Presentation

1. Basics of Oncology
By: Dr. Motuma ( Obgyn Resident)
Moderator: Dr. Yirgu G.
(Consultant Gynecologic
Oncologist, AAU)
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2. Outline
• Introduction
• Normal cell cycle and Cell-Cycle Inhibitors
• Origins of Genetic Alterations
• Molecular Basis of Cancer
• References
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3. Introduction
• Cancer is a complex disease that arises
because of genetic and epigenetic
alterations (mutations) that disrupt cellular
proliferation, senescence, and death.
• Mutations can be good, bad, or neutral
and are a means of evolution.
• The paradox of life is that the same
mutations responsible for an individual
organism’s death in the form of cancer or
metabolic error can account for the
evolution of the species as well.
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4. • After all, a replicating cell must copy three
billion base pairs—with each division
mistakes will occur.
• That progression from a normal to a
malignant cell is the result of the
accumulation of a series of mutations has
probably best been demonstrated in colon
cancer
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5. • The development of a cancer elicits a
considerable molecular response in the
local microenvironment that is
characterized by recruitment of stromal
elements such as new blood vessels and
by an active immunologic response.
• These secondary events play a critical role
in the evolution and progression of
cancers.
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6. Growth regulation
• All normal tissues have the capacity for
cellular division and growth
• Complex molecular mechanisms have
evolved to closely regulate
proliferation.
• These involve a finely tuned balance
between stimulatory and inhibitory growth
signals.
• Dysregulation of cellular proliferation is
one of the main hallmarks of cancer.
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7. Patterns of Normal Growth
• There are three general types of normal tissue
growth: static, expanding, and renewing.
• 1. The static population
– comprises relatively well-differentiated cells
– Typical examples are striated muscle and neurons.
• 2. The expanding population of cells
– is characterized by the capacity to proliferate under
special stimuli (e.g., liver or kidney)
• 3. The renewing population of cells
– is constantly in a proliferative state.
– This occurs in bone marrow, epidermis, and
gastrointestinal mucosa.
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8. THE NORMAL CELL CYCLE
• Understanding how normal cells and
cancer cells grow leads to better
understanding of:
– 1) the pharmacology of antineoplastic drugs
in the treatment of cancer; and
– 2) the toxicities associated with these agents
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9. • The cell cycle includes four key stages:
– Gap1 (G1),
– Synthesis (S),
– Gap2 (G2) and
– Mitosis (M)
• Resting (nondividing) cells are in the G0
stage of the cell cycle and need to be
recruited into the G1 stage and beyond in
order to undergo replication
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10. • Following cell division in mitosis, cells are
destined to either:
– Go back into the cell cycle at the G1 phase, or
– Enter a dormant or resting phase G0 where
cells can rest, proceed to cellular
differentiation, or die.
• This stage is not considered part of the cell cycle as
cells are not undergoing active division.
• Most normal human cells exist predominantly in
the differentiated G0 phase, during which they
perform the work for which they are intended
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11. Cell cycle overview
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12. Multi-Phase Cycle, Before and During Cell
Division
• G1 Phase
– Enzymes for Deoxyribonucleic acid (DNA) synthesis
are manufactured.
• S Phase
– In the Synthesis Phase DNA replication occurs.
– The DNA coil unwinds, and an identical strand of DNA
is synthesized with the help of the enzyme DNA
polymerase.
– When DNA replication is complete, new and old DNA
strands coil to form double-stranded DNA.
• G2 Phase
– This is a short, pre-mitotic phase during which
Ribonucleic acid (RNA) and specialized proteins are
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13. 1. M Phase mitosis or the cell division phase is further
categorized into four sub-phases:
1. Prophase
1. The nucleus of the cell disintegrates, releasing
chromosomes into the cytoplasm, and the
protein spindle structure is synthesized.
2. Metaphase
1. Chromosomes line up along the centre of the
cell.
3. Anaphase
1. Chromosomes separate and migrate to opposite
ends of the cell along the mitotic spindle.
4. Telophase
1. Two new nuclei are formed and cell division takes
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15. • The duration of
– The S phase (DNA synthesis phase) is 8
hours
– The M phase is about 1 hour
– The G2 phase is about 2 hours.
