Introduction to Neoplastics

- uncontrolled cell death the disruption between the cell growth - or loss of a cells ability to undergo apopand cell death balance is a result from: tosis(death of cells) how can mutations occur? - during cell division - from external agents - random event benign tumours: - also known as low grade or I or II tumours - slow growing - less likely to come back - do not spread to other parts of the brain and spinal cord malignant tumours: - also known as high grade or III or IV tumours - life threatening and fast growing - likely to come back - can spread by invasion or metastasis(when another tumour grows in a different part of the body) what is a proto-oncogene? - normal gene found in cells - responsible for making a specific protein during cell growth, division, apoptosis - essential for growth and development and for maintaing healthy tissues and organs can proto-oncogenes cause cancer? - cannot cause cancer unless mutation occurs and turns it into oncogene - when mutation occurs it permanently is turned on= the gain of function mutation - gene will make too many proteins for cell growth- uncontrolled - these mutations are dominant mutations= one copy of gene needs to be mutated to start a cancer - point mutation- mutation alters, alters or deletes one or more nucleotide in the 1/5 gene sequence what are the three different types of gain - gene amplification- extra copies of gene of function mutations that can cause pro- chromosomal translocation- gene is reto-oncogene to become an oncogene located to new chromosomal site what does it mean when the mutation is acquired not inherited? you aren't born with the gene error proto-oncogene activation: 1) point mutation in coding sequence :results in protein with altered function 2) gene amplification: duplication of sequence containing proto-oncogene= increased expression of protein= cell division 3) chromosome rearrangement: controlled under highly active promoter region= increased expression examples of proto-oncogenes: Ras - first proto-oncogene to turn into oncogene - encodes intracellular-transduction protein - when mutated= continuous stimulation of cells without an external trigger= uncontrollable growth - pancreatic, lung, colon, thyroid tumours examples of proto-oncogene: HER2 - makes protein receptors involved in growth and division of cells in breast - breast cancer= gene amplification of HER2 gene examples of proto-oncogene- Myc - associated with Burkitt's lymphoma - chromosomal translocation moves gene enhancer sequence near Myc proto-oncogene examples of proto-oncogene- cyclin D - normal job is to make Rb tumour suppressor protein - tumours of parathyroid gland - once mutated, can no longer make tumour suppressor protein 2/5 what are oncogenes? - when a proto-oncogene is changed, many copies are made, becomes more active than normal - oncogene mutation- gain of function and dominant tumour suppressor genes: - restrains cell growth(unlike oncogene which promote cell growth and division) - encode proteins for secreted hormones that inhibit cell proliferation - loss of function and recessive - located on 17p13.1 chromosome - highly conserved gene and involved in important deregulated pathways in canmany human tumours cer: p53/ MDM2/ p14 - inactivated- unable to send signals for apoptosis- increase in cancer cells -functional- dna damage- p53 accumuwhen p53 protein is induced in response lated in nucleus- G1 arrest- dna reto DNA damage: pair/apoptosis - functional p53 - inactivated- dna damage- no g1 arrest- inactivated p53 dna damaged- genomic instability p14ARF protein - acts as a growth suppressor - homozygously deleted in cancers - regulates p53 activity - encoded by CDN2A gene p16ink4a/CDK4/RB1 pathway -p16ink4a-inhibits activity of CDK4 - CDK4 and 6- form complexes with cyclin D proteins and activate RB1 - activation= G1 arrest, cells can repair DNA carcinogenesis normal cells turn into cancer cells - normal somatic cells proliferate a number of times before they die cell immortalisation and tumorigenesis - senescent cells(entered irreversible growth) remain metabolically active - telomerase- responsible for making 3/5 telomeres at the end of chromosomes. most tumours have active telomerase - cancer spreads to different parts of the body via blood stream/lymphatics - metastatic cells- cancer cells that spread from the primary tumour to other cellular principles of invasion of metastaparts sis - invasion-metastasis cascade- local site found, invasion of cell i to blood and transport to distant tissues, cells adapt to local tissue environment signs for genomic changes in cancer - change in chromosome numbers- aneuploidy(abnormal number of chromosomes) - chromosomal changes- increase in DN copy number, genetic instability of tumour cells - genetic abnormalities due to lack of active p53 protein and ability of cancer cells to go through apoptosis epigenetica - study of stable changes in cell function that dont involve dna causes of cancer - mutations-chemical mutagens can modify DNA from alkylation or deamination, DNA intercalating agents, oxidative damage - radiation- UV- induce skin cancer by damaging dna, ionizing radiation or therapeutic radiation= leukaemia, breast cancer - drugs- oestrogen=breast cancer, uterine cancer, anabolic steroids=liver cancer, chemotherapy= second cancer - diet- high fatty diet, alcohol, obese - immune disorder viral causes of cancer - oncogenic viruses contain viral oncogenes derived from proto-oncogenes 4/5 importance of DNA repair systems - they fix damage occurred to the dna 5/5