• Sustained angiogenesis
• Invasion and metastasis
• Evasion of immune surveillance
1.Self-sufficiency in growth signals
 oncogene

Nuclear Signal
Growth factor Cell cycle
Growth factor regulatory transduction
receptor regulator
protein protein
Self-sufficiency in growth signals

• Normal cells require growth signals (GS) before they start dividing (by moving from a
quiescent state into an active proliferative state).

• These signals are transmitted into the cell by transmembrane receptors that bind
distinctive classes of signaling molecules.

• Tumor cells generate their own growth signals, thereby reducing their dependence on
stimulation from their normal tissue microenvironment.

• This liberation from dependence on external signals disrupts a critically important

homeostatic mechanism that normally operates to ensure a proper behavior of the various
cell types within a tissue.
• Three common strategies for achieving growth signal autonomy:

• Alteration of extracellular growth signals

• Many cancer cells acquire the ability to synthesize GFs to which they are responsive,
creating a positive feedback signaling loop

• Alternation of transcellular transducers of those signals

• Receptor overexpression may enable the cancer cell to become hyperresponsive to

ambient levels of GF that normally would not trigger proliferation

• Alternation of intracellular circuits that translate those signals into action.

• Alterations in components of the downstream cytoplasmic circuitry that receives and

processes the signals emitted by GF receptors can release a flux of signals into cells,
without ongoing stimulation by their normal upstream regulators
Growth Factors
• Normally cell require stimulation by GFs to undergo proliferation.

• Mostly these GFs are secreted by one cell type and act on a neighboring cell to stimulate
proliferation. (paracrine action)

• Cancer cells acquire the ability to synthesize their own GFs generating an autocrine loop.

• Examples:

- Glioblastomas secrete PDGF

- Sarcomas secrete TGF-α

Growth Factor Receptors
• Several oncogenes that encode growth factor receptors have been found. Ex.
Transmembrane proteins with an external ligand-binding domain and a cytoplasmic
tyrosine kinase domain.
• In the normal forms of these receptors, the kinase is transiently activated.
• The oncogenic versions of these receptors, kinase is constitutively activated. Resulting in
continuous mitogenic signals to the cell, even in the absence of growth factor in the
environment
• Examples of Growth Factor receptor oncogenes and associated cancer:
• RET - dominantly inherited MEN types 2A and 2B and familial medullary thyroid
carcinoma
• receptor tyrosine kinase c-KIT - gastrointestinal stromal tumors
• ERBB1 - squamous cell carcinomas of the lung, glioblastomas, head and neck tumors.
• ERBB2 gene (also called HER-2/NEU) - breast cancers and in human adenocarcinomas
arising within the ovary, lung, stomach, and salivary glands.
 Signal transduction protein
• Two important members in this category are RAS and ABL.
RAS is a member of a family of small G proteins that bind
[GTP] and [GDP], similar to the larger trimolecular G
proteins. Due to mutation RAS is locked into its active GTP
form and the cell is forced into a continuous proliferating
state.
• Activated RAS then causes the activation of a cellular kinase
called RAF­1. RAF­1 kinase then phosphorylates another
cellular kinase called MEK. This cause the activation of
MEK. Activated MEK then phosphorylates another protein
kinase called MAPK causing its activation i.e MAP Kinase
Pathway and ultimately causing changes in gene transcription.
• RAF (rapidly accelerated fibrosarcoma) and MEK are
targeted sites for anti-cancer drugs.
Nuclear regulatory protein

• all signal transduction pathways converge to the nucleus where stimulation of nuclear
transcription factors allow them for DNA binding.

• Binding of these proteins to specific sequences in the genomic DNA activates

transcription of genes.

• Growth autonomy may thus occur as a consequence of mutations affecting genes that
regulate transcription.
• Example:
• MYC is a nuclear regulatory protein with very broad range of activity which includes
histone acetylation, reduced cell adhesion, increased telomerase activity and other
changes in cellular metabolism that enable a high rate of cell division.
• MYC also plays an important role in the selection of origins of replication.
• Thus, overexpression of MYC may drive activation of more origins than needed for
normal cell division, or bypass checkpoints involved in replication, leading to genomic
damage and accumulation of mutations.
• Dysregulation of MYC expression is seen in Burkitt’s lymphoma
• MYC is amplified in some cases of breast, colon, lung, and many other carcinomas.
• The related N-MYC and L-MYC genes are amplified in neuroblastomas and small-cell
cancers of the lung, respectively.
Cell cycle
• The process of replicating DNA and dividing a cell can be described as a series of
coordinated events that compose a “cell division cycle.’’