– The G1 phase is highly variable (6 hours to
several days or longer)
– The length of the cell cycle in human
tumors varies from slightly more than half
a day to perhaps 5 days.
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16. • The orderly progression of cells through
the various phases of cell cycle is
orchestrated by cyclins and cyclin-
dependent kinases (CDKs), and by their
inhibitors
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18. Cyclin D and RB Phosphorylation
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19. Cell-Cycle Progression Beyond the
G1/S Restriction Point
• Further progression through the S phase and
the initiation of DNA replication involve the
formation of an active complex between
cyclin E and CDK2
• Cyclin A-CDK2 complex regulates events at
the mitotic prophase,,,,, G2/M transition
• Cyclin B-CDK1 activation causes the
breakdown of the nuclear envelope and
initiates mitosis
• However, the absence of both isoforms of
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20. Cell-Cycle Inhibitors
• Cip/Kip family: p21, p27
– Block the cell cycle by binding to cyclin-CDK
complexes
– P21 binds to Cyclin D/CDK4 complex
– P27 binds to Cylin E/CDK2 complex
• INK4/ARF family: p16INK4A, p14ARF
– p16INK4a binds to cyclin D-CDK4 and
promotes the inhibitory effects of RB.
– p14ARF increases p53 levels by inhibiting
MDM2 activity
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21. Cell-Cycle Checkpoints
• To minimize the possibility of errors,
checkpoints exist at four different points in
the cell cycle,
– G1/S,
– intra-S,
– G2/M, and
– at metaphase to anaphase.
• At the G1/S transition: by P53
– The S phase is the point of no return
– prevents the replication of cells that have defects
in DNA
– causes cell-cycle arrest and apoptosis
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22. Growth regulation cont…
• The intra- S phase checkpoint
– is initiated by ATR-CHK1 to stabilize stalled
replication forks and block replication.
• At the G2/M checkpoint: by P53 or ATM
– monitors the completion of DNA replication
– Cells damaged by ionizing radiation activate the
G2/M checkpoint and arrest in G2
• The spindle assembly checkpoint
– inhibits anaphase until there is bipolar attachment
of chromosomes to microtubules of the mitotic
spindle
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23. Growth regulation cont…
• To function properly, cell-cycle
checkpoints require
– sensors of DNA damage,:- proteins of the RAD
family and ataxia telangiectasia mutated
(ATM)
– signal transducers, and effector molecules:-
CHK kinase families
• The sensors and transducers of DNA
damage appear to be similar for the G1/S
and G2/M checkpoints.
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24. Growth regulation cont…
• In addition to being driven by increased
proliferation, growth of a cancer may be
attributable to cellular resistance to death.
• At least three distinct types of cell death
pathways have been characterized, including
– apoptosis,
– necrosis, and
– autophagy
• All three pathways may be ongoing
simultaneously within a tumor
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25. Growth regulation cont…
• Apoptosis is an active, energy-dependent
process that involves cleavage of the DNA by
endonucleases and proteins by proteases
called caspases.
• Extrinsic pathway
– External stimuli such as TNF, TNF-related
apoptosis-inducing ligand, fatty acid synthase
(Fas), and other death ligands that interact with
cell surface receptors can induce activation of
caspases, and lead to apoptosis
• The intrinsic pathway is activated in response
to a wide range of stresses including DNA
damage and deprivation of growth factors
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26. Growth regulation cont…
• Necrosis is a type of cell death and is the
result of bioenergetic compromise.
– Morphologic changes include swollen
organelles and rupture of the cell membrane,
leading to loss of osmoregulation and cellular
fragmentation
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27. Growth regulation cont…
• Autophagy is a potentially reversible process
in which a cell that is stressed “eats” itself
• is characterized by the formation of
cytoplasmic autophagic vesicles, into which
cellular proteins and organelles are
sequestered.
– allow for cell survival if damaged organelles can
be repaired.
– Conversely, the process may lead to cell death if
these vesicles fuse with lysosomes
– Several cancer therapeutic agents have been
shown to induce autophagy
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28. Origins of Genetic Alterations
• Most cancer cells are genetically unstable,
with an average of 30 to 100 acquired
mutations per cancer.
• Some of these may be simply “passenger”
mutations that occur as a result of
generalized genetic instability.
