Overviewof cell cycle regulation. Growth factor binding leads to receptor dimerizationand phosphorylation, activation of Ras and the mitogen‐activated proteinkinase (MAPK) signal transduction pathway leading to cyclin D production. Manyof the genes encoding growth factors, receptors, components of the signaltransduction pathway and cyclins are proto‐oncogenes, genes that whenactivated by mutation (now oncogenes) can contribute to cancer development.pRb, p53 and the (CKIs) all act as a brakeon cell cycling and are the products of (TSGs);when inactivated by mutation, loss or viral proteins, they also contribute tocancer development. The phosphorylation of pRb is necessary for the release ofE2F‐DP dimers that promote the transcription of cell cycle‐associatedgenes. pRb can be inactivated by virally encoded oncoproteins such asadenovirus E1a and (HPV) E7. p53 is negatively regulatedby Mdm2, an enzyme required to produce a polyubiquitinated p53 for degradationby the proteasome. p53 can be disabled by adenovirus E1b and HPV E6. The Ink4alocus also encodes p14^ARF whose function is to activatep53 by binding to and inactivating Mdm2, making ARF another TSG. DNA,deoxyribonucleic acid; DHFR, dihydrofolate reductase; TGFβ,transforming growth factor β.

Summary ofangiogenesis. (1) ‘Stressed’ tumour cells, perhaps sufferingfrom hypoxia, release (2) proangiogenic growth factors that, in concert with(3) growth factors produced by the endothelial cells themselves acting in anautocrine manner, stimulate (4) endothelial cell migration and division. Thestimulated endothelial cells release (5) extracellular matrix (ECM)‐bustingenzymes such as urokinase‐type and tissue‐type plasminogen activators, andcollagenases, as well as inhibitors such as plasminogen activator inhibitor 1.Endothelial cells also (6) release basement membrane components such aslaminin, type IV collagen and tenascin, and (7) expressECM receptors such asthe α₅β₃ and α₅β₅integrins.

(a)Multistage carcinogenesis from the genetic perspective. (b) The consequentmalignant phenotype.

(a) The development of a malignant tumour begins with a mutation in along‐lived cell, probably a stem cell. That mutation gives the cell a growthadvantage over its normal neighbours and it undergoes clonal expansion. Othermutations that give any progeny a growth advantage lead to successive roundsof mutation and clonal expansion until the malignant genotype is acquired. Inmany cases, one of the first mutations is likely to be in a‘caretaker’ gene that maintains genome integrity. The malignantphenotype is likely to be a manifestation of disturbances in the control ofcell proliferation, cell death and cell adhesion. CAM, cell adhesionmolecule; TERT, telomerase reverse transcriptase.

(b) Malignant tumours can (1) invade beyond normal tissue boundaries, (2)detach from the primary tumour mass and (3) enter vascular or lymphaticvessels before (4) adhesion to suitable endothelium and exit from thecirculation. Establishment of the metastasis requires (5) local tissueinvasion and (6) induction of angiogenesis.