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PATHO_NEOPLASIA

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PATHO_NEOPLASIA Powered By Docstoc
					NEOPLASIA
All tumors, benign and malignant, have two basic components:
     (1) proliferating neoplastic cells that constitute their parenchyma
              proliferating "cutting edge" determine their nature,
     (2) supportive stroma made up of connective tissue and blood vessels.
          growth and evolution of neoplasms are critically dependent on their
                  stroma.
           adequate stromal blood supply is requisite, and the stromal connective tissue
                 provides the framework for the parenchyma.
                 stromal support is scant - neoplasm is soft and fleshy.
           parenchymal cells stimulate the formation of an abundant collagenous
                   stroma--referred to as desmoplasia.
The nomenclature of tumors
 based on the parenchymal component.
Benign Tumors.
    In general, benign tumors are designated by attaching the suffix -oma to the cell of
           origin.
However nomenclature of benign epithelial tumors is more complex.
     They are variously classified, some based on their cells of origin, others on
      microscopic architecture, and still others on their macroscopic patterns.
Adenoma
     benign epithelial neoplasm that forms glandular patterns as well as to the tumors
     derived from glands but not necessarily reproducing glandular patterns.
     Benign epithelial neoplasms producing microscopically or macroscopically visible
finger-like or warty projections from epithelial surfaces are referred to as papillomas
Those that form large cystic masses - cystadenomas. Some tumors produce papillary
patterns that protrude into cystic spaces and are called papillary cystadenomas. When a
neoplasm, benign or malignant, produces a macroscopically visible projection above a
mucosal surface and projects - a polyp.
Malignant Tumors.
The nomenclature essentially follows the same schema used for benign neoplasms,
with certain additions.
Malignant tumors arising in mesenchymal tissue - sarcomas
Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers -
carcinomas.
      a glandular growth pattern microscopically is termed an adenocarcinoma.
      the organ of origin Not infrequently,
      a cancer is composed of undifferentiated cells and must be designated merely as a
poorly differentiated or undifferentiated malignant tumor.
In most neoplasms, benign and malignant, the parenchymal cells bear a close
resemblance to each other
     divergent differentiation of a single line of parenchymal cells creates what are called
mixed tumors.
. The great majority of neoplasms, even mixed tumors, are composed of cells
representative of a single germ layer.
 The teratoma, in contrast, is made up of a variety of parenchymal cell types
representative of more than one germ layer, usually all three. They arise from
totipotential cells and so are principally encountered in the gonads, although, rarely, they
occur in sequestered primitive cell rests elsewhere.
  An ectopic rest of normal tissue is sometimes called a choristoma-
  Analogously, aberrant differentiation may produce a mass of disorganized but mature
specialized cells or tissue indigenous to the particular site, referred to as a hamartoma.
CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS
in general, there are criteria by which benign and malignant tumors can be differentiated,
and they behave accordingly:
    (1) differentiation and anaplasia,
    (2) rate of growth,
    (3) local invasion,
     (4) metastasis.
Differentiation and Anaplasia
These terms apply to the parenchymal cells of neoplasms.
 Differentiation - extent to which parenchymal cells resemble comparable normal cells,
both
                    morphologically and functionally.
          Well-differentiated tumors are thus composed of cells resembling the mature
normal cells of the tissue of origin of the neoplasm
          Poorly differentiated or undifferentiated tumors have primitive-appearing,
unspecialized cells.
 In general,
benign tumors are well differentiated
Malignant neoplasms range from well differentiated to undifferentiated.
 . Lack of differentiation, or anaplasia - hallmark of malignant transformation.
            means "to form backward," implying a reversion from a high level of
differentiation
             to a lower level.
            arise from stem cells present in all specialized tissues.
Marked by a number of morphologic and functional changes.
    Both the cells and the nuclei characteristically display pleomorphism--variation in
size and shape
 Cells may be found that are many times larger than their neighbors, and other cells may
be extremely small and primitive appearing.
Characteristically the nuclei contain an abundance of DNA and are extremely dark
staining ( hyperchromatic). The nuclei are disproportionately large for the cell, and the
nuclear-to-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. The
nuclear shape is usually extremely variable, and the chromatin is often coarsely clumped
and distributed along the nuclear membrane.
   Large nucleoli are usually present in these nuclei.
undifferentiated tumors usually possess large numbers of mitoses, reflecting the higher
proliferative activity of the parenchymal cells. The presence of mitoses, however, does
not necessarily indicate that a tumor is malignant or that the tissue is neoplastic.
. More important as a morphologic feature of malignant neoplasia are atypical, bizarre
mitotic figures sometimes producing tripolar, quadripolar, or multipolar spindles .
Formation of tumor giant cells, some possessing only a single huge polymorphic nucleus
and others having two or more nuclei.



