Download 01A cell transformation

Cell transformatin and cancer
I
Subjects treated in this lecture
- definition of cancer
- transformation of the cell; from benign to malign
- mutations underlying cancer: oncogenes and
tumor suppressors
- construction of cancer in a Petri dish
- consequences of cancer
Cancer
from cancrum = crab, probably derived from Cancrena (16ème
siècle) describing a disease that slowly and secretely destroys
the body
Cancer are not the disease of this agen they have been observed
in corals and in 70 million year old dinosaures skeletons (bone of
3% of the Edmontosaurus is affected)
Caracteristic of cancer
1) Acquisition of a cellular mass (tumour) as a consequence of new
growth (neoplasm)
2) Loss of control of cellular function by organism
Tumours may disseminate into different tissues of the organisme
and form secondary tumours (metastasis)
Cancer cells
Are little differentiated
- have lost of 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
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 therefore often 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 loss of sensitivity to programmed cellular death (apoptosis)
Benign
A benign tumour shows an increased number of cells (hyperplasia)
that have not lost their physiological function and morphology.
Esentially, other tissues have not yet been infiltrated (in
particular no sign of tumour cells in adjacent lymph nodes)
Malign (or malignant)
Malign tumours, or cancer, signifies a loss of physiological function
(or an excess of function). This is accompanied by altered
morphology and infiltration of other tissues (metastases). The
cells are said to be fully transformed.
Lack of contact
inhibition results in the
formation of structures
like a polyp in the colon;
a cell mass that
extends well beyond
the bounderies of a
single layer gut
epithelium but does not
yet invade surrounding
tissues
La 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:
- very 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, ultimate consequence of the
aforementioned characteristics
Transformed cells
can 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. It is believed that 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)
Compiling and validating proto oncogenes
Classification of genes as proto-oncogenes is
ultimately based upon the conviction that
mutant forms of these genes have a functional
role in the development of cancer
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
Mutations that favour the development of cancer are
carried by genes that code for the following proteins: :
-
growth factors and their receptors (c-Sis, ERBB2*)
components of signal transduction pathways (Ras, DPC4)
those that control the cell division cycle (TP53*, Rb, Ink4B)
those that 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
- * these proteins are subject of the breast cancer course project
Negative balance: no proliferation
Balance positive: aberrant growth
Genomic instability accelerates the process of cell
transformation
The number of mutations necessary to cause cancer should normally
not be attained in a lifetime, unless exposed to highly cancerogenic
substances. Yet, one in three inhabitants of Western Europe and
North Americ develops a cancer.
The explanation comes from the observation that certain mutations
occur in proteins that occupy an important role in the control of the
integrity of the genome (BRCA, TP53). Their loss-of-function
causes « genetic instability » and this augments dramatically the
number of mutations and thus the chance of acquiring the unlucky
combination that leads to cell transformation. In other cases, the
control of the cell division cycle is diminished and cells easily start a
cell division cycle (loss of Rb).
« From here on things go from bad to worse »
Cells do not easily accept « transforming mutations »
Cells normally prefer to die than to accept alterations that creep into
their genome and that, in the long run, may turn out to be detrimental to
the organism. In other words, the cells sacrifice themselves for the sake
of the organism.
Cellular responses to damage or alterations
-
Loss of cell-cell or cell-matrix contact
damage of DNA
errors in DNA replication
insufficient DNA repair
excess of proliferative signal
loss of telomeres
apoptose
cell cycle arrest/apoptosis
cell cycle arrest
apoptose
senescence or apoptosis
senescence or apoptosis
Predisposition to cancer (familial or hereditary)
Predisposition to cancer is often the consequence of
a mutation that occurs in germ cells (ovum or
spermatozoid). All the cells of the embryo carrry
this mutant. As a consequence a fewer number of
alterations suffices to acquire the unlucky
transforming mutation. Moreover, in the case of
breast cancer, loss-of-function of BRCA means an
increased genetic instability. This may explain why
the penetration of this mutation is so high (a very
high change that a breast tumour.
Another example is the loss of function of the
retinoblastoma protein (Rb), which means that cells
have lost one important control point of the cell
division cycle.
Construction of cancer in a Petri dish
normal cell
limited number of replications
limited growth factor signal accepted
mortal
hTERT,
increased telomerase activity
unlimited number of replications
SV40 loss of cell cycle suppressors
large T, and protection against apoptosis
unlimited number of replications
immortalization
H-v12Ras, excessive proliferative signal
unlimited number of replications
immortalization
enhanced proliferation
transformed cell
Sequential mutations in human cancers
LOH = loss of heterozygosity GBM glioblastoma multiforme (malignant astrocye cancer)
Consequences of cell transformation: metastatic cancer
Advanced cell transformation means reduced survival chance
Consequences of cancer
-Anorexia- Cachexia: loss of appetite and loss of body
weight due to systemic inflammation caused by tumour
cells. Even « forced » feeding is hardly efficient
Pain: in particular in the bones as a consequence of
infiltrating tumour cells. Pain sensations increases with
increased inflammation but tumours also release factors
that affect the senstive nerves in the spinal cord
Asthenia: general weakness as a consequence of muscle
waisting
Anemia: loss of red blood cells, in particular in the case
of leucemie which causes the loss of « red bone marrow »
- Dysfunctioning of the liver, the brain, endocrine glands,
kidney (loss of homeostasis) and lungs (asphyxia)
- cataclysmic Hemorrhage