– not involved in malignant transformation,
– these may contribute to evolution of the
malignant phenotype with respect to growth,
invasion, metastasis, and response to therapy,
– results in evolution of heterogeneous clones
within a tumor
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29. Origins of Genetic Alterations
cont…
• Human cancers arise because of a series of genetic
and epigenetic alterations that lead to disruption
of normal mechanisms that govern cell growth,
death and senescence
• Genetic damage may be
– Inherited or
– Acquired:
• exposure to exogenous carcinogens or
• endogenous mutagenic processes within the cell
• The stem cell theory
– small numbers of progenitor cells (stem cells) exist
within a tumor and have the capacity to regenerate
tumors …… responsible for the development of
recurrent disease
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30. • It is thought that at least three to six
critical “driver” alterations are required to
fully transform a cell.
• As age increase incidence of cancer
increase because cell will acquire sufficient
damage to become fully transformed.
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31. Inherited genetic damage
• The most common forms of hereditary
cancer syndromes predispose to
breast/ovarian (BRCA1, BRCA2) and
colon/endometrial (Lynch syndrome genes
such as MSH2 and MLH1) cancers
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33. Inherited genetic damage cont..
• There is no relationship between
expression patterns of these genes in
various organs and the development of
specific types of cancers.
– E.g, BRCA1 expression is high in the testis
• The penetrance of cancer susceptibility
genes is incomplete because not all
individuals who inherit a mutation develop
cancer.
• The emergence of cancers in carriers
depends on the occurrence of additional
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34. Inherited genetic damage cont..
• The familial cancer syndromes result from rare
mutations that occur in less than 1% of the
population.
• High penetrance genes have been discovered that
are mutated infrequently but confer dramatically
increased cancer risks
• Low-penetrance genes common genetic
polymorphisms may also affect cancer
susceptibility, albeit less dramatically
– There are more than 10 million polymorphic genetic
loci in the human genome,
– They do not increase risk sufficiently to produce
familial cancer clustering,
– they could account for sporadic cancers, because
of their relatively high prevalence
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35. Inherited genetic damage cont..
• Epigenetics changes
– are heritable changes that do not result from
alterations in DNA sequence
– Methylation of cytosine residues that reside next
to guanine residues is the primary mechanism of
epigenetic regulation,
– regulated by a family of DNA methyltransferases
– Most cancers have globally reduced DNA
methylation, which may contribute to genomic
instability.
– Conversely, selective hypermethylation of
cytosines in the promoter regions of tumor
suppressor genes can cause silencing
– Acetylation and methylation of the histone
proteins that coat DNA
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36. Inherited genetic damage cont..
• There is a family of imprinted genes in
which either the maternal or paternal copy
is normally completely silenced because of
methylation
• Examples:
– The hydatidiform mole is composed of
paternal chromosomes
– The teratoma is composed of only maternal
chromosomes
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37. Acquired Genetic Damage
• For many common forms of cancer (colon, breast,
endometrium, ovary), a strong association with
specific carcinogens does not exist.
• Endogenous mutagenic processes
– such as methylation, deamination, and hydrolysis of DNA.
– spontaneous errors in DNA synthesis
– free radicals generated in response to inflammation and
other cellular damage may cause DNA damage
– These endogenous processes produce many mutations
each day in every cell in the body.
• Exogenous carcinogens
– Chemicals
– Radiation
– Microbial agents
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38. Molecular Basis of Cancer
• Fundamental principles
– Nonlethal genetic damage lies at the heart of
carcinogenesis
– A tumor is formed by the clonal expansion of a
single precursor cell that has incurred the genetic
damage (i.e., tumors are monoclonal).
