Cell transformatin and cancer. I Subjects treated in this lecture - definition of cancer - transformation of the cell; from benign to malign - mutations.

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 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)

Cancerfrom cancrum = crab, probably derived from Cancrena (16ème siècle) describing a disease that slowly and secretely destroys the body

Caracteristic of cancer1) 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)

Are characterized by - an enlarged nucleus with a big

nucleolus- little cytoplasm and altered

morphology- fewer contacts with neighbours

Normal breast duct cells

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)

BenignA 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 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

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.

Predisposition to cancer (familial or hereditary)

nor mal cell

t r ansf or med cell

limit ed number of r eplicat ionslimit ed growt h f act or signal accept ed

mor t al

unlimit ed number of r eplicat ions

unlimit ed number of r eplicat ionsimmor t aliz at ion

unlimit ed number of r eplicat ionimmor t alizat ion

enhanced prolif er at ion

incr eased t elomer ase act ivit y

loss of cell cycle suppr essor sand pr ot ect ion against apopt osis

excessive pr olif er at ive signal

s

hT ERT ,

S V40large T ,

H - v12Ras,

Construction of cancer in a Petri dish

Sequential mutations in human cancers

LOH = loss of heterozygosityGBM 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