Cancer

Benign

non-invasive, localised and mantain normal function

Malignant

invasive and metastatic, tissue shows loss of form and function

carcinomas

tumours originating from epithelial cells

can be a squamous cell carcinoma (protective layer epithelia) or adenocarcinoma (secretory epithelial cells)

sarcomas

tumours originating from mesenchymal cells (connective tissue)

haematopoietic tumours

leukemia - malignant cell derivatives that circulate in the blood

lymphoma - solid tumours of B or T lymphocytes

neuroendodermal tumours

examples include glioblastomas, neuroblastomas, Schwannomas and astrocytomas

oncogenesis

process of cancer formation

influenced by both genetics and environment

hallmarks of cancer cell (1)

sustaining proliferative signalling via growth signal autonomy

cancer cells display mutations for either enhanced external GF stimulation or alternative proliferative signalling activation

hallmarks of a cancer cell (2)

evasion of growth inhibitory or suppressive signals

cancer cells can display inactivtiy of tumour suppressor genes and/or aberration in developmental signalling pathways

hallmarks of a cancer cell (3)

evasion of apoptosis via mutations affecting the apoptotic pathway itself or preventing the extrinsic pathway from stimulating apoptosis

hallmarks of a cancer cell (4)

angiogenesis

required to provide sufficient O2 supply for tumour to continue growing and facilitates metastasis

hallmarks of a cancer cell (5)

maintaining replicative immortality via mutation for higher telomerase expression giving the cell unlimited replicative potential and increasing opportunity for mutation

hallmarks of cancer cells (6)

invasion and metastasis occur when cancer cell degrades ECM to enter circulation and spread to a distant site

hallmarks of cancer cells (7)

deregulating cellular energetics to favour aerobic glycolysis for energy metabolism due to hypoxic conditions not meeting OXPHOS demand, and to provide intermediates from Kreb’s cycle used in growth pathways

hallmarks of cancer cells (8)

avoiding immune destruction by loss of tumour antigens, downregulation of antigen presenting molecules and overexpression of immune checkpoint proteins and anti-apoptotic proteins

additional enabling characteristics of cancer cells

genomic instability and inflammation

driver mutation

confers growth/survival advantage

passenger mutation

does not confer any survival or growth advantage

carcinogens - radiation

caused via direct ionisation of DNA or indirect damage via radiolysis of H2O and ROS generation

risk factors include X rays, living at altitude, UV exposure

carcinogens - chemical

electrophilic form reacts with nucleophilic sites in purine and pyrimidine rings of nucleic acids

risk factors include smoking and diets high in cooked meats

carcinogens - infectious agents

oncogeneic viruses encode viral proteins that block tumour suppressor action

bacteria can cause chronic inflammation and affect signalling proteins that regulate proliferation, survival and invasion

carcinogens - endogenous reactions

natural endogenous generation of ROS and other molecules such as oestrogen metabolites which can DNA damage or unusual activation of proliferative pathways

proto-oncogenes

normally involved in cell proliferation and survival

gain of function, dominant mutation converts to oncogenes

tumour suppressor genes

normally inhibit cell survival and negatively regulate proliferation

mutation is loss of function and recessive

hereditary mutations include loss of Rb and APC genes

caretaker genes

normally repair or prevent DNA damage such as DNA mismatch repair, nucleotide excision repair and double stranded DNA breaks

cell cycle regualtors

cyclin and cyclin dependent kinases (CDKs)

p53

multifunctional tumour suppressor responsible for cell cycle arrest via production of CDK inhibitors and activating DNA repair mechanisms

activation of receptor tyrosine kinase (RTK)

ligand binds inactive monomers, initiates receptor mediated dimerisation, activated RTK trans-auto-phosphorylates, causes conformtional change to expose binding sites

activated binding sites initiate signal transduction pathways for cell proliferation, differentiation and survival

oncogenic activation of GF induced pathways

hyperactive mutant GF, elevated levels of normal GF

increased expression of RTK

mutation in RTK

activation of RTK by viral protein

loss of RTK regualtory elements

abnormalities in GF receptor signalling

increased ligand production, increased receptor expression

mutations create constitutively active variant receptors

pro-apoptotic molecules

BAX, BAD, BAK

anti-apoptotic molecules

BCL-2, BCL-Xi

intrinsic apoptotic pathway

apoptotic signal activates BAX/BAK to release cytochrome C

cytochrome C activates adaptor proteins, which assemble to recruit procaspase-9 = apoptosome

procaspase-9 activation initiates caspase cascade = apoptosis