– Four classes of normal regulatory genes—
• the growth-promoting protooncogenes,
• the growth-inhibiting tumor suppressor genes,
• genes that regulate programmed cell death (apoptosis),
and
• genes involved in DNA repair—are the principal targets
of genetic damage
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39. – DNA repair genes affect cell proliferation or
survival indirectly by influencing the ability of
the organism to repair nonlethal damage in
other genes, including protooncogenes,
tumor suppressor genes, and genes that
regulate apoptosis
– Carcinogenesis is a multistep process at both
the phenotypic and the genetic levels
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40. ESSENTIAL ALTERATIONS FOR
MALIGNANT TRANSFORMATION
• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Defects in DNA repair
• Limitless replicative potential
• Sustained angiogenesis
• Ability to invade and metastasize
• The escape from immunity and rejection
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42. SELF-SUFFICIENCY IN GROWTH
SIGNALS: ONCOGENES
• Proto oncogenes :-
• Are normal cellular genes
involved with growth and
cellular differentiation and
proliferation
• Oncogenes are derived from
proto- oncogenes by either
–Change in the gene sequence (new
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43. Oncogenes cont…
• In cell culture systems, many genes that are
involved in normal growth regulatory
pathways can elicit transformation when
altered to overactive forms via
amplification, mutation, or translocation.
– HER2-neu amplification
– The BCR-ABL translocation in chronic
myelogenous leukemia
– KIT in gastrointestinal stromal tumors (GIST), may
become overactive when affected by point
mutations at codons that change a single amino
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44. Oncogenes cont…
• Mutant alleles of protooncogenes are
considered dominant because they
transform cells despite the presence of a
normal counterpart
• Studies indicated that alteration of just
one copy, of these proto oncogenes was
enough to transform and cause cancerous
(one hit hypothesis ) that is to say one hit
is enough to express the disease
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45. Oncogenes cont…
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46. Oncogenes cont…
• Proteins encoded by protooncogenes may
function as
– growth factor ligands and receptors,
– signal transducers,
– transcription factors, and
– cell-cycle components
• Oncoproteins encoded by oncogenes
generally serve similar functions as their
normal counterparts
• However, because they are constitutively
expressed, oncoproteins endow the cell with
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47. Oncogenes cont…
• Cell Membrane Oncogenes—Peptide
Growth Factors and Their Receptors
– Peptide growth factors in the extracellular
space–such as those of
• the epidermal growth factor (EGF),
• platelet-derived growth factor (PDGF), and
• fibroblast growth factor (FGF) families— stimulate
a cascade of molecular events that leads to
proliferation by binding to cell membrane
receptors
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48. Oncogenes cont…
• Aberrant proliferative signaling through
these peptide growth factor pathways can
occur through a number of mechanisms:
– Increased or inappropriate autocrine production
of growth factors,
– increased paracrine production of growth factors
by tumor stromal environment,
– increased responsiveness of receptors to growth
factor ligands or ligand independent activation of
the receptor, and
– constitutive activation of components
downstream of the receptor.
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49. Oncogenes cont…
• Intracellular Oncogenes
– Signal-transducing proteins
– Many of these signals involve phosphorylation
of proteins by enzymes known as nonreceptor
kinases
– The activity of kinases is regulated by
phosphatases, such as PTEN, which act in
opposition to the kinases by removing
phosphates from the target proteins
– The ras family of G proteins is among the
most frequently mutated oncogenes in human
cancers (e.g., gastrointestinal and endometrial
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50. Oncogenes cont…
• Nuclear Oncogenes
– Examples include the fos and jun oncogenes,
which dimerize to form the activator protein 1
(AP1) transcription complex.
– When inappropriately overexpressed, these
transcription factors can act as oncogenes.
– amplification or overexpression of members of
the myc family
• Finally, genes encoding nuclear proteins
that inhibit apoptosis (e.g., bcl-2) can act
as oncogenes
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51. Oncogenes cont…
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52. INSENSITIVITY TO GROWTH INHIBITORY
SIGNALS: TUMOR SUPPRESSOR GENES
• Tumor suppressor genes are responsible
for making a product that inhibits cell
growth.
• These types of genes are expressed in a
recessive manner, and therefore both
alleles need to be lost before the
phenotype becomes apparent
• This usually involves a two-step process in
which both copies of a tumor suppressor
gene are inactivated
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53. Tumor suppressor genes cont…
• In most cases, there is mutation of one copy
of a tumor suppressor gene and loss of the
other copy caused by deletion of a segment of
the chromosome where the gene resides
• This two-hit paradigm is relevant to both
hereditary cancer syndromes, in which one
mutation is inherited and the second
acquired, and sporadic cancers, in which the
two hits are acquired
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54. Tumor suppressor genes cont…
• Nuclear Tumor Suppressor Genes
– The retinoblastoma gene was the first tumor
suppressor gene discovered
– The Rb gene plays a key role in the regulation
of cell cycle progression
– Mutations in the Rb gene have been noted
primarily in retinoblastomas and sarcomas
– Mutation of the TP53 tumor suppressor gene
is the most frequent genetic event described
in human cancers
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55. Tumor suppressor genes cont…
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56. Tumor suppressor genes cont…
• p53 has been described as the “guardian
of the genome” because it delays entry
into S phase until the genome has been
cleansed of mutations.
