4. CANCER
Cancer is a state of
rapid,abnormal,uncontrolled,and unwanted
multiplication,disorganized distribution ,anomalous
growth,and abnormal differentiation of some types
of cells.
Abnormal differentiation –neoplasia.
An uncontrolled division of abnormal cells in a part
of the body is called cancer.
When good cells go bed.
Loss of Cell-cycle Control.
Before a cell divides, the DNA is checked to make
sure it has replicated correctly. (If DNA does not
copy itself correctly, a gene mutation occurs.
5. T TUMOUR
The cells which undergo cancerous multiplication
are known neoplastic cells.They form hard lump
of undifferentiated
cells,tumours.(neoplasm,Neoplastic growth,or
cancerous growth)Tumor is an abnormal mass of
tissue resulting from uncontrolled division
(cancer).
The formation of tumour is called tumerogenesis
It is accomplished by a process ,metaplasia.It is
the transformation of one type of cells to another.
In medical context it is applied to denote tumour
formation by the formation of normal cells to
cancer cells.
6. Hyperplasia –abnormal increase in the size of an organ or
tissue due to non-cancerous cell proliferation.
In tumerogenesis ,metaplasia involves the transformation
of nomal cells to cancer cells.The spreading of tumours to
different parts is called matastasis.
Tumours do not form a part of the normal body design , nor
do they serve any useful functions. Most of the tumour cells
are cells are immature and abnormal and are not orderly
arranged and systematically organized.
Tumor is of two types;
(1)Malignant tumor (cancerous)
(2) Benign tumor (non-cancerous)
7. (1) Malignant
Tumor
Invade or spread to other parts of the
body.
High rate of division.
Spread by forming Metastasis.
Cells travel through circulation.
Very difficult to treat.
8. Cancer Metastasis
Metastasis is the spread of cancer to other location
in the body.
The new tumors are called metastatic tumors,
while the original site is called primary tumor.
Basal lamina of epithelium normally provides
barrier.
Malignant tumor cells break, free of attachments
to adjoining cells.
Attach to basal lamina.
Secrete enzymes that digest extracellular proteins.
Migrate into circulatory system.
9. Matastasis leads disruption or compression of vital
organs.Brain cells have no powers for cell division.
So,they do not normally . from other sites matastase
to brain.Cancer matastase through lymph forms
secondary tumour in glands.
Cancer that metastase though lymph usually form 2ry
in bones,lungs,liver etc.
The commonst locations of 2ry tumours –
liver,kidney,urinary bladder,larynx,testes,breasts.
12. Galectin-3 (Gal-3) is also a member of the beta-
galactoside-binding protein family that plays an
important role in cell-cell adhesion, cell-matrix
interactions, macrophage activation, angiogenesis,
metastasis, apoptosis
Integrins are transmembrane receptors that facilitate
cell-extracellular matrix (ECM) adhesion. Upon
ligand binding, integrins activate signal
transduction pathways that mediate cellular signals
such as regulation of the cell cycle, organization of
the intracellular cytoskeleton, and movement of new
receptors to the cell membrane.
13. (2) Benign Tumour
Do not spread to other part of the body.
Localzed and are separated from surrounding
tissue by fibrous capsule.Normally harmless
Generally localized and of small size
Slow rate of division.
Cells that closely resemble, and may function,
like normal cells.
Do not break out of originating organ.
Easily to removed by surgery.Some times they
may press nearby organ and fatal-cerebral
tumours
14. Classification of Cancer
Cancers are classified by the type of
cell.
(1)Carcinoma-85%
(2) Sarcoma
(3)Lymphoma and Leukemia
(4) Germ Cell Tumor
(5) Blastoma
15. Classification (Cont…)
(1) Carcinoma:85%Brain breast throat,skin
Cancers derived from epithelial cells.
(2) Sarcoma:2%
Cancers arising fromMesodermal connective
and muscular tissue (i.e. bone, cartilage,
muscle etc).osteo,chondro,myo-sarcomas
(3) Lymphoma5% originate in lymph glands
4 - Leukemia4%
originate from hematopoietic (blood forming) cells of
bone marrow ,lymph nodes. Myeloproliferative
disorder.