• A set of checkpoints that monitor completion of critical events, leading to cell division
and duplication that produce two daughter cells.

• 1st type of cell cycle regulation, checkpoint control, is more supervisory. Cell cycle
checkpoints sense flaws in critical events such as DNA replication and chromosome
segregation. When checkpoints are activated, for example by under replicated or damaged
DNA, signals are relayed to the cell cycle-progression machinery. These signals cause a
delay in cycle progression until the danger of mutation has been averted.
• 2nd is the cascade of protein phosphorylation's that relay a cell from one stage to the
next. Cyclin-dependent kinases (CDKs) are a family of protein kinases discovered for
their role in regulating the cell cycle. They are also involved in regulating transcription,
mRNA processing, and the differentiation of cells. CDK binds a regulatory protein called
a cyclin, form cyclin-CDK complex and phosphorylate their respective substrate and
regulate cell cycle.

Summary;
CDK and Cyclin  two protein  both combine and form a
complex cyclin-CDK complex add phosphate to protein
phosphorylation  form phosphorylation specific protein
regulate the cell cycle
Cell Cycle Regulators (Cyclins and Cyclin-Dependent Kinases)

• Regulatory phosphorylation and dephosphorylation fine-tune the activity of CDK–cyclin

complexes, ensuring well-delineated transitions between cell cycle stages.

• Mutation or deregulation of this process has been associated with many types of cancers
i.e., uncontrolled cell proliferation. Hence, CDKs are considered as a potential target for
anti-cancer medication.
2.Insensitivity to Growth-
Inhibitory Signals
Insensitivity to growth-inhibitory signals

• The growth of normal cells is kept under control by growth inhibitors in the surrounding
environment, in the extracellular matrix and on the surfaces of neighboring cells. These
inhibitors act on the cell cycle clock, by interrupting cell division in the interphase.
Cancer cells are generally resistant to these growth­preventing signals.

Tumor
suppressor gene

Inner aspect of
Cell surface plasma Cytoskeleton Cytosol Nucleus
membrane
Tumor suppressor genes
• Tumor suppressor genes encode proteins that inhibit cellular
proliferation by regulating the cell cycle.
• Unlike oncogenes, both copies of the gene must be lost for tumor
development, leading to loss of heterozygosity at the gene locus.
• In cases with familial predisposition to develop tumors, the affected
individuals inherit one defective (non-functional) copy of a tumor
suppressor gene and lose the second one through somatic mutation.
• In sporadic cases both copies are lost through somatic mutations.
RB gene
• Mutation in RB gene involve in a no. of cancers.
• Although the loss of normal RB genes was discovered initially in
retinoblastomas, it is now evident that homozygous loss of this gene is
a fairly common event in several tumors, including breast cancer,
small-cell cancer of the lung, and bladder cancer.
• Patients with familial retinoblastoma also are at great risk of
developing osteosarcomas and some soft tissue sarcomas.
• Almost all cancer cells show dysregulation of the G 1-S checkpoint as a
result of mutation in one of four genes that regulate the
phosphorylation of RB, these genes are
• RB
• CDK4, cyclin D
• CDKN2A [p16]
• EGF, epidermal growth factor; PDGF, platelet-derived growth
factor.
RB gene & Cell cycle
p53 gene
• The p53 gene is located on chromosome and it is the most common target for genetic
alteration in human tumors.

• p53 acts as a ―molecular policeman that prevents the propagation of genetically

damaged cells.

• P53 inhibits neoplastic transformation by three interlocking mechanisms: activation of

temporary cell cycle arrest (quiescence), induction of permanent cell cycle arrest
(senescence), or triggering of programmed cell death (apoptosis).

• Homozygous loss of p53 occurs in virtually every type of cancer, including carcinomas of
the lung, colon, and breast—the three leading causes of cancer death.
• Many activities of the p53 protein are related to its function as a
transcription factor.

