BS10003 | Science of Living Systems | 2nd Jan 2023

Cell Biology of Development and Cancer

Arindam Mondal
School of Bio Science | Arindam.mondal@iitkgp.ac.in | 03222-284572
 Development of
Multicellular Organisms
Cycle of life depends on two modes of cell division
Mitosis
Fertilization
Zygote
(single cell)

Sperm Ovum Morula

(Multicellular)

Meiosis Mitosis and

Differentiation

Adult Embryo
Mitosis and
Morphogenesis
Expansion of Zygote (single cell ) to adult human (1013 cells):
Mitosis cell division
❑ The fundamental events in cell division cycle
of any living system:
➢ Duplication of genetic material/information
(DNA) in the parent cell.
➢ Accurate distribution (segregation) of
identical DNA into two cells of next
generation (progeny/daughter cells)

❑ The duration of the cell division cycle vary

from organism to organism, and in a single
organism it may vary between cell types:
➢ During early development i.e. embryonic
stage, cells divide once in 8 minutes.
➢ The epithelial cells in the lining of our
intestine divide once in 1 day.
➢ Liver cells divide in 1 year.
➢ Most brain cells (neurons) don’t divide.
Key components of the machinery of cell division cycle:
• Microtubules – One of the three major classes of the filaments of the
cytoskeleton. Tubulins are the monomeric units.
• Kinetochores – Complex structure formed from proteins on a mitotic
chromosome to which microtubules are attached. Helps in the movement of
chromosomes to the poles.
• Centrioles – Short cylindrical array of microtubules.
• Contractile ring – Ring containing actin and myosin that contracts to pinch the
two daughter cells apart.
Stages of Mitosis
Mitosis cell division: equational division

• Division of 1 parent cell produces 2 daughter cells

• Chromosome number remains same after Mitosis (2n to 2n)-
equational division
• Replication doubles the genomic content (2c to 4c), Mitosis
halves it (4c to 2c)
 Somatic cells are diploid (2n) and
Gametes (sperm/ovum) are haploid (n)
❖ Most higher eukaryotes are diploid (2n); i.e. their body
(somatic) cells contain two copies of the genome set
❖ Their sex cells (gametes) are haploid (n) i.e. these cells
contain one copy of the genome set

Chromosomes
haploid 1 set
diploid 2 sets
triploid 3 sets
tetraploid 4 sets
hexaploid 6 sets
octaploid 8 sets
Diploid set of human chromosomes
How does the ‘2n’ genome arise in embryo?
Through fertilization of two sex cells (gametes): one basic
genome set (n) from male gamete (father’s sperm) and
another set (n) from female gamete (mother’s egg).

Sperm Ovum
n
X n (gametes)
fertilization

(n) 2n

Embryo
(n) ❖ So, in order to keep chromosome number
constant, gametes need to be haploid (n)

➢ How do we get haploid gametes in a diploid organism?

Production of sex cells (gametes):
Meiosis cell division
❑ Two rounds of division of 1 parent cell
produces 4 daughter cells
❑ Chromosome number becomes half after
Meiosis; i.e. diploid (2n) cell divides to
generate haploid (n) gametes- reductional
division
❑ Replication doubles the genomic content (2c
to 4c), Meiosis reduces it (4c to c)

Spermatogenesis Oogenesis

2n 2n

Meiosis

n
Ovum

Sperms
Unique features of mitosis and meiosis compared
Meiosis: single round of
2n, 2C 2n, 2C
chromosome duplication
followed by two rounds of
2n, 4C 2n, 4C c h r o m o s o m e
segregation.
1 st round (Meiosis-I)
segregates the homologs
that pair up.
2 nd round (Meiosis-II)
segregates the sister-
chromatids
n, 2C n, 2C 2n, 4C

Mitosis: homologs do not

pair up and segregate
but the sister-chromatids
segregate
n,C n,C n,C n,C 2n,2C 2n,2C
Chromosome orientation in mitosis and meiosis
Mitosis: Separation of chromatids

Meiosis: Separation of
homologous chromosomes
 Mitosis vs Meiosis
❑ Mitosis (equational division): Somatic (body) cells increase in number in this
mode
❑ Meiosis (reduction division): Specialized diploid cells (meiocytes) undergo two
sequential nuclear divisions to form four haploid gametes (sperms and eggs in
plants, animals) or spores (fungi, algae).