.
In addition to the cytologic abnormalities described here, the orientation of anaplastic
cells is markedly disturbed (i.e., they lose normal polarity). Sheets or large masses of
tumor cells grow in an anarchic, disorganized fashion. Although these growing cells
obviously require a blood supply, often the vascular stroma is scant, and in many
anaplastic tumors, large central areas undergo ischemic necrosis.
Dysplasia - means disordered growth.
      is encountered principally in the epithelia, and it is characterized by a constellation
of changes that include a loss in the uniformity of the individual cells as well as a loss in
their architectural orientation.
     also exhibit considerable pleomorphism (variation in size and shape) and often
possess deeply stained (hyperchromatic) nuclei, which are abnormally large for the size
of the cell.
     Mitotic figures are more abundant than usual, although almost invariably they
conform to normal patterns. Frequently the mitoses appear in abnormal locations within
the epithelium.
     There is considerable architectural anarchy.
     almost invariably antedates the appearance of cancer, dysplasia does not
necessarily progress to cancer.
      the better the differentiation of the cell, the more completely it retains the functional
capabilities found in its normal counterparts.
     Highly anaplastic undifferentiated cells, whatever their tissue of origin, come to
resemble each other more than the normal cells from which they have arisen.
    The more rapidly growing and the more anaplastic a tumor, the less likely it is that
there will be specialized functional activity.
The cells in benign tumors are almost always well differentiated and resemble their
normal cells of origin; the cells in cancer are more or less differentiated, but some loss of
differentiation is always present.
Rate of Growth
The generalization can be made that most benign tumors grow slowly over a period of
years, whereas most cancers grow rapidly, sometimes at an erratic pace, and eventually
spread and kill their hosts. Such an oversimplification, however, must be extensively
qualified. Some benign tumors have a higher growth rate than malignant tumors.
Moreover, the rate of growth of benign as well as malignant neoplasms may not be
constant over time.
In general,
      the growth rate of tumors correlates with their level of differentiation, and thus most
malignant tumors grow more rapidly than do benign lesions. There is, however, a wide
range of behavior. Some malignant tumors grow slowly for years then suddenly increase
in size virtually under observation, explosively disseminating to cause death within a few
months of discovery. It is believed that such behavior results from the emergence of an
aggressive subclone of transformed cells. At the other extreme are those that grow more
slowly than benign tumors and may even enter periods of dormancy lasting for years.
On occasion, cancers have been observed to decrease in size and even spontaneously
disappear
Local Invasion
Nearly all benign tumors grow as cohesive expansile masses that remain localized to
their site of origin and do not have the capacity to infiltrate, invade, or metastasize to
distant sites, as do malignant tumors.
 Because they grow and expand slowly, they usually develop a rim of compressed
connective tissue, sometimes called a fibrous capsule, that separates them from the
host tissue. This capsule is derived largely from the stroma of the native tissue as the
parenchymal cells atrophy under the pressure of expanding tumor. Such encapsulation
tends to contain the benign neoplasm as a discrete, readily palpable, and easily
movable mass that can be surgically enucleated . Although a well-defined cleavage
plane exists around most benign tumors, in some it is lacking. Most malignant tumors
are obviously invasive and can be expected to penetrate the wall of the colon or uterus,
for example, or fungate through the surface of the skin. They recognize no normal
anatomic boundaries. Such invasiveness makes their surgical resection difficult, and
even if the tumor appears well circumscribed, it is necessary to remove a considerable
margin of apparently normal tissues about the infiltrative neoplasm. Next to the
development of metastases, invasiveness is the most reliable feature that differentiates
malignant from benign tumors. We noted earlier that some cancers seem to evolve from
a preinvasive stage referred to as carcinoma in situ. This is best illustrated by carcinoma
of the uterine cervix (Chapter 24) . In situ cancers display the cytologic features of
malignancy without invasion of the basement membrane. They may be considered one
step removed from invasive cancer, and with time, most penetrate the basement
membrane and invade the subepithelial stroma.
Metastasis
  tumor implants discontinuous with the primary tumor.
  unequivocally marks a tumor as malignant because benign neoplasms do not
metastasize.
The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics,
and body cavities, providing the opportunity for spread. With few exceptions, all cancers
can metastasize.
The major exceptions are most malignant neoplasms of the glial cells in the central
nervous system, called gliomas, and basal cell carcinomas of the skin. Both are highly
invasive forms of neoplasia (the latter being known in the older literature as rodent
ulcers because of their invasive destructiveness), but they rarely metastasize.
It is evident then that the properties of invasion and metastasis are separable.
In general
     the more aggressive, the more rapidly growing, and the larger the primary neoplasm,
the greater the likelihood that it will metastasize or already has metastasized. There are
innumerable exceptions,
PATHWAYS OF SPREAD
Dissemination of cancers may occur through one of three pathways:
  (1) direct seeding of body cavities or surfaces,
  (2) lymphatic spread, and
  (3) hematogenous spread. Seeding of Body Cavities and Surfaces.
    may occur whenever a malignant neoplasm penetrates into a natural "open field."
Most often involved is the peritoneal cavity, but any other cavity--pleural, pericardial,
subarachnoid, and joint space--may be affected.
Lymphatic Spread.
Transport through lymphatics is the most common pathway for the initial dissemination
of carcinomas, but sarcomas may also use this route.
The pattern of lymph node involvement follows the natural routes of drainage.
.Hematogenous Spread.
    is typical of sarcomas but is also used by carcinomas.
      Arteries, with their thicker walls, are less readily penetrated than are veins,
        however, may occur when tumor cells pass through the pulmonary capillary beds
        or pulmonary arteriovenous shunts or when pulmonary metastases themselves
       give rise to additional tumor emboli
     Venous invasion, the blood-borne cells follow the venous
EPIDEMIOLOGY
Study of cancer patterns in populations - origins of cancer.
Cause of cancer can be obtained by epidemiologic studies that
relate particular
     environmental,
     racial (possibly hereditary), and
    cultural influences
    certain diseases associated with an increased risk of
     developing cancer
Cancer Incidence
Individual's likelihood of developing a cancer is expressed by
national incidence and mortality rates.
Geographic and Environmental Factors
Remarkable differences can be found in the incidence and
death rates of specific forms of cancer around the world.
There is no paucity of environmental factors:
   ambient environment,
   workplace,
   in food,
   personal practices.
Age
important influence on the likelihood of being afflicted with
    cancer.
Most carcinomas occur in the later years of life (55 years).
Each age group has its own predilection to certain forms of
   cancer
   striking increase in mortality from cancer in the age group
        55 to 74 years.
   The decline in deaths in the 75-year-and-over group merely
   reflect the dwindling population reaching this age
    children under the age of 15 are not spared
        acute leukemias and CNS - 60% account for all death
        other common neoplasm of infancy and childhood
           neuroblastoma
           Wilms tumor
           retinoblastoma
          rhabdomyosarcoma
Heredity
   large number of types of cancer, including the most common
   forms, there exist not only environmental influences, but
     also hereditary predispositions.
   NO MORE THAN 5 % TO 10% of all human cancers fall into
     the following categories
Hereditary forms of cancers
      contribution of heredity to the fatal burden of human
      cancer - no more than 5 to 10% of all human cancers.
1. Inherited Cancer Syndromes.
   Several well-defined cancers in which inheritance of a
        single mutant gene greatly increases the risk of
        developing a tumor.
   Predisposition to these tumors shows an autosomal
        dominant pattern of inheritance.
        Childhood retinoblastoma
        Familial adenomatous polyposis (FAP)
    Often associated with a specific marker phenotype.
        multiple adenoma >100 in Familial adenomatous polyp
         there are abnormalities in tissue that are not the target
           of transformation
        Lisch nodules and café-au-lait spot – neurofibromatosis
       specific sites and tissues -
         MEN syndrome In each syndrome, tumors involve
2. Familial Cancers.
  Virtually all the common types of cancers that occur
      sporadically have also been reported to occur in familial
      forms.
     brain, colon, breast, ovary
  Characteristic features
      a. Early age at onset
      b. tumors arising in two or more close relatives of the
          index case, and
      c. sometimes multiple or bilateral tumors.
      d. Not associated with specific marker phenotypes.
      e. Transmission pattern is not clear.
          In general, sibs have a relative risk between 2 and 3.
              predisposition to the tumors is dominant, but
              multifactorial inheritance cannot be easily ruled
          Certain familial cancers can be linked to the inheritance
              of mutant genes - linkage of BRCA-1 and BRCA-2
                                 genes to familial breast and
                                 ovarian cancers.
3. Autosomal Recessive Syndromes of Defective DNA Repair.
  Small group of autosomal recessive disorders is collectively
  characterized by chromosomal or DNA instability.
     Xeroderma pigmentosum - in which DNA repair is
                              defective.