16. (4) Germ Cell Tumor:
Cancers derived from pluripotent cells, most often
presenting in the testicles and ovary (seminoma
and dysgerminoma-ovary respectively).
(5) Blastoma:Cancer of undifferentiated embryonic
cells.Cancers derived from immature “precursor” cells
or embryonic tissue.
Hodkins disease-Cancer of lymph glands.
Neuroblastoma-Cancer of embryonic stem cells
Retinoblastoma-Cancer of differentiating retinal cells.
Nephroblastoma-cancer of embryonic renal cells.
17. Properties of Cancer Cells
Cancer cells show uncontrolled mitotic divisions causing
unorganised
growth.abnormal differentiation --neoplasia
Due to uncontrolled growth and division of cells, a tumor (also
called Neoplasm is generally formed).
They are far less adhesive than the normal cells.
They exhibit a number of alterations on cell surface, in the
cytoplasm and in their genes.
They do not undergo differentiation.Anaplasia and dysplasia.
They lose the ability to communicate with other cells through
chemical
signals.
They also lose sensitivity to anti-growth signals from surrounding
cells.
They lose the adhesion molecules that keep them bonded
to neighboring cells.
Cancer arises from a loss of normal growth control.
18. Reduced cellular adhesion –loss of contact
inhibition
Normal cells stick together –a cell coat protein-
fibronectin.cellular adhesion.
Adjescent cell membranes are held together by the
transmembrane linker protein cadherins.
Anchorage independent.
Loss of cell recognition and tissue specificity—
Normal cell recognize the cells of their own kind.so
they attach to tissues of their own kind.-tissue
specificity.
Inability to respond to stimuli
19. Ability to produce embryonic type proteins-reason
cancer cells are undifferentiated ,immature and
embryonic.
Metabolic imbalance.Prevalence of catabolism over
anabolism..
Defective differentiation-totally undifferentiated—
anaplasia…partially cataplasia.
Inability to respond to stimuli
Potential immortality.
Hayflick limit,Normal cell can undergo only a fixed or
limited number of division
Enhanced glycolysis and high utilization of sugar.
20. Enhanced glycolysis and high utilization of sugar.—
High energy requirement for rapid growth and
multiplication.Aerobic respiration is very slow So
glycolysis –anaerobic become highly enhanced
.inc.uptake and utilization of sugar.
Increased production of Proteolytic enzymes—These
activate the inactive serum protein plasminogen
,forming active plasmin.which removes the extrinsic
membrane proteins and there by triggers cell
division.
21. Chromosomal inconsistency and genetic instability.-
Chromosome no and DNA content of all normal
cells of a given species would be specific and
constant.They are genetically stable.But in cancer
cells they changing. So cells are genetically
abnormal and unstable.Chromosomes in cancer
cells undergo qualitative changes (rearrangement of
segments) and quantitative structural
change(addition or loss of the chromosome
material.
Inactive Golgi bodies and disorganized cytoskeleton-
Numerous golgibodiesBut inactive and
functioless.Cytoskeleton disintegrated and
depolymerized So,cellular movts.are not well co-
ordinated.
22. Cancer is a genetic disease:
–Inherited cancer
–Sporadic cancer-no family historyl
Cancer typically involves a change in gene
expression/function:
–Qualitative change
–Quantitative change
lack of contact inhibition
Loss of limitations on the number of cell divisions
Ability to grow in culture (medium) – normal cells do
not grow well in
culture.
In laboratory cultures, normal cells divide only
when attached to a surface.
Angiogenesis – secrete substances that cause blood
vessels to grow towards tumor.
23.
24. Model depicting genomic and epigenetic events during
cancer progression. Numerous genetic events, like gene
amplifications, deletions, gene fusions, and mutations of
oncogenes and tumor suppressor genes, are common in
cancer. In addition, many histone modifiers also show
aberrant regulation in cancer. These changes modulate
gene expression during cancer progression. DNA
methylation and demethylation are also common
occurrence in cancer and lead to altered regulation of
gene expression. Many of these genomic and epigenetic
regulators are effective therapeutic targets in cancer.