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58. Tumor suppressor genes cont…
• WNT Pathway
– β-catenin (CTNNB1) is involved along with
cadherins in cell-cell adhesion junctions
– play a role in inhibition of excessive growth when
cells come in contact with each other
– β-catenin activity is regulated by the WNT
pathway resulting in an increase in the amount of
β-catenin translocated to the nucleus
– Genes encoding WNT signaling inhibitors are
often downregulated during carcinogenesis
– APC, Axin, GSK-3a, a-catenin
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59. Tumor suppressor genes cont…
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60. Tumor suppressor genes cont…
• Extranuclear Tumor Suppressor Genes
– The APC tumor suppressor gene
– TGF-β
– phosphatases such as PTEN
– Cadherins
– The INK4a/ARF locus
• MicroRNA
– genes consist of a single RNA strand of
approximately 21 to 23 nucleotides that does not
encode proteins.
– They bind to messenger RNAs that contain
complementary sequences and can block protein
translation.
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62. EVASION OF APOPTOSIS
• BCL-2 protects cells from apoptosis by the
mitochondrial pathway
• Because lymphomas that overexpress BCL-
2 arise in large part from reduced cell
death rather than explosive cell
proliferation, they tend to be indolent
(slow growing)
• p53 and MYC
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63. DNA REPAIR DEFECTS AND
GENOMIC INSTABILITY IN CANCER
CELLS
• Defects in three types of DNA repair
systems, namely, mismatch repair,
nucleotide excision repair, and
recombination repair
• E.g. BRCA-1 and BRCA-2 Genes
– involved in transcription regulation
– BRCA-1 is involved in the regulation of
estrogen receptor activity and is also a co-
activator of the androgen receptor
• HNPCC
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64. There are six repairing genes :-
 TGF-BR2H(A10)
 hMSH3 (A8)
 hMSH6/GTBP (C8,
 IGF2R (G8)
 BAX (G8)
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65. LIMITLESS REPLICATIVE POTENTIAL:
TELOMERASE
• Normal cells are capable of undergoing
division only a finite number of times
before becoming senescent.
• Cellular senescence is regulated by a
biologic clock related to progressive
shortening of repetitive DNA sequences
(TTAGGG) called telomeres that cap the
ends of each chromosome.
• Telomeres are thought to be involved in
chromosomal stabilization and in
preventing recombination during mitosis.
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66. • At birth, chromosomes have long
telomeric sequences (150,000 bases) that
become progressively shorter by 50 to 200
bases each time a cell divides.
• Telomeric shortening is the molecular
clock that triggers senescence.
• Malignant cells often avoid senescence by
turning on expression of telomerase
activity to prevent telomeric shortening.
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68. DEVELOPMENT OF SUSTAINED
ANGIOGENESIS
• Tumors cannot enlarge beyond 1 to 2 mm
in diameter or thickness unless they are
vascularized
• Neovascularization has a dual effect on
tumor growth:
– perfusion supplies nutrients and oxygen, and
– newly formed endothelial cells stimulate the
growth of adjacent tumor cells by secreting
polypeptide growth factors such as insulin-like
growth factors and PDGF.
• Angiogenesis is a requisite not only for
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69. • Tumor-associated angiogenic factors are
produced by tumor cells or may be
derived from inflammatory cells (e.g.,
macrophages) that infiltrate tumors.
• The two most important are VEGF and
basic fibroblast growth factor (bFGF).
• Tumor cells not only produce angiogenic
factors, but also induce anti-angiogenesis
molecules
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70. INVASION AND METASTASIS
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71. Mechanisms of metastasis
development within a primary
tumor
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72. Mechanisms of metastasis
• Studies in mice reveal that although
millions of cells are released into the
circulation each day from a primary tumor,
only a few metastases are produced.