• Several hundred genes have been shown to be regulated by p53 in

numerous different contexts, but which genes are the key for the p53
response is not yet clear.
Impairment of p53 functions
Mutations in p53 gene
• Approximately 80% of the p53 point mutations present in human
cancers are located in the DNA-binding domain of the protein.
Blockade of p53 pathway
• The function of the p53 pathway is blocked by mutation in another
gene that regulates p53 function. For example, MDM2 and
MDMX stimulate the degradation of p53.
• MDM2 is amplified in 33% of human sarcomas, thereby causing
functional loss of p53 in these tumors.
p53 – DNA damage
• The manner in which p53 senses DNA damage is not completely
understood.
• The key initiators of the DNA-damage pathway are two related protein
kinases: ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia
and Rad3 related (ATR).
• The types of damage sensed by ATM and ATR are different, but the
downstream pathways they activate are similar.
• Once triggered, both ATM and ATR phosphorylate a variety of targets,
including p53 and DNA-repair proteins.
TGF-β gene
• In most normal epithelial, endothelial, and hematopoietic cells, TGF-β is
a potent inhibitor of proliferation.
• It regulates cellular processes by binding to a serine-threonine kinase
complex composed of TGF-β receptors I and II.
• Dimerization of the receptor upon ligand binding leads to activation of
the kinase and phosphorylation of receptor SMADs (R-SMADs).
• Upon phosphorylation, R-SMADs can enter the nucleus, bind to SMAD-
4, and activate transcription of genes, including the CDKIs p21 and p15.
• In addition, TGF-β signaling leads to repression of c-MYC, CDK2,
CDK4, and cyclins A and E.
Cell surface
• TGF-β receptors I and II are involved in regulation of cellular process by binding to serine-
threonine kinase complex .

• TGF-β signaling activate transcription of genes, including the CDKIs p21 and p15/INK4b.
In addition, TGF-β signaling leads to repression of CDK2, CDK4, and cyclins A and E.
these changes result in decreased phosphorylation of RB and cell cycle arrest.

Mutation:

• TGF-β type II receptor mutations - cancers of the colon, stomach, and endometrium.

• TGF-β pathway mutation - In 100% of pancreatic cancers and 83% of colon cancers
Inner aspect of plasma membrane
• protein product of the NF1 gene (Neurofibromin), contains a GTPase-activating domain,
which regulates signal transduction through RAS proteins.

• Neurofibromin facilitates conversion of RAS from an active to an inactive state. With loss
of neurofibromin function, RAS is trapped in an active, signal-emitting state.

• Individuals who inherit one mutant allele of the NF1 gene develop numerous benign
neurofibromas and optic nerve gliomas as a result of inactivation of the second copy of
the gene. This condition is called neurofibromatosis type 1.
Cytoskeleton
• The product of the NF2 gene, called neurofibromin 2 or merlin are related to the family of
membrane cytoskeleton-associated proteins.

• Cells lacking this protein are not capable of establishing stable cell-to-cell junctions and
are insensitive to normal growth arrest signals generated by cell-to-cell contact.

• Germline mutations in the NF2 gene predispose to the development of neurofibromatosis

type 2.

• Individuals with mutations in NF2 develop benign bilateral schwannomas(non-cancerous

tumors that develop from Schwann cells )
Nucleus
• RB protein the product of the RB gene, is a ubiquitously expressed nuclear
phosphoprotein that plays a key role in regulating the cell cycle.

• Germline loss or mutations of the RB gene - retinoblastomas and osteosarcomas.

• Somatically acquired RB mutations - glioblastomas, small-cell carcinomas of lung, breast

cancers, and bladder carcinomas.
 Tumors Associated Tumors Associated
Subcellular with Somatic with Inherited
Locations Gene Function Mutations Mutations
Inner aspect of NF1 Inhibition of RAS signal Neuroblastomas Neurofibromatosis type
transduction and of p21 1 and sarcomas
plasma cell cycle inhibitor
membrane
Cytoskeleton NF2 Cytoskeletal stability meningioma Neurofibromatosis type
2, meningioma