EGFR, epidermal growth factor receptor.
25. A substance that blocks the activity of a protein called
epidermal growth factor receptor (EGFR). EGFR is
found on the surface of some normal cells and is
involved in cell growth. It may also be found at high
levels on some types of cancer cells, which causes
these cells to grow and divide. Blocking EGFR may
keep cancer cells from growing. Some EGFR
inhibitors are used to treat cancer. Also called
EGFR tyrosine kinase inhibitor, epidermal growth
factor receptor inhibitor, and epidermal growth
factor receptor tyrosine kinase inhibitor.
26. Multiple molecular events are responsible for the initiation
and progression of cancer. Change in the DNA sequence
of the genome of a cancer cell is one of the major causes
for cancer initiation. With the advent of new
technologies, it is possible now to obtain a complete
DNA sequence of large numbers of cancer genomes
and identify the alterations between normal and cancer
genomes between patients and between different tumor
types. These studies, in addition to identifying other
molecular correlates like transcriptome and metabolome,
provide insights into the tumor heterogeneity and the
history of tumor development.
27. The DNA sequence of a cancer cell genome generally acquires
a set of aberrations or somatic mutations.2 These include
substitutions, insertions, or deletions of small or large
fragments of DNA, genomic amplification, and
rearrangements.2 Although some of these somatic mutations
play a role in cancer initiation and progression, others may act
as passenger aberrations.2 In addition, completely new DNA
sequences are acquired from human papilloma virus, Epstein
Barr virus, hepatitis B virus, human T lymphotropic virus, and
human herpes virus 8, which are known to contribute to the
genesis of one or more types of cancer.3
Mutations that provide a selective growth advantage, and thus promote cancer
development, are termed driver mutations, and those that do not are
termed passenger mutations (4). The terms driver and passenger may also be
used to refer to the genes harboring driver mutations.
28. In many human cancers, somatic mutations in the
mitochondrial genomes have been documented,
although their role is not clear.2 The mutations in the
cancer genome were acquired by exposure to both
internal and external mutagens. Studies have shown
that the mutation rates increase in the presence of
substantial exogenous mutagenic exposures, like
tobacco smoke carcinogens, aflatoxins, and radiation,
which are associated with lung, liver, and skin
cancers, respectively.2, 4
29. Somatic mutations, on the basis of their function, consist
of driver mutations, which confer growth advantage to
the cancer cells and have been positively selected during
cancer development.5 On other hand, the passenger
mutations are those that neither confer any growth
advantage to the cancer cells nor contribute to cancer
development.5 Thus, the main goal of cancer genome
analysis is the identification of mutations in genes that
harbor driver mutations. Most of the cancers harbor more
than one driver gene mutation. It is suggested that the
breast, colorectal, and prostate require five to seven
driver mutations for cancer initiation and progression,
whereas hematological malignancies may require
fewer.6 Some of the well-characterized genes carrying
mutations include TP53, RB1, EGFR, and KRAS, which
are frequently mutated in various cancer types, whereas
others are rare and/or restricted to one cancer.2
30. Apart from genomic events that are evident during cancer
progression, modifications of the nucleotides,
particularly that of the cytosine and post-translational
histone modifications, are common in cancer These
modifications, referred to as epigenetic changes, are
independent of alterations in the primary DNA sequence
and involve changes in DNA methylation and histone
modifications.7 In addition, these changes in cancer
constitute the cancer epigenome and play crucial roles in
control of gene activity and nuclear architecture.8 The
chromatin-modifying enzymes act on histones in a highly
regulated manner. As many as four different DNA
modifications and 16 classes of histone modifications
have been identified.7 Chromatin structure is altered by
these modifications both locally and globally, depending
on the activity and specificity of the modifying enzymes.
