Figure 1. Overview of cell cycle regulation. Growth factor binding leads to receptor dimerization and phosphorylation, activation of Ras and the mitogen-activated protein kinase (MAPK) signal transduction pathway leading to cyclin D production. Many of the genes encoding growth factors, receptors, components of the signal transduction pathway and cyclins are proto-oncogenes, genes that when activated by mutation (now oncogenes) can contribute to cancer development. pRb, p53 and the cyclin-dependent kinase inhibitors (CKIs) all act as a brake on cell cycling and are the products of tumour suppressor genes (TSGs); when inactivated by mutation, loss or viral proteins, they also contribute to cancer development. The phosphorylation of pRb is necessary for the release of E2F-DP dimers that promote the transcription of cell cycle-associated genes. pRb can be inactivated by virally encoded oncoproteins such as adenovirus E1a and human papillomavirus (HPV) E7. p53 is negatively regulated by Mdm2, an enzyme required to produce a polyubiquitinated p53 for degradation by the proteasome. p53 can be disabled by adenovirus E1b and HPV E6. The Ink4a locus also encodes p14^ARF whose function is to activate p53 by binding to and inactivating Mdm2, making ARF another TSG. DNA, deoxyribonucleic acid; DHFR, dihydrofolate reductase; TGF, transforming growth factor .

Figure 2. Summary of angiogenesis. (1) ‘Stressed’ tumour cells, perhaps suffering from hypoxia, release (2) proangiogenic growth factors that, in concert with (3) growth factors produced by the endothelial cells themselves acting in an autocrine manner, stimulate (4) endothelial cell migration and division. The stimulated endothelial cells release (5) extracellular matrix (ECM)-busting enzymes such as urokinase-type and tissue-type plasminogen activators, and collagenases, as well as inhibitors such as plasminogen activator inhibitor 1. Endothelial cells also (6) release basement membrane components such as laminin, type IV collagen and tenascin, and (7) express ECM receptors such as the ₅₃ and ₅₅ integrins.

Figure 3. (a) Multistage carcinogenesis from the genetic perspective. (b) The consequent malignant phenotype.

(a) The development of a malignant tumour begins with a mutation in a long-lived cell, probably a stem cell. That mutation gives the cell a growth advantage over its normal neighbours and it undergoes clonal expansion. Other mutations that give any progeny a growth advantage lead to successive rounds of mutation and clonal expansion until the malignant genotype is acquired. In many cases, one of the first mutations is likely to be in a ‘caretaker’ gene that maintains genome integrity. The malignant phenotype is likely to be a manifestation of disturbances in the control of cell proliferation, cell death and cell adhesion. CAM, cell adhesion molecule; 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 lymphatic vessels before (4) adhesion to suitable endothelium and exit from the circulation. Establishment of the metastasis requires (5) local tissue invasion and (6) induction of angiogenesis.