There is an emerging evidence that the influence of
 hereditary factors is subtle and indirect
 The genotype may influence the likelihood of one’s
 developing environmentally induced cancers
Acquired Preneoplastic Disorders
Predispositions - cell replication is involved in cancerous
                   transformation - Great majority of instances
                   they are not complicated by neoplasia.
       regenerative,
       hyperplastic, and
       dysplastic proliferations
       are fertile soil for the origin of a malignant neoplasm
Precancerous conditions
   well-defined association with cancer
   great majority of instances no malignant neoplasm emerges,
   but it calls attention to the increased risk.
  1. non-neoplastic disorders
      chronic atrophic gastritis of pernicious anemia;
      solar keratosis of the skin;
      chronic ulcerative colitis; and
      leukoplakia of the oral cavity, vulva, and penis-
  2. benign neoplasia - most do not become cancerous
       villous adenoma of the colon,
       tubular adenoma
Are benign tumor cancerous?
   In general, the answer is NOT, but invariably there are
               exceptions, and perhaps it is better to say that
               each type of benign tumor is associated with a
               particular level of risk, ranging from HIGH to
               virtually NONEXISTENT
MOLECULAR BASIS OF CANCER
 Nonlethal genetic damage
 lies at the heart of
 carcinogenesis.
 genetic damage (or mutation)
 may be acquired by the
 action of environmental
 agents inherited in the germ
 line.
Mutations
permanent
changes in the
DNA

Germs cells
transmitted to the
progeny and may
give rise to
inherited diseases

Somatic cells
 not transmitted to
the progeny but
are important in
the causation
of cancers and
some congenital
malformations
Mutation is corrected     carcinogens
by a mechanism of
DNA repair
1. recognition and
incision of the
affected DNA strands
by an
ENDONUCLEASE
2. excision and
broadening of the
gap by an
EXONUCLEASE
 - DNA polymerase
3.filling of the gap by
repair replication –
DNA polymerase
 4. covalent joining of
the polynucleotides
by LIGASE
Genetic
hypothesis of
cancer
tumor mass
results from the
clonal expansion
of a single
progenitor cell
that has incurred
the genetic
damage


Tumors
are
  monoclonal
DNA repair genes affect cell proliferation
 ( regulate repair of damaged DNA )
 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.
  A disability in the DNA repair genes can predispose to
    mutations in the genome - neoplastic transformation.
  Both alleles of DNA repair genes must be inactivated to
    induce such genomic instability;

When the genes that normally sense and repair DNA damage
are impaired or lost, the resultant genomic instability favors
mutation in genes that regulate six acquired capabilities of
cancer cells
MOLECULAR BASIS
     OF
   CANCER
Three classes of normal regulatory genes
principal targets of genetic damage.
  1. Growth-promoting protooncogenes,
  2. Growth-inhibiting cancer-suppressor genes
     (antioncogenes),
  3. Genes that regulate programmed cell death, or apoptosis
  4. DNA repair genes

Mutant alleles of protooncogenes - oncogenes
    are considered dominant because they transform cells
    despite the presence of their normal counterpart.
Tumor-suppressor genes
    both normal alleles of the must be damaged for
     transformation to occur - recessive oncogenes.
Genes that regulate apoptosis
 may be dominant, as are protooncogenes, or
 may behave as cancer-suppressor genes.
Genetic changes that fuel tumor progression involved
  Growth-regulatory genes
  Genes regulate angiogenesis,
               invasion, and
               metastases

Cancer related genes in the context of six
fundamental changes in cell physiology that together
dictate malignant phenotype
  1. self-sufficiency
  2. insensitivity to growth-inhibitory signals
  3. Evasion of apoptosis
  4. limitless replicative potential – overcome cellular
                                      senescence
  5. sustained angiogenesis
  6. ability to invade and metastasize
Carcinogenesis
  molecular basis of cancer
 Multistep process at both the phenotypic and the genetic
  levels
 A malignant neoplasm has several phenotypic attributes
 these characteristics are acquired in a stepwise fashion
 Tumor Progression.
        as excessive growth,
        local invasiveness,
        ability to form distant metastases.
 At the molecular level,
    progression results from accumulation of genetic lesions
    that in some instances are favored by defects in DNA
    repair.
A. Self-sufficiency in growth signal
  Oncogenes – mutant allele of protooncogenes
            genes that promote autonomous cell growth in
               cancer cells
            promote cell growth in the absence of normal
                growth-promoting signals
            products – oncoproteins
                       resemble the product of normal
                       protooncogenes except it is devoid
                       of important regulatory elements
and
                       their production in transformed cells
                       does not depend on growth factors
                       or other external signals
Steps of cell proliferation

1. Binding of a GF to its
   specific receptor on
   CM
2. Transient and limited
   activation of the
   growth factor receptor,
   which in turn activates
   several signal-
   transducing proteins
   on the inner leaflets of
   the CM
3. Transmission of the
   transduced signal
   across the cytosol to
   the nucleus via a
   second messengers
4. Induction and
   activation of nuclear
   regulatory factors that
   initiate DNA
   transcription
5. Entry and progression
   of the cell into the cell
   cycle, resulting
   ultimately in cell
   division
Signal transduction cascade and
Cell Cycle Regulation

