Cell transformatin and cancer

1. Cell transformatin and cancer

2. I

3. 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

4. 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)

5. 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

6. 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)

7. 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.

8. 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

9. 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

10. 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)

11. 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

12. 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

13. 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

14. Negative balance: no proliferation

15. Balance positive: aberrant growth

16. 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 »

17. 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

18. 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.

19. Construction of cancer in a Petri dish

20. Sequential mutations in human cancers LOH = loss of heterozygosity GBM glioblastoma multiforme (malignant astrocye cancer)

21. Consequences of cell transformation: metastatic cancer

22. Advanced cell transformation means reduced survival chance

23. 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