Cellular Kinetics

Generation time is the time required for a quiescent cell to

complete a cycle in cell division and give rise to 2 daughter
cells.

Malignant cells usually have a shorter generation time than

nonmalignant cells from the same tissue, and there usually
are a smaller percentage of cells in G0 (resting phase).

The slowing in growth rate is likely related to exhaustion of

the supply of nutrients and O2 for the rapidly expanding
tumor. Small tumors have a greater percentage of actively
dividing cells than do large tumors.
Cellular kinetics of particular tumors is an important
consideration in the design of anti neoplastic drug
regimens and may influence the dosing schedules and
timing intervals of treatment.

Many anti neoplastic drugs are effective only if cells are

actively dividing, and some drugs work only during a
specific phase of the cycle and thus require prolonged
administration to catch dividing cells during the phase
of maximal sensitivity.
 Cell cycle

G0 = resting phase (nonproliferation of cells); G1 = variable pre-DNA

synthetic phase (12 h to a few days); S = DNA synthesis (usually 2 to 4
h); G2 = post-DNA synthesis (2 to 4 h)a tetraploid quantity of DNA is
found within cells; M1 = mitosis (1 to 2 h).
 Molecular Abnormalities
Genetic mutations are responsible for the generation
of cancer cells.
These mutations alter the quantity or function of
protein products that regulate cell growth and division
and DNA repair.
4 major categories of mutated genes are oncogenes
and tumor suppressor genes :
proto-oncogenes
tumor suppressor genes
regulate programmed cell death (apoptosis) genes
DNA repair genes
 ONCOGENES
These are abnormal forms of normal genes
(proto-oncogenes) that regulate various aspects
of cell growth.
Mutation of these genes may result in direct
and continuous stimulation of the pathways eg :
- intracellular signal transduction pathways,
transcription factors,
secreted growth factors
that control cellular growth and division, DNA
repair, angiogenesis, and other physiologic
processes.
 Oncogen . . . cont
Specific oncogenes may have important implications for
diagnosis, therapy, and prognosis (see individual discussions
under the specific cancer type).

Oncogenes typically result from :

- acquired somatic cell mutations secondary to point
mutations (eg, from chemical carcinogens),
- gene amplification (eg, an increase in the number of
copies of a normal gene), or
- translocations.

Occasionally, mutation of genes results in inheritance of a

cancer predisposition, as in the inheritance of BRCA1 or
BRCA2 in families with a high incidence of breast or ovarian
cancer.
Gene amplification, Deletion,
Rearrangement , Mutation
 ONCOGENES . . . cont
There are > 100 known oncogenes that may contribute to
human neoplastic transformation. For example, the ras gene
encodes the Ras protein, which regulates cell division.
Mutations may result in the inappropriate activation of the
Ras protein, leading to uncontrolled cell growth and division.
In fact, the Ras protein is abnormal in about 25% of human
cancers.
Other oncogenes have been implicated in specific cancers.
These include :
Her2/neu (breast cancer)
bcr-abl (chronic myelocytic leukemia, B-cell acute
lymphocytic leukemia)
C-myc (Burkett's lymphoma)
N-myc (small cell lung cancer, neuroblastoma)
 Tumor suppressor genes
Genes that brakes the cell proliferation.

Genes such as the p53 gene play a role in normal cell

division and DNA repair and are critical for detecting
inappropriate growth signals in cells.

If these genes, as a result of inherited or acquired

mutations, become unable to function, genetic mutations in
other genes can proceed unchecked, leading to neoplastic
transformation.
Chromosomal abnormalities
Gross chromosomal abnormalities can occur through
deletion, translocation, or duplication. If these
alterations activate or inactivate genes that result in a
proliferative advantage over normal cells, then a tumor
may develop.

Chromosomal abnormalities occur in certain human

cancers.