I. GROWTH FACTORS
    normal cell require stimulation by growth factors to
undergo
    proliferation – most soluble GF are made by one cell type
    and act on a neighboring cell to stimulate proliferation
    ( paracrine action) Tumor cells
   1. ability to synthesize the growth factor to which they
         responsive – autocrine
      1.1 altered/mutated growth factor genes – excessive
                                       production Growth Factor
       1.2 Most common
       Growth factor genes itself is not altered or mutated,
          but the products of other oncogene cause
          overexpression of growth factor genes
             cells are forced to secret large amount of Growth
             Factors
II. GROWTH FACTOR RECEPTORS
    1. Mutation
       oncogenes encode growth factor receptors –
       overexpression of mutant receptor proteins deliver
       continuous mitogenic signals to cells even in the absence
       of the growth factors in the environment
    2. Most common
        growth factor receptor genes itself is not altered or
        mutated but there are overexpression of GF from other
                               sources
         – can render cancer cells hyperresponsive to normal
        levels of growth factors, a level that would not normally
        trigger proliferation
        HER2 (EGF receptor family ERBB1, ERBB2)in breast CA

III. SIGNAL TRANSDUCING PROTEINS
     mutation in genes that encode various components of the
     signaling pathways ( overexpression of signaling proteins ) –
     couple with GF receptors to their nuclear targets
        RAS and ABL
        30% of all human tumor contain mutated version of the
        RAS genes – undergo point mutation
Mutated RAS
Genes
produced
Mutant RAS
Proteins
can bind GAPs
but their
GTPase
activity fails to
be augmented –
mutant RAS is
trapped in its
activated GTP-
bound form and
the cell is led
to believed that
it must
continue to
proliferate

Neurofibromin1
Nonreceptor-associated tyrosine kinase - signal transduction
pathways
 ABL – protooncogene is dampened by negative regulatory
       domains
       chromosome 9 and is translocated to chromosome 22,
       where it fuses with part of the break point cluster
       region ( BCR) gene – BCR-ABL hybrid gene has a
       potent tyrosine kinase activity, and it activates
       several pathways including RAS-RAF cascade
   chronic myeloid leukemia
   certain acute leukemia

IV. NUCLEAR TRANSCRIPTION FACTORS
    responder genes in the nucleus that orchestrate the cells
    orderly advance through the mitotic cycle – genes that
    regulate transcription of DNA
    oncogenes - MYC, MYB, JUN, FOS productions of
                 oncoproteins
      MYC oncogene – associated with persistent expression
                        or overexpression – overexpression of
                                            MYC oncoproteins
MYC proteins – bind to the DNA – transcriptional activation of
several growth-related genes, including CYCLIN-DEPENDENT
KINASE – drives cells into cell division
 translocation t(8:14) Burkitt’s lymphoma
 amplification breast, colon, lung and others

Cyclin and Cyclin-dependent kinase
  growth promoting stimuli – entry of quiescent cells into cell
                               cycle
 cyclin are synthesized during specific phase of the cell cycle
 and their function is to activate the CDK which is in inactive
 form and ones activated by cyclins phosphorylate crucial
 target proteins
 on completion of their task cyclin degenerate
 CDK inhibitors silence the CDK and exert negative control
 over the cell cycle
B.INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS
   Normal cell
   antigrowth signal
     may cause dividing cell to go to G0 ( queiscence) or
         enter postmitotic, differentiated pool and lose
          replicative potential
     exert their effects on G1 to S phase check point of the cell
          cycle – this transition is controlled by RB protein
1.RB gene suppressor gene – product is a DNA-binding proteins
   RB protein serves as a brake in the advancement of cells
   from G1 to S phase
   when the cells are activated by growth factor – RB protein
   is inactivated by phosphorylation, ( phosphorylated RB –
   allow cell proliferation ) the break is released and
   the cells traverse the G1 to S phase when the cells enter S
   phase they are committed to divide without additional
   GF stimulation. During M phase the phosphate groups are
   removed from RB by cellular phosphate generating the
   dephosphorylated form of RB – prevent cell proliferation
Mutated RB genes – absence or RB protein or its ability to
   sequester transcription factors is derailed by mutation
2. TGF B pathways
   TGF B in normal cells
     potent inhibitor of proliferation
     it regulate cellular processes by binding to three
          receptors Type I, II,III
     antiproliferative effects are mediated in large part by
        regulating RB pathways
     arrests cells in the G1 phase by stimulating CDK1 p15
     ( inhibitors of CDK1), and by inhibiting the transcription of
     CDK2, CDK4and cyclin A and E
   Mutation of TGF B signalling pathways
       affect type II receptor
          colon stomach and endometrium
       SMAD molecules
          pancreatic tumor
       serve to transduce antiproliferative signal from the
       receptor to the nucleus
3. Adenomatous polyposis coli B-catenin pathway
   APC gene – suppressor gene - APC protein
              it is a cytoplasmic protein whose dominant
              function is to regulate the intracellular level of
              B catenin protein –
                  bind to the to the cytoplasmic portion E-
                        cadherin – a cell surface protein that
                        maintain intercellular adhesiveness
                   translocate to nucleus and activate cell
                        proliferation – important component of
                                        WTN signaling pathways
                                        allows the transcription of
                                        growth promoting genes –
                                        D1 and MYC
APC genes
   one mutant gene – develop hundreds to thousands of
adenomatous polyps in the colon during their teens or 20s, one
or more polyps undergo malignant transformation – both
copies of APC genes must be lost for tumor development –
ADENOMA
70% to 80% of sporadic colon cancers
TP53 gene - guardian of the genome
  suppressor gene
  one of the most commonly mutated genes in human cancers
  antiproliferative – cell cycle
  regulate apoptosis
  DNA repair gene
      senses DNA damage and assists in DNA repair by causing
       G1 arrest and inducing DNA repair genes
       A cell with damaged DNA that cannot be repaired is
       directed by TP53 to undergo apoptosis
  Mutated TP53
      DNA damaged is goes unrepaired, mutations becomes
      fixed in dividing cells, and the cell turnsonto a one-way
      street leading to maligant transformation
   70% of human cancers have defect in this gene and the
    remaining have defects in genes up-stream or down-stream
    TP53
Homozygous loss – found virtually every type of cancer
      including carcinomas of the lung, colon, and breast.
Heterozygous allele – inherited, predisposes to develop
    malignant tumor – Li Fraumeni
Normal TP53
   can be rendered nonfunctional by certain viruses
    proteins encoded by oncogenic HPVs, HBV, EBV – bind to
    normal TP53 proteins and nullify their protective
    functions