Cytosol PTEN PI3 kinase signal Endometrial and Cowden syndrome

transduction prostate cancers

Nucleus WT1 Nuclear transcription Wilms' tumor Wilms' tumor

P16/INK4a Regulation of cell cycle Pancreatic, breast, and Malignant melanoma

by inhibition of cyclin esophageal cancers
dependent kinases

BRCA1 and DNA repair Unknown Carcinomas of female

breast and ovary;
BRCA2 carcinomas of male
breast
APC-gene
• In the rare hereditary disease called adenomatous polyposis coli
(APC), patients develop numerous adenomatous polyps in the colon
that have a very high incidence of transformation into colonic cancers.
• The APC gene exerts antiproliferative effects in an unusual manner.
• It is a cytoplasmic protein whose dominant function is to regulate the
intracellular levels of β-catenin.
• β-catenin is an important component of the WNT signaling pathway
that regulates cell proliferation.
3.Evasion of Apoptosis
Evasion of apoptosis
• Apoptosis represents a barrier that must be surmounted for cancer to occur. In the adult, cell
death by apoptosis is a physiologic response to several pathologic conditions that might
contribute to malignancy if the cells remained viable.
• Reduced CD95 level.

• Inactivation of death-induced signaling complex by FLICE protein (caspase 8; apoptosis-

related cysteine peptidase).
• Reduced egress of cytochrome c from mitochondrion as a result of up- regulation of
BCL2.
• Reduced levels of pro-apoptotic BAX resulting from loss of p53.

• Loss of apoptotic peptidase activating factor 1

• Up-regulation of inhibitors of apoptosis (IAP) FADD, Fas-associated via death domain.

4.LIMITLESS REPLICATIVE
POTENTIAL
Limitless Replicative Potential
• most normal human cells have a capacity of 60 to 70 doublings. After this, the cells lose
their ability to divide and become senescent. This phenomenon has been ascribed to
progressive shortening of telomeres at the ends of chromosomes.
Cell aging & Senescence
• Most somatic cells have a ‘molecular clock’ that limits the number of
times they can divide.

• This is known as the‘Hayflick limit’, and in most cells this is between

50 and 70 doublings, after which cells enter a state of senescence and
cease dividing.

• The molecular clock is telomere shortening.

Telomeres

• Telomeres are protective caps on the ends of chromosomes, commonly

composed of short, repeated, sequences that are guanosine-rich (e.g.
(GGGTTA)n).

• The conventional DNA replication machinery which replicates the

middle regions of chromosomes cannot replicate the ends, and
replication here depends on a ribonucleoprotein enzyme called
‘telomerase’.
Telomerase
• This enzyme is a RNA-dependent DNA polymerase that can extend
one strand of telomeric repeats by having a short RNA template (e.g.
CCCAAT).

• These extensions are then a template for synthesis of complementary

DNA by DNA polymerase a.

• The catalytic subunit of telomerase is known as TERT for telomerase

reverse transcriptase (a reverse transcriptase makes DNA from
complementary RNA).
Limitless replicative potential: telomerase
5.SUSTAINED ANGIOGENESIS
Sustained Angiogenesis
• Angiogenesis is the growth of blood vessels from the existing vasculature. It is also a
fundamental step in the transition of tumors from a dormant state to a malignant one.

• Tumors cannot grow beyond a certain size, generally 1– 2 mm3, due to a lack of oxygen
and other essential nutrients.

• Like normal tissues, tumors require delivery of oxygen and nutrients and removal
of waste products; presumably the 1- to 2-mm zone represents the maximal
distance across which oxygen, nutrients, and waste can diffuse from blood vessels.

• To supply nutrients and oxygen, tumors induce blood vessel growth (angiogenesis) by
secreting various growth factors (e.g. VEGF). Growth factors such as bFGF and VEGF
can induce capillary growth into the tumor.
Sustained Angiogenesis
• Cancer cells can stimulate neo-angiogenesis, during which new vessels sprout from previously existing
capillaries, or, in some cases, vasculogenesis, in which endothelial cells are recruited from the bone
marrow.
• These vessels are leaky, dilated, and have a haphazard pattern of connection.

• Neovascularization has a dual effect on tumor growth:

 Perfusion supplies needed nutrients and oxygen, and
 Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth
factors, such as insulin-like growth factors, PDGF, and granulocyte-macrophage colony-stimulating
factor.

• Angiogenesis is required not only for continued tumor growth but also for access to the vasculature and
hence for metastasis.
• Angiogenesis is involved in the growth of cervix, breast and melanoma tumors. Anti­VEGF antibodies
slowed the growth of tumors in mice. Anti­ angiogenesis compounds are under investigation as drugs to
6. Ability to Invade and
Metastasize
Invasion
• Growth by progressive infiltration, destruction, and penetration of the surrounding
tissue.