• the metastatic cascade will be divided into
two phases:
– (1) invasion of the extracellular matrix and
– (2) vascular dissemination and homing of
tumor cells
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73. Invasion of Extracellular Matrix
• Invasion of the
ECM is an active
process that can
be resolved into
several steps
A. Detachment
("loosening up")
of the tumor
cells from each
other
B. Attachment to
matrix
components
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74. Mechanisms of metastasis
C. Degradation of ECM
• to create a path for
invasion by tumor
cells,
• cleavage products of
matrix components,
also have growth-
promoting,
angiogenic, and
chemotactic activities.
D. Migration of tumor
cells
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75. Mechanisms of metastasis
• Vascular Dissemination and Homing of
Tumor Cells
– Once in the circulation, tumor cells are particularly
vulnerable to destruction by innate and adaptive
immune defenses
– Tumor cells tend to aggregate in clumps,
particularly with platelets
– Adhesion molecules (integrins, laminin receptors)
and proteolytic enzymes. E.g. CD44
– Chemokines and chemoattractants
– The target tissue may be an unpermissive
environment. E.g. skeletal muscles
Is cancer a communicable disease?
Is it transmitted by blood transfusion?
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76. ANTITUMOR EFFECTOR
MECHANISMS
• About 5% of persons with congenital
immunodeficiencies develop cancers, about
200 times the prevalence in
immunocompetent individuals
• Both cell-mediated and humoral immunity
• The principal mechanism of tumor immunity
is killing of tumor cells by CD8+ CTLs
• Natural killer cells
• Macrophages
• Antibodies
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77. IMMUNE SURVEILLANCE
• Tumor cells must develop mechanisms to
escape or evade the immune system in
immunocompetent hosts
– Selective outgrowth of antigen-negative
variants
– Loss or reduced expression of MHC molecules
– Lack of costimulation:
– Immunosuppression: TGF-β, secreted by many
tumors
– Antigen masking: glycocalyx molecules
– Apoptosis of cytotoxic T cells: tumors kill Fas-
expressing T lymphocytes
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78. TUMOR PROGRESSION AND
HETEROGENEITY
• Thus, despite the fact that most malignant
tumors are monoclonal in origin, by the time
they become clinically evident, their
constituent cells are extremely
heterogeneous.
• Differ with respect to several phenotypic
attributes such as
– invasiveness,
– rate of growth,
– metastatic ability,
– karyotype,
– hormonal responsiveness, and
– susceptibility to antineoplastic drugs.
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79. • At the molecular level, tumor progression
and associated heterogeneity most likely
result from multiple mutations that
accumulate independently in different
cells, thus generating subclones with
different characteristics.
• However, tumor progression also depends
on the
– tumor microenvironment and
– changes in the tumor stroma and
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80. • Gompertzian growth
• When tumors are
extremely small, growth
follows an exponential
pattern
• means that as a tumor
mass increases in size,
the time required to
double the tumor’s
volume also increases.
• This suggests that small
tumors and micro
metastases should be
more sensitive to
chemotherapy
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81. • The doubling time
– Is the time it takes for
the mass to double its
size
– A 1-mm mass will have
undergone
approximately 20
tumor doublings
– A 1-cm mass will have
undergone 30
doublings
– Vary on type of tumors
• The growth fraction
– Is the number of cells
in the tumor mass that
are actively dividing
– Determine rate at
which tumors grow
along with rate of cell
loss
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82. Summary
• The number of cells in normal tissues is
tightly regulated by a balance between
cellular proliferation and death
• Dysregulation of cellular proliferation is
one of the main hallmarks of cancer.
• Most human cancers that have been
analyzed reveal multiple genetic
alterations involving activation of several
oncogenes and loss of two or more tumor
suppressor genes: Gatekeeper and
Caretaker Genes
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83. References
1. Berek & Hacker’s gynecologic oncology
6th ed
2. Disaia, Creaseman clinical oncologic
gynecology 8th ed
3. NOVAK’S GYNECOLOGY 14TH ed
4. Robbin’s basic pathology,8th ed
5. UPTO DATE 21.2
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