C. EVASION OF APOPTOSIS
    CD95 is bound to its Ligand – CD95L – trimerizes and its
cytoplasmic death domain attract the intracellular adaptor
protein –FADD recruit – Procaspase 8 to form death-inducing
signaling complex


                 activated to caspase 8 –activates caspase 3
                                         executioner caspase
                                         that cleaves DNA
                                         and other substrate

               mitochondria – release cytochrome c form
complex with apoptosis-inducing factor 1( APAF 1 ) activates
Procaspase 9 to caspase 9 – which activates caspase 3
  release of cytochrome c regulated by genes of the BCL2
       family
         BCL2 and BCL-X - inhibit apoptosis
         BAD, BAX, BID - promote apoptosis by favoring
                           cytochrome release
 TP53- regulate BAX synthesis
 caspase 8 – activates BID
D. LIMITLESS REPLICATIVE POTENTIAL
 Normal cells
   Have a capacity of 60 to 70 doubling. After this, the cells
      lose the capacity to divide and enter a nonreplicative
      senescence. - due to progressive shortening of the
      TELOMERES At the end of chromosomes with each cell
      division – massive chromosomal abnormalities and death
      To avoid senescence – acquire telomerase is active in
      normal stem cell but is absent from most somatic cells
 Tumor cells
      telomerase maintenance present in virtually all types of
       cancers
E. DEVELOPMENT OF SUSTAINED ANGIOGENESIS
     tumor cannot enlarge beyond 1 to 2 mm in diameter
    unless they are vascularized
   required for tumor growth and metastasis
     Neovascularization
       1. supplies nutrients and oxygen
       2. newly formed endothelial cells stimulate the growth of
          adjacent tumor cells by secreting polypeptides – IGF,
          PDGF, GM-CSF IL-1
Tumor-associated angiogenic factor
    VEGF – vascular endothelial growth factor
   Basic fibroblast growth factor
    early tumor growth do not induce angiogenesis
       they remain small or in situ for years until the angiogenic
       switch terminates the stage of vascular quiscence
    molecular basis
     increase production of angiogenic factors or loss of
     angiogenesis inhibitors
     wild type TP53 – inhibit angiogenesis by inducing synthesis
                      of thrombospondin-1, with mutation of
both
                       allele of TP53
                       Decrease in thrombospondin-1 tilt the
                       balance in favor of angiogenic factors
 hypoxia
    release hypoxia-inducible factor – HIF-1 – control
    transcription of VEGF - also under the control RAS
 Proteases
    can release FGF stored in ECM
   cleavage of plasmin – give rise to angiostatin – potent
F. ABILITY TO
INVADE AND
METASTASIZE
   A carcinoma
first must
breach the
underlying BM,
then traverse
the interstitial
CT, and
ultimately gain
access to the
circulation by
penetrating
the vascular
BM
Detachment of tumor cells
from each other
  E-cadherins intercellular glue
    and transmit antigrowth
    signals via B-catenin
   Mutation of E-cahedrin gene
    or activation B-catenin
    gene
  Free B-catenin – activate
     transcription of growth
     promoting genes

Attachment of tumor cells to
matrix components
receptors for BM laminin are
  distributed around the cell
   membrane
 loss of integrins
Degradation of
extracellular matrix
 tumor cells secrete
proteolytic enzymes or
induce the host cell to
elaborate proteases
metalloproteinases
  gelatinases
   type IV collagenases
  stromelysins

Migration of tumor cells
 mediated by tumor
cell-derived cytokines
cleavage products of
matrix components
   some growth factor
stromal cell paracrine
   effectors of cell
   motility
Genomic Instability - Enabler of malignancy
     are encountered in inherited disorders in which genes that
     encode proteins involved in DNA repair are defective
 HNPCC syndrome
  hereditary nonpolyposis colon carcinoma
  characterized by familial carcinoma of the colon affecting
       predominantly the cecum and proximal colon
 Xeroderma pigmentosum
     increased risk for the development of cancers of the skin
        exposed to the UV light contained in sun rays
     UV causes cross-linking of pyrimidine residues preventing
        normal DNA replication
 Autosomal recessive disorders
    characterized by hypersensitivity to other DNA – damaging
         agents
    Ionizing radiation
        Bloom syndrome
        ataxia-telangiectasia
    DNA cross-linking agents
     Fanconi anemia
Hereditary breast cancer
    mutation in two genes
      account for 80% of cases
   BRCA 1 and
     also higher risk of epithelial ovarian cancers
   BRCA 2
     also increased risk of breast CA in male and women and
     cancers of the ovary, prostate pancreas bile ducts
     stomach and melanocytes
Tumor
Progression
and
Heterogeneity

acquisition of
of more
aggressive
behaviour and
greater
    malignant
potential
Karyotypic Changes in Tumors
The genetic damage that activates oncogenes or inactivates tumor-suppressor genes
      may be subtle (e.g., point mutations) or be large enough to be detected in a
      karyotype.
  In certain neoplasms,
  karyotypic abnormalities are nonrandom and common.
  Specific abnormalities have been identified in most leukemias and lymphomas and in
       an increasing number of nonhematopoietic tumors.
   The common types of nonrandom structural abnormalities in tumor cells are
            (1) balanced translocations, - chromosome 22 and chromosome 9
            (2) deletions - chromosome 13q14 – retinoblastoma
                                          17p, 5q, 18q – colorectal CA
                                          3p small cell CA
            (3) cytogenetic manifestations of gene amplification.
                    homogeneously staining regions on single chromosomes
                    double minutes
            In addition, whole chromosomes may be gained or lost.
   The study of chromosomal changes in tumor cells is important on two
        accounts.
        First, molecular cloning of genes in the vicinity of chromosomal breakpoints or
               deletions has been extremely useful in identification of oncogenes (e.g.,
               bcl-2, c- abl) and tumor-suppressor genes (e.g., APC, Rb).
        Second, certain karyotypic abnormalities are specific enough to be of diagnostic
              value, and in some cases they are predictive of clinical course.
ETIOLOGY OF CANCERS
 Carcinogenic agents
  several may act in concert or sequentially to produce the
  multiple genetic abnormalities characteristic of neoplastic
  cells
   1. chemicals
   2. radiant energy
   3. microbial agents
Chemical carcinogen
  indirect-acting
      procarcinogen
      require metabolic conversion before they become active
  Direct-acting
     ultimate carcinogen
     require nometabolic conversion to become carcinogen
Mechanism of action
   RAS and TP53
 Initiator – mutational activation of an oncogene
 Promoter
    nontumorigenic
    cause clonal expansion of mutated cells
Radiation carcinogenesis
 1. chromosomal breakage
 2. translocation
 3. point mutation
Nonlethal doses of radiation may induce genomic instability
  Fanconi anemia
  Bloom syndrome
  ataxia-telangiectasia
Double stranded DNA breaks – most important
UV light causes mutation in the TP53 gene