Metastasis
• The development of secondary implants (metastases) discontinuous with the primary
tumor, in remote tissues.

• The properties of invasiveness and, even more so, metastasis, more

unequivocally identify a neoplasm as malignant than any of the other attributes
of a tumor.
Invasion and metastasis

• Invasion and metastasis are biologic Invasion and metastasis are biologic hallmarks of
malignant tumors hallmarks of malignant tumors

• For tumor cells to break loose from a primary mass, enter blood vessels or lymphatics and
produce a secondary growth at a distant site

• For this, they must go through a series of steps (the metastatic cascade)

• The metastatic cascade is divided into two phases:

1. Invasion of the extracellular matrix (ECM)

2. Vascular dissemination, homing of tumor cells, and colonization

Invasion of Extracellular Matrix
• Invasion of the ECM is an active process that requires four steps

A. Detachment of tumor cells from each other

B. Degradation of ECM
C. Attachment to novel ECM components
D. Migration of tumor cells
 Invasion of Extracellular Matrix
• Matrix Two types of ECM:
1. Basement membrane (BM) and
2. Interstitial connective tissue
Composition: ECM is made up of collagens, glycoproteins,
Breach Basement Membrane Traverse
and proteoglycans Interstitial Tissue  Penetrate Vascular
3. A carcinoma must first breach the underlying BM Basement Membrane  Enter Circulation 
Metastasis  Extravasation at Distant Site
4. Then traverse the interstitial connective tissue, and  Traverse Interstitial Tissue Penetrate
5. Gain access to the circulation by penetrating the Target Tissue's Basement Membrane
vascular BM This process is repeated in reverse when Establish Secondary Tumor
tumor cell emboli extravasate at a distant site
• Matrix Invasion of the ECM initiates the metastatic
cascade:
1. Changes (“loosening up”) of tumor cell- cell
interactions
2. Degradation of ECM
3. Attachment to novel ECM components
4. Migration of tumor cells
Loosening of intercellular connections between tumor cell
• E-cadherins act as intercellular glues, and their
cytoplasmic portions bind to β-catenin

• Adjacent E-cadherin molecules keep the cells together

• E-cadherin can transmit anti-growth signals by

sequestering β-catenin.

• E-cadherin function is lost in almost all epithelial

cancers, either by mutational inactivation of E-
cadherin genes, activation of β-catenin genes,
Local degradation of the basement membrane and interstitial connective tissue.

• Elaboration of proteases by

• Tumor cells themselves or

• Induced Stromal cells (e.g. fibroblast and

inflammatory cells)

• Many different families of proteases

• Matrix metalloproteinases (MMPs)

• Cathepsin D &

• Urokinase plasminogen activator

Attachment to novel ECM components
• Normal epithelial cells have receptors, such as integrins, for basement membrane laminin
and collagens that are polarized at their basal surface
• These receptors help to maintain the cells in a resting, differentiated state

• Loss of adhesion in normal cells leads to induction of apoptosis [tumor cells are resistant
to this form of cell death]

• The matrix itself is modified in ways that promote invasion and metastasis

• Eg: cleavage of the basement membrane proteins collagen IV and laminin by MMP2
or MMP9 generates novel sites that bind to receptors on tumor cells and stimulate
migration
 Migration of tumor cells- Locomotion
• Tumor cells propel themselves through the degraded basement membranes and zones of
matrix proteolysis
• It involves many families of receptors and signaling proteins that eventually Intrude on the
actin cytoskeleton
• Cells must attach to the matrix at the leading edge, detach from the matrix at the trailing
edge, and contract the actin cytoskeleton to ratchet forward - Ameboid migration
• Such movement are potentiated by tumor cell–derived
cytokines
• Cleavage products of matrix components (e.g.,
collagen, laminin) and some growth factors (e.g.,
IGFs I and II) have chemotactic activity for tumor
cells
• Stromal cells also produce paracrine effectors of cell
motility
• HGF–scatter factor, which bind to receptors on
tumor cells
MMPs
• Tumors either elaborate large quantities of MMPs or they may reduce the concentrations of MMP-
inhibitors

• They regulate tumor invasion by:

• Dissolving components of the BM & interstitial matrix

• Releasing ECM-sequestered growth factors

• Cleavage products of collagen and proteoglycans also have chemotactic, angiogenic, and
growth-promoting effects
• Eg: MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular
basement membrane and also stimulates the release of VEGF from ECM-sequestered pools
• Eg: Benign tumors of the breast, colon, and stomach show little type IV collagenase activity,
whereas their malignant counterparts overexpress this enzyme
Evasion of Immune system
• Tumor cells must develop mechanisms to escape or evade the immune system. Several
such mechanisms may be operative:

• Selective outgrowth of antigen-negative variants: Tumor cells may eliminate strongly

immunogenic subclones during progression, reducing immune recognition.