31. These modifications serve multiple purposes during cancer
initiation and progression. Some modifications serve as
docking sites for specific proteins that can specifically
recognize these modifications. Other modifications, like
histone H3 acetylation and methylations, alter the chromatin
compaction and relaxation status, leading to repression or
activation of transcription, thus regulating gene
expression.9 In contrast to above, relatively small molecular
modifications to amino acid side chains, ubiquitination is a
larger covalent modification. H2BK123ub1 modification
involves the addition of ubiquitin chain to histone H2B and
this modification results in regulating transcriptional initiation
and elongation, whereas H2AK119ub1 is involved in gene
silencing.10 Similarly, phosphorylation of histones plays a
crucial part of the histone code. Phosphorylated forms of
histones, H3S10ph and H2BS32ph, are known to be involved
in the expression of proto-oncogenes, such as MYC, JUN,
and FOS.11
32. Ras is involved in the signals passed between cells that
control the amount of growth that is allowed at any
time. Cancer-causing mutation of Ras creates a form
of the protein that is always on.
When Ras is 'switched on' by incoming signals, it
subsequently switches on other proteins, which
ultimately turn on genes involved in cell
growth, differentiation and survival. Mutations
in ras genes can lead to the production of permanently
activated Ras proteins. As a result, this can cause
unintended and overactive signaling inside the cell,
even in the absence of incoming signals.
Because these signals result in cell growth and division,
overactive Ras signaling can ultimately lead to cancer
38. Normal Cell VS Cancer
Cell
.
Cells anchor to dish surface and
divide (anchorage dependent).
When cells have formed a
complete single layer, they
stop dividing (density-
dependent inhibition).
If some cells are scraped away,
the remaining cells divide to fill
the dish with a single layer and
then stop (density-dependent
inhibition).
40. Normal Cell VS Cancer
Cell
Cells in culture and in vivo
exhibit contact-inhibition
Cancer cells lack contact
inhibition feedback mechanisms.
Clumps or foci develop.
41. Causes of
Cancer
The great majority of cancers 90-95% cases, are due
to environmental factors.
The remaining 5-10% are due to inherited genetics.
43. (2) Inherited Genetics
Cancer is fundamentally a disease of tissue
growth regulation failure.
In order for a normal cell to transform into a
cancer cell, the genes that regulate cell growth
and differentiation must be altered.
The affected genes are divided into two
broad categories;
(i) Oncogenes
(ii) Tumor Suppressor Genes
44. (Cont
…)
(i) Oncogenes:
Oncogenes are genes that promote cell growth
and reproduction.
(ii) Tumor Suppressor Genes:
Tumor suppressor genes are genes that inhibit
cell division and survivals.
45.
46. Somatic mutation theory—Mutational origin of cancer-
Mutagens
Oncogene theory---Genetic origin of cancer---Oncogenes
and tumour suppressor gene.
Nonmutated normal forms of oncogenes in normal cells,-
proto-oncogenes.
They regulate the signal transduction pathway of cell
cycle,and govern the controlled growth and multiplication
of normal cell.
TSG-undergo recessive mutation
Viral Gene theory—Oncovirus –the integration of the viral
oncogene with the host cell genome may result in the
transformation of normal cells to cancer cells.
Polygenic or multifactorial basis of cancer
47. Signs and
Symptoms
When cancer begins, it invariably produces
no symptoms.
Signs and symptoms only appear as the mass
continues to grow (tumor).
50. Apoptosis (Programmed Cell
Death)
Apoptosis is a tightly regulated form of cell death, also
called the programmed cell death. Morphologically,
it is characterized by chromatin condensation and cell
shrinkage in the early stage. Then the nucleus and
cytoplasm fragment, forming membrane-bound
apoptotic bodies which can be engulfed by phagocytes.
Initiated by signal transduction process.
Does not cause inflammation.
Ends with fragmentation of cell into smaller bodies.
51. Necrosis (Lethal
Injury)
In contrast, cells undergo another form of cell death,
necrosis, swell and rupture. The released
intracellular contents can damage surrounding cells
and often cause inflammation.