Microbial Carcinogenesis
  RNA oncogenic viruses
    retroviruses transform cell by two mechanism
        acute transforming viruses – contains transforming
                                     viral oncogene ( v-onc )
       slow transforming viruses – do not contain a v-onc, but
               the proviral DNA is always found inserted near a
              cellular oncogene – insertional mutagenesis
Human T-cell leukemia
virus type
   no v-onc
   no consistent
     integration next to
     a cellular oncogene
   retroviral gene with
     unique region pX –
     encodes TAX
     protein
  activate
     transcription of
     host cell gene
     including gene
     encoding – IL2,
     GM-CSF
  repress tumor
    supressor genes –
    CDK1, CDKN2A/p16,
    TP53
DNA oncogenic viruses
  HPV, EBV, HHV-8, HBV

   Human papillomavirus
     infection with high-risk HPV type
      simulate the loss of tumor suppressor genes
      activate cyclins
      inhibit apoptosis and
      combat cellular senecence
    infection with is not sufficient for carcinogenesis
       cotransfection with a mutated RAS genes – full malignant
                                                   transformation


Helicobacter pylori
    chronic gastritis – development of reactive T-cell which
          cause – polyclonal B-cell proliferation - additional
     accumulated mutation – monoclonal B-cell proliferation
Tumor immunity - Host defense against tumor
  Tumor antigens
       cancer-testis antigens – MAGE family of gene
  Tissue-Specific antigens
       differentiation-specific antigen
       expressed on tumor cells and their untransformed
          counterpart
  Antigens resulting from mutational change in proteins
       B-catenin, TP53, RAS, CDK4 genes
  Overexpressed antigens
    product of normal genes that overexpressed –amplification
    HER-2
  Viral antigens
  Other tumor antigens
     MUC – 1 antigen
  Oncofetal antigens
     CEA, alpha-feto proteins
  Differentiation-specific antigens
    CD10, PSA
Antitumor effector mechanism
   Cytotoxic T lymphocytes
   NK cells
   Macrophages
   Humoral mechanism
      activation of complements
      induction of antibody-dependent cellular cytotoxicity by
            NK cells

Immunosurveillance
   increased frequency of cancers in immunodeficient host
     in about 5% of patient with congenital
immunodeficiencies
   immunosuppressed transplant
   patient with AIDS
       most are lymphopmas
Cancer cells evades immune system by the following
mechanism
  selective overgrowth of antigen negative variant
  loss or reduced expression of histocompatibility antigens
      HLA class I
lack costimulation – B7-1 – prevent sensitization
                               render T cell anergic or cause
                               them to undergo apoptosis
Immunosuppression
      oncogenic agents – suppress host immune response
      tumor or tumor products also may be immunosuppressive
             TGF-B
CLINICAL
FEATURES
   OF
NEOPLASIA
  protooncogenes are named after their viral homologs. (viral oncogenes [v- oncs])
  sequences were almost identical to sequences found in the normal
Molecular dissection of their genomes revealed the presence of unique transforming
  sequences not found in the genomes of nontransforming retroviruses..
  From this evolved the concept that during evolution,
     retroviral oncogenes were transduced (captured) by the virus through a chance
     recombination with the DNA of a (normal) host cell that had been infected by the
     virus.
    Insertional mutagenesis - mode of protooncogene activation
       proviral DNA is always found to be integrated (inserted) near a protooncogene.
       One consequence of proviral insertion near a protooncogene is to induce a
       structural change in the cellular gene, thus converting it into a cellular oncogene
        ( c-onc) .
      Alternatively, strong retroviral promoters inserted in the vicinity of the
         protooncogenes lead to dysregulated expression of the cellular gene.
Human tumors, which (with rare exceptions) are not caused by
infection with retroviruses.
Do nonviral tumors contain oncogenic DNA sequences?
         DNA of spontaneously arising cancers contains
         oncogenic sequences, or oncogenes.
 Protooncogenes may become oncogenic
 by retroviral transduction (v-oncs) or
 by influences that alter their behavior in situ
 converting them into cellular oncogenes (c-oncs)

Two questions follow
  1. what are the functions ofoncogene product?
  2. how do the normally “civilized” protooncogenes turn into
     “enemies” within
PROTEIN PRODUCTS OF ONCOGENES
Oncogenes encode proteins - oncoproteins, which resemble
   the normal products of protooncogenes, with the exception
   that
       (1) oncoproteins are devoid of important regulatory
           elements, and
      (2) their production in the transformed cells does not
           depend on growth factors or other external signals.

Sequence of events that characterize normal cell proliferation
Under physiologic conditions, cell proliferation can be readily
resolved into the following steps:
The binding of a growth factor to its specific receptor on the
    cell membrane
Transient and limited activation of the growth factor receptor,
    which, in turn, activates several signal-transducing proteins
    on the inner leaflet of the plasma membrane
Transmission of the transduced signal across the cytosol to the
     nucleus via second messengers
Induction and activation of nuclear regulatory factors that
     initiate DNA transcription
Entry and progression of the cell into the cell cycle, resulting
   ultimately in cell division
SELECTED ONCOGENES, THEIR MODE OF ACTIVATION, AND ASSOCIATED
  HUMAN TUMORS
Category        Protooncogene  Mechanism      Associated Human Tumor