• Loss or reduced expression of MHC molecules: Tumor cells often downregulate MHC
class I molecules (HLA class I), making it harder for cytotoxic T cells to recognize and
attack them.

• Lack of co-stimulation: Tumor cells frequently lack co-stimulatory molecules necessary

for proper T-cell activation, preventing effective immune responses.
• Immunosuppression: Tumors often secrete immunosuppressive molecules like TGF-β,
inhibiting immune cell function.

• Antigen masking: Tumor cell surface antigens may be concealed by glycocalyx

molecules, making them less visible to the immune system.

• Apoptosis of cytotoxic T cells: Some tumors, like melanomas and hepatocellular

carcinomas, express FasL, leading to the killing of Fas-expressing T cells, eliminating
tumor-specific immune responses.
Lab diagnosis
• Histopathology: This involves the examination of tissue samples (biopsies) under a
microscope to identify cancer cells and determine the type of cancer.

• Cytology: Cytology involves the examination of individual cells, often collected through
procedures like Pap smears or fine-needle aspirations. It is commonly used to diagnose
cancers like cervical cancer or thyroid cancer.

• Immunohistochemistry (IHC): IHC is a technique that uses antibodies to detect specific

proteins in tissue samples. It helps pathologists identify the presence or absence of certain
markers associated with specific cancer types.

• Blood Tests: Blood tests can detect certain cancer-related markers or substances, such as
tumor markers (e.g., PSA for prostate cancer or CA-125 for ovarian cancer).
• Imaging: Various imaging techniques like X-rays, CT scans, MRI, and PET scans are
essential for locating tumors, determining their size, and evaluating their spread (staging).

• Liquid Biopsies: Liquid biopsies analyze circulating tumor cells (CTCs) or cell-free
DNA (cfDNA) in the blood. They can provide information about the genetic makeup of a
tumor and monitor treatment response or recurrence.

• Flow Cytometry: This technique is used to analyze the physical and chemical properties
of cells. It can help characterize and sort cancer cells based on their characteristics.

• Genomic Profiling: This involves sequencing a patient's tumor DNA to identify specific
genetic mutations or alterations that can be targeted with precision medicine treatments.

• Biopsy of Lymph Nodes: If cancer has spread to lymph nodes, a biopsy of the affected
lymph nodes may be performed to confirm cancer's presence and assess its spread.
Treatment
• Surgery: Surgery is often used to physically remove cancerous tumors or a portion of
tissue containing cancer cells. It is most effective for localized tumors and is commonly
used in the early stages of cancer.

• Radiation Therapy: Radiation therapy uses high-energy X-rays or other forms of

radiation to target and destroy cancer cells. It can be used as a primary treatment or in
combination with surgery or chemotherapy. Radiation therapy is often used to treat
localized tumors or to shrink tumors before surgery.
• Chemotherapy: Chemotherapy involves the use of drugs that can kill cancer cells or
prevent them from dividing and growing. Chemotherapy drugs can be administered orally
or intravenously and are used to treat cancer throughout the body, including metastatic
cancer. It is often used when cancer has spread or in combination with other treatments.
• Immunotherapy: Immunotherapy works by boosting the body's immune system to
recognize and attack cancer cells. It has been particularly effective in certain types of
cancer, such as melanoma and lung cancer, and is being researched for use in other cancer
types.
• Hormone Therapy: Hormone therapy is used to treat cancers that are hormone-sensitive,
such as breast and prostate cancer. It works by blocking the effects of hormones that
promote cancer growth.
• Stem Cell Transplant: Stem cell transplant (also known as bone marrow transplant) may
be used in some cases, particularly in blood-related cancers like leukemia and lymphoma.
It involves replacing damaged or cancerous bone marrow with healthy stem cells.
Anticancer agents