Mitosis Meiosis

Chromosome sets Genomic content Chromosome sets Genomic content

Parent cell 2n 2C 2n 2C
Genome
2n 4C 2n 4C
duplication

Progeny cells 2n 2C n C

 
 One copy of Genome (n) in each Sperm/Ovum
The gametes of most higher eukaryotes are haploid (n) i.e. these cells
contain one copy of the basic genome set (one set of chromosomes)

Somatic Cells (2n) Somatic Cells (2n) Gametes (n)

Mitosis Meiosis
(22 x 2) + XX 22 + X Egg

2n F

Mitosis Meiosis 22 + X Sperm

(22 x 2) + XY or
22 + Y Sperm
2n M
 Diploid (2n) Genome arises during fertilization
Through fertilization of two haploid gametes, i.e., one genome set (n)
from male gamete (i.e. sperm) and another genome set (n) from female
gamete (i.e. egg).
Gamete formation (2n  n) Fertilization (n + n  2n)

Meiosis
Egg: 22 + X
(n)
2n F 2n F

Meiosis Sperm: 22 + X
(n)
Sperm: 22 + Y
2n M (n) 2n M
 Asymmetric cell division is essential to generate
different cell types in multicellular organisms
SC
NB
Asymmetric division ❑ In multicellular organisms, stem cells can
&
give rise to two different cells, one that
Self Renewal of the
Stem Cell resembles the parent cell and one that
SC IP does not. Such asymmetric cell division
generates all different cell types in the
body
Symmetric ❑ Daughter cells produced by such
IP
SC division asymmetric cell division may differ in size,
shape, composition of protein/RNA and
most crucially in gene expression which
IP confers different fates on the two cells
SC
❑ In symmetric cell division, the parental cell
Differentiating gives rise to two daughter cells that
cells resemble each other, at least visually
SC= stem cell NOTE: GENOMIC CONTENT IS SYMMETRICALLY SEGREGATED
IP= intermediate progenitor EVEN IN ASYMMETRIC DIVISION
How does asymmetric cell division
occur?• Essential to asymmetric cell
division is polarization of the
parental cell and then
differential incorporation of
parts of the parental cell into
the two daughters
• Some cytoplasmic components
(such as mRNA or proteins) are
localized in some part of the cell
• The unequal distribution of
these components to the
daughter cells results in
transcription of different sets of
genes
• The resulting proteins
determine the cell-fate
Cell and Molecular
Biology of Cancer
 Cell Division Cycle Alternates Between Mitosis (M)
and Interphase (G1, S, G2)
❑ Interphase – long period between two
divisions during which cells grow, duplicate
chromosomes and prepare for division
➢ G1 (Gap phase 1) – birth of cell to the
onset of chromosome duplication
➢ S (Synthesis phase) – chromosome
duplication (formation of sister
chromatids) due to replication of DNA
➢ G2 (Gap phase 2) – end of chromosome
duplication to the onset of mitosis.

❑ M: Mitosis phase – nuclear division follows division of cytoplasmic content

(cytokinesis) to separate sister chromatids into daughter cells
❑ G0: resting phase – cells exit from cell cycle and survive for days or years
Cell cycle control system

The eukaryotic cell cycle

control system has three
major checkpoints as
surveillance mechanism
for cell cycle progression
or transitions :
1. Start or restriction point
(between G1 and S)
2. G2/M checkpoint
3. Metaphase/anaphase
transition
 Cyclins & cyclin-dependent kinases (Cdks):
central components of the cell cycle control system

Central component of cell cycle control

system are cyclin-dependent kinases
(Cdks). Their activities rise and fall as
the cell progresses through its cycle.
This leads to cyclical changes in the
phosphorylation of proteins that initiate
or regulate major cell cycle events.
Cdk activity is primarily controlled by
Cyclin proteins. Cdks are active only
when they tightly bind cyclin.
The levels of cyclin proteins
periodically rise and fall which result in
periodic activation and deactivation of
the Cdks.
 Different classes of cyclins undergo cyclical
synthesis and degradation
Cyclin concentration

Three classes of cyclins are required in all Eukaryotic cells:

1. G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication.
2. S-cyclins bind Cdks during S phase and are required for the initiation
of DNA replication.
3. M-cyclins promote the events of mitosis.
In most cells, a fourth class of cyclins, the G1-cyclins, helps promote passage
through Start or the restriction point in late G1.
What happens when cell cycle regulation goes wrong?
• Uncontrolled proliferation- TUMOUR
• Cell division without checking for DNA damage-
1. DNA replication errors are not corrected
2. DNA damage due to external mutagens are not corrected
➢ACCUMULATION OF MUTATIONS IN GENOME
❑ Error rate of DNA Polymerase= 1 in 105 nucleotides
➢ A human cell has 6 billion base pairs
➢ So 1 round of replication of the human genome will make 120,000 errors!!!

❑ How are those errors repaired?

➢ During replication: DNA Polymerase has proofreading activity
➢ After replication: A well designed DNA repair machinery repairs the damage

❑ If the DNA damage is beyond repair, the cell dies by initiating Apoptosis
 What happens when DNA is damaged?
Replication Ionizing UV Mutagenic Cigarette
ROS
errors Radiation exposure chemicals smoking

Cell cycle pauses DNA repair Apoptosis (Programmed

at Checkpoint programme Cell Death)
 What is a mutation?
A mutation is an alteration in the nucleotide
sequence of the genome of an organism
▪ Mutation in a gene results in alteration in the
protein product
▪ Spontaneous mutations: due to replication
error
▪ Induced mutations: caused by mutagens

▪ Mutagen: a physical or chemical agent that changes the DNA sequence

▪ Examples: radiation (UV, X ray etc.), tobacco, chemical agents
▪ Carcinogen: a substance or agent that promotes carcinogenesis or cancer
formation
▪ Examples: Asbestos, tobacco smoke, aflatoxin, arsenic, radiation, food
colors, certain viruses etc.
 Germline mutations vs Somatic Mutations
Spermatogenesis Oogenesis
Germline
mutation
Zygote

Mutation Somatic
in gamete mutation
genome Ovum

Sperms fertilization

Somatic
mutation

Zygote
Mutation transmitted to progeny Mutation may lead to Cancer
 What causes cancer?- Gene Mutations

A. Tumor Suppressor Genes: B. Proto-oncogenes:

• Products are involved in
➢Cell cycle regulation
➢DNA repair
➢Cell death
• Loss-of-function mutation
leads to uncontrolled cell
division
• Products are involved in
➢Growth regulation
➢Regulation of cell division
➢Cellular communication
➢Cell death
• Gain-of-function mutation
converts them to Oncogenes,
which leads to uncontrolled
cell division

❑ About One Percent of the Genes in the Human Genome Are Cancer-Critical
 p53
Role of tumour suppressor gene GUARDIAN
OF
p53 THE GENOME

Normal cell division DNA damage – rise in P53 level:
does not depend on (i) cell cycle arrest for DNA repair
p53 protein
or
(ii) Induction of cell death
DNA damage and p53 absent-
(i) no cell cycle arrest
and
(ii) no apoptosis
the cell continues to divide with
DNA damage/genetic abnormality
Cancer is a multistep process:
in each step accumulating mutations
and altering cells properties
 Hallmarks of Cancer Cells

❑Uncontrolled mitotic division- TUMORIGENESIS

❑Evasion of cell death signals- IMMORTALIZATION

❑Induce formation of blood vessels- ANGIOGENESIS

❑Invade healthy tissue- METASTASIS

 1. Development of Tumor

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nc
Ca
of
ks
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 2. Angiogenesis:

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nc
Ca
of Formation of blood vessels in tumour
ks
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Ha

Normal angiogenesis
Tumour-induced angiogenesis
 3. Immortalization:

r e
nc
Ca
of Evading Apoptosis
ks
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llm
Ha

Dividing cell Dividing cell

DNA Damage DNA Damage

High p53 No p53

Cell cycle arrest No cell cycle arrest

Uncontrolled
or cell division
DNA damage Induction of
repaired Apoptosis

Normal cell (If DNA damage is No DNA No

division beyond repair) damage Apoptosis
repair

Daughter cells Tumour

 4. Metastasis:

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nc
Ca
ks
of Invasion and tumor formation at a new site
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Ha
Various modalities of cancer treatment
Books