Growth Factors
 PDGF-B chain                sis      Overexpression    Astrocytoma
                                                        Osteosarcoma
 Fibroblast growth factors   hst-1    Overexpression    Stomach cancer
                             int-2    Amplification     Bladder cancer
                                                         Breast cancer
                                                         Melanoma
Growth Factor Receptors
  EGF-receptor family        erb-B1   Overexpression     SCS of lung
                             erb-B2   Amplification      Breast,
                                                         ovarian,
                                                         lung,
                                                         stomach cancers
                             erb-B3   Overexpression     Breast cancers
                             fm        Point mutation    Leukemia
                             ret      *Point mutation    MEN 2A and B.
                                                         Familial medullary
                                                            thyroid CA
                                      Rearrangement      Sporadic papillary
                                                            CA of thyroid
Proteins Involved in Signal Transduction
 GTP-binding               ras           Point mutations   A variety of human
                                                            cancers, including
                                                            lung, colon,
                                                            pancreas; many
                                                              leukemias
 Nonreceptor
 tyrosine kinase            abl          Translocation     Chronic myeloid
                                                              leukemia
                                                           Acute lymphoblastic
                                                               leukemia


Nuclear Regulatory Proteins
 Transcriptional activators      myc       Translocation     Burkitt lymphoma
                              N- myc       Amplification     Neuroblastoma
                                                             Small cell CA of
                                                               lung
                              L- myc       Amplification     Small cell CA of
                                                               lung
Cell Cycle Regulators
  Cyclins                   cyclin D   Translocation      Mantle cell
                                                            lymphoma
                                       Amplification      Breast, liver,
                                                            esophageal
                                                             cancers
  Cyclin-dependent kinase   CDK4       Amplification or   Glioblastoma,
                                       point mutation     melanoma,
                                                          sarcoma
ACTIVATION OF ONCOGENES
Mechanisms by which protooncogenes are transformed into
  oncogenes.
 two broad categories of changes:
   1. Changes in the structure of the gene,
       resulting in the synthesis of an abnormal gene product
       (oncoprotein) having an aberrant function
   2. Changes in regulation of gene expression,
       resulting in enhanced or inappropriate production of the
       structurally normal growth-promoting protein.
Point Mutations.
   The ras oncogene represents the best example of activation
    by point mutations – codon 12
       reduce the GTPase activity of the ras protein
 Normal ras protein
    GTPase activity augmented by GAP
 mutant ras protein
    GTPase activity poorly stimulated by GAP
    Result – mutant ras remains in the active GTP-bound form
Large number of human tumor carry ras mutations
   90% - pancreatic adenocarcinoma and cholangiocarcinoma
   50% - colon, endometrial and thyroid cancers
     30% - lung adenocarcinoma and myeloid leukemia
In general
   carcinoma has K-ras while hematopoeitic has N-ras
 ras mutations are infrequent or even nonexistent in certain
   other cancers
 ras mutation are extremely common, but their presence is not
   essential for carcinogenesis

Chromosomal Rearrangements.
Two types of chromosomal rearrangements
can activate protooncogenes
  A. Inversions.
  B. Translocations - much more common – induced
                     overexpression of a protooncogene
     activate protooncogenes in two ways:
1.In lymphoid tumors,
  specific translocations result in overexpression of protooncogenes by placing them
  under the regulatory elements of the immunoglobulin or T-cell receptor loci.
Burkitt lymphoma,
  the most common form of translocation results in the movement of the c- myc-
  containing segment of chromosome 8 to chromosome 14q band 32 places
  c- myc close to the immunoglobulin heavy-chain (IgH) gene - coding sequences
  of the gene remain intact, and the c- myc gene is constitutively expressed at high
 levels.
Mantle cell lymphoma,
   the cyclin D1 gene on chromosome 11q32 is overexpressed by juxtaposition to
   the IgH locus on 14q32.
Follicular lymphoma,
    a t(14;18)(q32;q21) translocation causes activation of the bcl-2 gene

2.In many hematopoietic tumors,
    the translocations allow normally unrelated sequences from two different
    chromosomes to recombine and form hybrid genes that encode growth-promoting
    chimeric proteins
Philadelphia chromosome
    oncogene formed by fusion of two separate genes.
   a reciprocal translocation between chromosomes 9 and 22 relocates a truncated
   portion of the protooncogene c- abl (from chromosome 9) to the bcr on chromosome
   22. hybrid c- abl-bcr gene encodes a chimeric protein
Chronic myeloid leukemia - chimeric protein 210 kD
Acute lymphoblastic leukemias - chimeric protein 180-kD, abl-
                              bcr fusion protein is formed.
SELECTED EXAMPLES OF ONCOGENES ACTIVATED BY TRANSLOCATION
Malignancy           Translocation Affected    Genes

CML                               (9;22)(q34;q11)           Ab1 9q34
                                                             bcr 22q11

AML and ALL                        (4;11)(q21;q23)     AF4 4q21 MLL 11q23
                                    (6;11)(q27;q23)    AF6 6q27 MLL 11q23

Burkitt lymphoma                    (8;14)(q24;q32)     c- myc 8q24 IgH 14q32

Mantle cell lymphoma                (11;14)(q13;q32)   Cyclin D 11q13 IgH 14q32

Follicular lymphoma                 (14;18)(q32;q21)    IgH 14q32 bcl-2 18q21

T-cell acute lymphoblastic leukemia (8;14)(q24;q11)    c- myc 8q24
                                                       TCR-alpha 14q11
                                    (10;14)(q24;q11)   Hox 11 10q24
                                                       TCR-alpha 14q11

Ewing sarcoma                      (11;22)(q24;q12)     FL-1 11q24 EWS 22q12

Melanoma of soft parts             (12;22)(q13;q12)    ATF-1 12q13 EWS 22q12

.
 3. Gene Amplification.
  Activation of protooncogenes associated with overexpression
    of their products may result from reduplication and manifold
    amplification of their DNA sequences
    may produce several hundred copies of the protooncogene
in
         the tumor cell.
    detected by molecular hybridization with the appropriate
     DNA probe produce cytogenetic changes that can be
     identified microscopically.
Two mutually exclusive patterns are seen:
     1. double minutes (dms)
        Multiple small, chromosome-like structures or
     2. Homogeneous staining regions (HSRs).
        assembly of amplified genes into new chromosomes
        lack a normal banding pattern – homogenous in a G -
                                        banded karyotype
Cancer-Suppressor Genes
     apply brakes to cell proliferation.
     is to regulate cell growth - not to prevent tumor formation
PROTEIN PRODUCTS OF TUMOR-SUPPRESSOR GENES
. The tumor-suppressor genes seem to encode various components of this growth
   inhibitory pathway.
 SELECTED TUMOR-SUPPRESSOR GENES INVOLVED IN HUMAN NEOPLASMS
Subcellular
 Location
 Gene
 Function
 Tumors Associated with Somatic Mutations
Tumors Associated with Inherited Mutations

