Carcinogenesis - Molecular Hallmarks of Cancer Cells (21) Flashcards
Caretaker genes (TSG)
Maintain genetic stability by repairing damaged DNA and replication errors (control accuracy of mitosis)
Gatekeeper genes (TSG)
Regulate normal growth (positively regulate apoptosis and cell differentiation, negatively regulate cell cycle and proliferation)
Carcinogens and TSGs
Cause reduced/lack of protein expression/inactivation of protein > loss of function
2nd hit inactivation of TSG
Both chromosomes need to be inactive to inactivate TSG (1 copy can do work of 2)
Retinoblastoma
RB1/Retinoblastoma (Gatekeeper)
Li-Fraumeni
p53/Sarcomas, breast (Gatekeeper/care taker)
Familial adenomatous polyposis
APC/Colorectal (Gatekeeper)
Familial breast cancer
BRCA1/BRCA2, Breast, ovarian (Care taker)
Hereditary non-polyposis colorectal cancer
hMLH1, hMSH2, colon, endometrial (Care taker)
Proto-oncogenes
Promote cell proliferation, survival, angiogenesis and inhibit of apoptosis
Oncogenes
Mutations lead to activated versions of increased expression of proto-oncogenes (gain of function), only 1 copy of genes needs to be activated
Mechanisms of oncogene activation
Translocation, point mutation, amplification
Multi-step tumourigenesis
Activation of oncogenes/inactivation of TSGs, minimum of 3 genetic alterations needed
Self-sufficiency in growth signals
Normal cells require the stimulus of positive growth factors, tumour cells acquire ability to growth in absence (RB key regulator of cell cycle prevents GI > S phase, inactivated in most tumours)
Insensitivity to antigrowth signals
Normal cells have finite life span, after so many divisions they die due to loss of DNA from telomeres, tumour cells express telomerase that replaces lost material and cells become immortal
Telomeres
Thousands of repeats of hexanucleotide sequence, protect end of chromosomes, everytime divides gets shorter > apoptosis
Evading apoptosis
Tumour cells lose ability to apoptose (Tp53 main player in apoptosis, transcription factor induces transcription of >100 genes, induces cell cycle arrest to allow repair of DNA damage/apoptosis, inactivation > loss of apoptotic response >50% tumour)
Sustained angiogenesis
Tumour grow >2mm require good blood supply, out grow blood supply (hypoxia stabilises HIF-1 transcription factor, induces VEGF, actively recruit endothelial cells, construct new capillaries and vessels, angiogenesis decrease in dysplasia, extensive in invasive tumours - metastasis)
Tissue invasion and metastasis
Normal cells are unable to detach from neighbouring cells/grow into new compartments outside their own tissue, malignant tumour cells acquire ability to invade new tissues, detach and migrate, epithelial cells held tightly together by adhesion E-Cadherin - tumour cells have no E-Cadherin due to mutation/hypermethylation > epithelial-mesenchymal transition (EMT), mesenchymal cells are motile and secrete proteases (allowing them to break through basement membrane and invade underlying stroma)
Prostate-specific antigen
Serum protein marker (1/3rd with raised don’t have prostate cancer)
CA-125 serum antigen
Ovarian cancer - not good at detecting early stage disease
Predictive markers for prognosis
Arrays, AML subtypes (t(11q23)/MLL, t(8;21), t(15;17), inv(16))
Correlate with prognosis outcome
Predictive markers for therapeutic response
HER2 positive growth factor receptor, over expression found in 30% breast tumours, Herceptin antibody drug targeted to HER2 dampens effects of overactive HER2
