Oncogenesis - Cancer

Oncogenesis

·        Cancer causing agents:

o   „Natural‟ – eg fungus and plant toxins. Eg aflatoxin from fungus contaminating peanuts in Africa ® liver cancer

o   Man-made: enormous diversity. Mainly the metabolites/intermediates in the body that are carcinogenic. Very often organ specific. Most precarcinogens detoxified to non-carcinogenic metabolites.

·        Cancer = uncontrolled cell proliferation due genetic change

·        The more uncontrolled the proliferation, the more mutations – in final stages anuploidy, translocations, etc will be very common

·        Oncogenes: cells related to normal cell proliferation and differentiation. If one allele is mutated then uncontrolled proliferation (Þ autosomal dominant)

·        Tumour suppressor genes: regulatory genes that inhibit cell proliferation. Need to loose both alleles to have an effect (Þ autosomal recessive)

·        Carcinogenesis:

o  Multifactorial – needs multiple DNA mutations

o  P53 Gene:

§  Regulates cell cycle

§  Inactivated in over ½ human tumours

§  Activated by hypoxia, DNA damage, viruses

§  If there is minor cell damage ® small amount of P53 ® arrest cell cycle and repair 

§  If major damage ® ­­ P53 ® apoptosis

§  Activated P53 binds to DNA activating other genes

§  Normal P53 can be inactivated by mutating co-factors

o  Philadelphia Chromosome:

§  Arises from balanced translocation t(9, 22)(q34,q11)

§  Brings C-ABL gene beside BCR gene. C-ABL is an oncogene, and is now regulated by BCR Þ normal regulation has failed

§  Causative in CML, also seen in other tumours.

o  Telomere

§  Non-coding cap to genome

§  During replication, an enzyme binds and prevents replication Þ telomere shortens with each replication

§  Telomerase can produce telomere – usually only in germ cells. But also active in cancer cells ® unlimited potential to divide

§  Research aim: find drug to inhibit telomerase Þ give cancer cells a limited number of divisions

o  Tumour starts with single clone, quickly becomes heterogeneous. Only a few descendants will be able to metastasise

o  Growing tumour needs blood supply – secrets angiogenic factors. Research aim: find ways of inhibiting this process. An advantage would be that this would kill all tumour cells, whereas chemotherapy is selective, leaving resistant cells to grow