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Cell transformatin and cancer
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• 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

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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)
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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
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• 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)

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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.
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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
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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
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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)
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Compiling and validating proto oncogenes Classifi
cation 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
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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
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• 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

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Negative balance no proliferation
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Balance positive aberrant growth
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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 
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• 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 apoptose
• damage of DNA cell cycle arrest/apoptosis
• errors in DNA replication cell cycle arrest
• insufficient DNA repair apoptose
• excess of proliferative signal senescence or
  apoptosis
• loss of telomeres senescence or apoptosis

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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.
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Construction of cancer in a Petri dish
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Sequential mutations in human cancers
LOH loss of heterozygosity
GBM glioblastoma multiforme (malignant astrocye
cancer)
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Consequences of cell transformation metastatic
cancer
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Advanced cell transformation means reduced
survival chance
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• 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