Un-programmed cell death and living tissues. (opposite
to apoptosis).
Initiated by direct cell damage mostly physically.
Cause inflammation.
Ends with total cell lysis.
55. Lung
Cancer
■ In 2013, 174,470 people died from lung cancer
■ Since 1987, more women have died from
lung cancer that breast cancer
■ Symptoms: persistent cough, blood-streaked
sputum, chest pain
56. Cont
….
■ Treatment: surgery, radiation therapy, and
chemotherapy
■ Prevention: avoid smoking and environmental
tobacco smoke
57. Breast
Cancer
■ 1 out of 8 women will develop breast
cancer (lifetime risk)
■ 1 in 227: birth to age 39
■ 1 in 25: ages 40-59
■ 1 in 15: ages 60-79
■ Detection: mammograms, regular breast self-
exams
■ Symptoms: lump in the breast, thickening,
dimpling, skin irritation, distortion or tenderness
58. (Cont
…)
■ Risk factors: family history, hyperplasia, long
menstrual history, obesity after menopause, oral
contraceptives
■ Treatment: lumpectomy, radical mastectomy,
radiation, chemotherapy
■ Prevention: exercise
59. Colon And Rectal
Cancers
■ Third most common cancer in men and women with
over 148,610 new cases diagnosed in 2013
■ Risk factors: over 50 years old, obese, family history
of colon or rectum cancer or polyps, diets high in fats,
low in fiber, smoking, high alcohol consumption, lack of
exercise
■ 90% of colorectal cancers are preventable
60. (Cont
…)
■ Treatment: radiation, surgery, and
possible chemotherapy
■ Prevention: regular exercise, a diet heavy in fruits
and plant-origin foods, a health weight, and
moderation in alcohol consumption
61. Prostate
Cancer
■ Most common cancer in American men, excluding
skin cancer
■ In 2013, 234,460 new cases diagnosed
■ 1 in 3 men will be diagnosed in their lifetime
■ Prostate is a muscular, walnut-sized gland the
surrounds part of the urethra. Its primary function is
to produce seminal fluid.
62. (Cont
…)
■ Symptoms: nonspecific, weak or interrupted urine
flow, difficulty starting or stopping urination
■ Risk factors: age, race, nationality, family history,
diet, lifestyle, and vasectomy
■ Prevention: diet high in lycopenes, vitamin E
63. Skin
Cancer
■ Long term effects of sun exposure can result in skin
cancer
■ Malignant melanoma, deadliest form of skin cancer
■ Sun give off 3 types of harmful rays:
■ UVA
■ UVB
■ UVC
■ Prevention: limit exposure to harmful UV rays,
drink more fluids than usual, apply cool compresses
to skin, moisturize skin
64. (Cont
…)
■ What to look for – The ABCD rule
■ Asymmetry – half of mole does not look like the other
half
■ Border irregularity – the edges are uneven
■ Color – pigmentation is not uniform
■ Diameter – greater than 6mm
65. Testicular
Cancer
■ Affects nearly 8,250 young men in 2013
■ Men between the ages 15-35 are at the greatest risk
■ Important to practice regular testicular self exams
■ Lance Armstrong Foundation “LiveStrong”
campaign to raise awareness
66. Ovarian
Cancer
■ Fifth leading cause of cancer death for women, 20,180
new cases diagnosed reported in 2012
■ Most common symptom is enlargement of the abdomen
■ Risk factors include: family history, age,
childbearing, cancer history, fertility drugs, talc use in
genital area, genetic predisposition
68. Cervical and Endometrial
(Uterine) Cancer
■ 9,710 new cases of cervical cancer, 41,200
cases of endometrial cancer in 2010
■ Pap test – cells are taken from the cervical region
■ Risk factors:
■ Cervical cancer: early age at first intercourse,
multiple sex partners, cigarette smoking, and certain
STIs
■ Endometrial cancer: age, endometrial
hyperplasia, overweight, diabetes, and high blood
pressure