Cell surface
     TGF-beta receptor
     Growth inhibition
      Carcinomas of colon
      Unknown

     E-cadherin
     Cell adhesion
     Carcinoma of stomach, breast
     Familial gastric cancer
Under plasma membrane
    NF-1
    Inhibition of ras signal transduction
    Schwannomas
    Neurofibromatosis type I and sarcomas

Cytoskeleton
     NF-2
     Unknown
     Schwannomas and meningiomas
      Neurofibromatosis type II; acoustic schwannomas and meningiomas
Cytosol
     APC
     Inhibition of signal transduction
     Carcinomas of stomach, colon, pancreas; melanoma
     Familial adenomatous polyposis coli; colon cancer
Nucleus
     Rb
     Regulation of cell cycle
     Retinoblastoma; osteosarcoma; carcinomas of breast, colon, lung
     Retinoblastomas, osteosarcoma
p53
      Regulation of cell cycle and apoptosis in response to DNA damage
      Most human cancers
      Li-Fraumeni syndrome; multiple carcinomas and sarcomas

      WT-1
      Nuclear transcription
      Wilms tumor
      Wilms tumor

      p16(INK4a)
      Regulation of cell cycle by inhibiting cyclin-dependent kinases
      Pancreatic, esophageal cancers
      Malignant melanoma

      BRCA-1
      DNA repair

      Carcinomas of female breast and ovary

      BRCA-2
      DNA repair

      Carcinomas of male and female breast
Genes That Regulate Apoptosis
        bcl-2 is a member of a large family of homodimerizing and heterodimerizing
              proteins, some of which inhibit apoptosis (such as bcl-2 itself and bcl-xL),
        whereas others (such as bax, bad, and bcl-xS) favor programmed cell death.
Apoptosis is the end point of a cascade of molecular events that are initiated by several
stimuli and lead ultimately to the activation of proteolytic enzymes responsible for cell
death.
The bcl-2 family of proteins regulates the activation of these proteolytic enzymes
(caspases).
The proapoptotic and antiapoptotic members of the bcl-2 family act as a rheostat in
regulating programmed cell death. The ratio of death antagonists ( bcl-2, bcl-xL) to
agonists ( bax, bcl-xS, bad, bid) determines whether a cell will respond to an apoptotic
stimulus
Two other cancer-associated genes are also intimately connected with apoptosis:
    the p53 gene and
    the protooncogene c- myc.
The molecular mechanisms of cell death induced by these two intersect with the bcl-2
pathways
     Activation of p53, up-regulates bax synthesis and hence counteracts the
antiapoptotic action of bcl-2.
.
c- myc induces apoptosis when cells are driven by c- myc activation, but growth is
restricted by the limited availability of growth factors in the milieu.
When confronted by such conflicting signals, the cells are programmed to die by
up-regulation of p53 and other undefined signals.
 Overexpression of bcl-2 can rescue cells from c- myc-initiated apoptosis.
    Thus, it appears that myc and bcl-2 may collaborate in tumorigenesis: c- myc
     triggers proliferation, and bcl-2 prevents cell death, even if growth factors become
     limiting
Genes That Regulate DNA Repair
Humans literally swim in a sea of environmental carcinogens. Although exposure to
naturally occurring DNA-damaging agents, such as ionizing radiation, sunlight, and
dietary carcinogens, is common, cancer is a relatively rare outcome of such encounters.
This happy state of affairs results from the ability of normal cells to repair DNA
damage and thus prevent mutations in genes that regulate cell growth and
apoptosis.
In addition to possible DNA damage from environmental agents, the DNA of normal
dividing cells is also susceptible to alterations resulting from errors that occur
spontaneously during DNA replication. Such mistakes, if not repaired promptly, can
also push the cells along the slippery slope of neoplastic transformation

Hereditary non polyposis colon cancer ( HNPCC) syndrome - DNA mismatch repair.
When a strand of DNA is replicating, mismatch repair genes act as "spell checkers."
Thus, for example, if there is an erroneous pairing of G with T, rather than the normal A
with T, the mismatch repair genes correct the defect Cells with such defects in DNA
repair are said to have the replication error (RER) phenotype, which can be readily
documented by examination of microsatellite sequences in the tumor cell DNA.
Microsatellites
 are tandem repeats of one to six nucleotides scattered throughout the genome.
Microsatellite sequences of an individual are fixed for life and are the same in every
tissue. With errors in mismatch repair, there are expansions and contractions of these
repeats in tumor cells, creating alleles not found in normal cells of the same patient.
Such microsatellite instability is a hallmark of defective mismatch repair
xeroderma pigmentosum,
  The basis of this disorder is also defective DNA repair. UV light causes cross-linking of
pyrimidine residues, thus preventing normal DNA replication. Such DNA damage is
repaired by the nucleotide excision repair system

A group of autosomal recessive disorders comprising
   Bloom syndrome, ataxia telangiectasia, and Fanconi anemia
   are characterized by hypersensitivity to other DNA-damaging agents, such as
    ionizing radiation (Bloom syndrome and ataxia telangiectasia), or DNA cross-linking
    agents, such as nitrogen mustard (Fanconi anemia).

Ataxia telangiectasia (AT)
   have a complex phenotype, characterized by gradual loss of Purkinje cells in the
cerebellum, immunodeficiency, acute sensitivity to ionizing radiation, and profound
susceptibility to lymphoid malignancies.
Telomeres and Cancer
     with each cell division there is some shortening of specialized structures, called
telomeres, at the ends of chromosomes
    Once the telomeres are shortened beyond a certain point, the loss of telomere
function leads to end-to-end chromosome fusion and cell death.
   . Thus, telomere shortening is believed to be a clock that counts cell divisions.
           telomere shortening is a tumor-suppressive mechanism
     telomere shortening is prevented by the sustained function of the enzyme
     telomerase - telomerase hypothesis telomerase
                    loss is causally associated with loss of replication ability.
                   cancer cells must find a way to prevent telomere shortening.
                   reactivate telomerase.

				
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