23 Cell Transformation 2

Cell Transformation
Instructor: Siddharth Sharma, Ph.D

Associate Professor
Department of Biotechnology
T.I.E.T
WHAT IS TRANSFORMATION?
• Transformation implies a change in phenotype that is
dependent on the uptake of new genetic material
• Transformation of cultured cells implies a

spontaneous or induced permanent phenotypic
change resulting from a heritable change in DNA and
gene expression
• Transformation can arise from infection with a

transforming virus or from transfection with genes such
as mutant ras, it can also arise spontaneously or after
exposure to ionizing radiation or chemical carcinogens.
Transformation is associated with genetic instability and
phenotypic change, one or all of which may be expressed in
one cell strain:
(1) immortalization- the acquisition of an infinite life span
(2) aberrant growth control- the loss of contact inhibition of

cell motility, density limitation of cell proliferation, and
anchorage dependence
(3) malignancy- invasive tumors in vivo
The term transformation is used here to imply all three of

these processes
Tumour development
Tumours pass through successive stage (from benign to malign)

as a consequence of a successive alterations of different sort of
the cellular genome during many year).
This process is called “transformation” and cancer cells are

referred to as transformed cells.
The sequential changes in the genome cause:

 An increased sensitivity to proliferative signals
 A loss of necessity to interact strongly with extracellular

matrix and neighbouring cells (loss of tissue integrity)
 A los of sensitivity to programmed cellular death (apoptosis)

Cancer cells
Are little differentiated

 have lost normal functions
 adopt inappropriate functions
 excessive production of certain factors
Normal breast duct cells
Are characterized by
 - an enlarged nucleus with a big nucleolus
 - little cytoplasm and altered morphology
 - fewer contacts with neighbours
Breast duct in cancercells

Growth Properties of Transformed cells
• Immortal
• Anchorage independent
• Loss of contact inhibition
• Low serum requirement
• Growth factor independent
• Production of autocrine growth factors
• Transforming growth factor production
• High plating efficiency
• Shorter population-doubling time
Genetic Properties of Transformed cells
 High spontaneous mutation rate
 Aneuploid
 Overexpressed or mutated oncogenes
 Deleted or mutated suppressor genes
 Gene and chromosomal translocations

Mutations that favour the development of cancer are carried
by genes that code for the following proteins:
- Growth factors and their receptors (ERBB2)
- Components of signal transduction pathways (Ras, DPC4)
- Genes that control the cell division cycle (TP53*, Rb, Ink4B)
- Proteins communicate damage of DNA with the cell division

cycle or apoptosis machinery (TP53, BRCA*)
- Regulators of destruction of other proteins (APC)
- Inhibitors of apoptosis (Bcl-2, Bcl-Xl)

- Telomerases (hTERT)
- Regulators of inflammation
Genetic alterations that cause malignancy
Genomic alterations leading to cancer are diverses, certain

inherited, others the consequence of environmental factors
(smoking, radiation, asbsestos) or just a consequence of aging
(errors in replication)
Genes carrying alterations are classified as those carrying
a « gain-of-function » mutation,
oncogenes
or
a « loss-of-function » mutations,
tumour suppressor genes
Sequential mutations in human cancers
LOH = loss of heterozygosity GBM glioblastoma multiforme (malignant astrocye cancer)

Structural Properties of Transformed cells
 Modified actin cytoskeleton
 Loss cell surface-associated fibronectin
 Modified extracellular matrix
Altered expression of cell adhesion molecules (CAMs,

cadherins, integrins)
Disruption in cell polarity

Transformed cells
 Detach from their neighbours and extracellular matrix,
destroy their environment (or induce other cells to do so),
migrate, enter the bloodstream or the lymphe and colonize
other sites of the body.
 Normal cells would die throughout this process due to a

lack of sufficient survival signals during the journey.
 Cell death through detachment is referred to as anoïkis

(homeless)
Neoplastic properties of transformed cells
• Tumorigenic
• Angiogenic
• Invasive
• Enhanced protease secretion

(e.g.,plasminogen activator)
Malignancy is the consequence of an interplay between transformed
cells and their environment.
Highly transformed cells show one or more of the following

characteristics. They are:
 Sensitive to growth factors signals
 Insensitive to contact inhibition of cell differentation factors
 Capable of avoiding apoptosis
 Immortilized (meaning show unlimited divisions
 Able to induce a chronic inflammatory condition which, amongst

other effects, facilitates angiogenesis (and thus growth and
metastasis)
 Capables to disseminate
Construction of cancer in a Petri dish
norm al cell
limited num ber of replications

limited growth factor signal accepted
mortal
hTERT , increased telomerase activity
unlimited num ber of replications

SV40 loss of cell cycle suppress ors
large T , and protection against apoptosis
unlimited number of replications
imm ortalization
H -v12Ras, excessive proliferative signal
unlimited number of replication s

imm ortalization
enhanced proliferation
transform ed cell
Consequences of cell transformation: metastatic cancer
THANK YOU

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Cell Transformation

Instructor: Siddharth Sharma, Ph.D

• Transformation of cultured cells implies a

• Transformation can arise from infection with a

(2) aberrant growth control- the loss of contact inhibition of

(3) malignancy- invasive tumors in vivo

The term transformation is used here to imply all three of

Tumours pass through successive stage (from benign to malign)

This process is called “transformation” and cancer cells are

The sequential changes in the genome cause:

 A loss of necessity to interact strongly with extracellular

 A los of sensitivity to programmed cellular death (apoptosis)

Are little differentiated

Breast duct in cancercells

 High spontaneous mutation rate

 Overexpressed or mutated oncogenes

 Deleted or mutated suppressor genes

 Gene and chromosomal translocations

- Growth factors and their receptors (ERBB2)

- Components of signal transduction pathways (Ras, DPC4)

- Proteins communicate damage of DNA with the cell division

- Regulators of destruction of other proteins (APC)

- Inhibitors of apoptosis (Bcl-2, Bcl-Xl)

Genomic alterations leading to cancer are diverses, certain

Genes carrying alterations are classified as those carrying

LOH = loss of heterozygosity GBM glioblastoma multiforme (malignant astrocye cancer)

 Loss cell surface-associated fibronectin

 Modified extracellular matrix

Altered expression of cell adhesion molecules (CAMs,

Disruption in cell polarity

 Normal cells would die throughout this process due to a

 Cell death through detachment is referred to as anoïkis

• Enhanced protease secretion

Highly transformed cells show one or more of the following

 Sensitive to growth factors signals

 Insensitive to contact inhibition of cell differentation factors

 Capable of avoiding apoptosis

 Immortilized (meaning show unlimited divisions

 Able to induce a chronic inflammatory condition which, amongst

limited num ber of replications

unlimited num ber of replications

unlimited number of replication s

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