In some congenital diseases (Bloom syndrome, Fanconi

anemia, Down syndrome), DNA repair processes are
defective and chromosomes break easily, putting
children at high risk of developing acute leukemia and
lymphomas.ccur in certain human cancers
 Other influences
Most cancers likely involve several of the mechanisms
described above that lead to neoplastic conversion.

For example, the development of tumor in familial polyposis

takes place through a sequence of genetic events: epithelium
hyperproliferation (loss of a suppressor gene on
chromosome , early adenoma (change in DNA methylation),
intermediate adenoma (overactivity of the ras oncogene),
late adenoma (loss of a suppressor gene on chromosome ,
and finally, cancer(loss of a gene on chromosome )

Further genetic changes may be required for metastasis.

Other influences
Most cancers likely involve several of the mechanisms
described above that lead to neoplastic conversion.

For example, the development of tumor in familial polyposis

takes place through a sequence of genetic events: epithelium
hyperproliferation (loss of a suppressor gene on
chromosome , early adenoma (change in DNA methylation),
intermediate adenoma (overactivity of the ras oncogene),
late adenoma (loss of a suppressor gene on chromosome ,
and finally, cancer(loss of a gene on chromosome )

Further genetic changes may be required for metastasis.

 Telomeres
are nucleoprotein complexes that cap the ends of
chromosomes and maintain their integrity. In normal
tissue, telomere shortening (with aging) results in a
finite limit in cell division.
The enzyme telomerase provides for telomere
synthesis and maintenance; thus telomerase may
potentially allow for cellular immortality. Activation of
telomerase in tumors allows continuous proliferation
of tumors.
 TELOMERES . . cont

are short repeated sequences of DNA

TTAGGG (linear end of chromosomes) and
are important in :
ensuring THE COMPLETE
REPLICATION of chromosome ends
protecting chromosomal termini from fusion
and degradation
 Telomerase
The sequences are formed by a special
RHIBONUCLEOPROTEIN --- TELOMERASE

Enzym that stabilized

Telomere length by adding
to the ends of chromosomes

Activities of telomerase repressed by REGULATORY

PROTEINS ----
RESTRICT Telomere elongation
TELOMERASE ACTIVITY :
expressed in GERM CELL
present at low levels in STEM
CELLS
absent in most SOMATIC CELLS

Somatic cells replicate

Small section of the telomere is not
duplicated
Telomeres shorten
Signal in growth checkpoint
Cell become SENESCENT
IMMORTAL CELLS

Telomeresase REACTIVATED

Telomeres are NOT SHORTENED

Telomeres ELONGATION ----------- TUMOR /

NEOPLASM
 in cellular aging : after a fixed number of divisions,
normal cells become arrested in a terminally no dividing
CELLULAR SENESCENCE
How normal cells can count their divisions is not
known, but noted that in cell division there is some
shortening specialized structure called : TELOMERES
Once the telomeres are shortened beyond a certain point
the lost telomere function leads to end-to-end
chromosome
fusion and death
Thus, telomere shortening is believed to be clock
that Count divisions
 In germ cells, telomere shortening is prevented by
the sustained function of the enzyme telomerase ----
Explaining the ability of these cells to self replicate
This enzyme is absent from most somatic cells, and
hence they suffer progressive lost of telomeres
A recent study, shown that introduction of
telomerase into normal human cells causes
considerable extension of their life span ------- thus
supporting the hypothesis that telomerase loss is
causally associated with loss of replication ability.
If loss of telomerase is the basis of the finite life
span of cells, how do cancer cells continue to divide
indefinitely ?
 The telomerase, hypothesis of cellular ageing would
predict that in addition to the loss of normal growth
regulatory influences, cancer cells must find a way to
prevent telomere shortening ----- an obvious
mechanism to accomplish this might be to reactivate
telomerase
Telomerase actitivity has been detected in the
vast majority of human tumors, and in those that
lack of telomerase, other telomere-lenghthening
mechanisms have been found.
It could be hypothesized : that telomere shortening
is a tumor-suppresive mechanism
Carcinogenesis
Thank you