WCR-S3.Q (composition) 27/01/03 9:26 Page 1 3 Mechanisms of tumour development The phenotypic changes which a cell undergoes in the process of malignant transformation is a reflection of the sequential acquisition of genetic alterations. This multi-step process is not an abrupt transition from normal to malignant growth, but may take place over 20 years or more. The muta- tion of critical genes, including suppressor genes, oncogenes and genes involved in DNA repair, leads to genetic instability and progressive loss of differentiation. Tumours enlarge because cancer cells lack the ability to balance cell division by cell death (apoptosis) and by forming their own vascular system (angiogenesis). The transformed cells lose their abili- ty to interact with each other and exhibit uncontrolled growth, invade neighbouring tissues and eventually spread through the blood stream or the lymphatic system to distant organs. WCR-S3.Q (composition) 27/01/03 9:26 Page 84 MULTISTAGE CARCINOGENESIS SUMMARY During this process the cell develops : - Defects in terminal differentiation > Tumours consist of cells whose growth - Defects in growth control - Resistance to cytotoxicity and morphological characteristics are - Defects in programmed cell death markedly different from those of normal cells. Criteria for malignancy include increased cell proliferation, loss of differ- CHEMICALS Selective entiation, infiltrative growth and metasta- Genetic clonal Genetic Genetic Genetic sis to other organs. change expansion change change change > Malignant transformation is a multistage VIRUS process, typically a progression from PRE- benign lesions (e.g. adenoma) to malig- NORMAL INITIATED NEOPLASTIC MALIGNANT CLINICAL CANCER nant tumours (e.g. carcinoma). This evo- RADIATION CELL CELL LESION TUMOUR CANCER METASTASIS lution of malignant cells is caused by the sequential accumulation of alterations in genes responsible for the control of cellular proliferation, cell death and the These steps are caused by : maintenance of genetic integrity. - Activation of proto-oncogenes - Inactivation of tumour suppressor genes - Inactivation of genomic stability genes > The development of cancer may be initi- ated by environmental agents (chemical carcinogens, radiation, viruses) and inherited genetic factors (germline Fig. 3.1 Carcinogenesis is a multistage process involving multiple genetic and epigenetic events in proto- mutations). oncogenes, tumour suppressor genes and anti-metastasis genes. Cancer arises from a single cell Malignant tumours (or “cancers”) are specific cell populations may be identified cells or tissues exposed to them. DNA- described as monoclonal, meaning that as marking a commitment towards malig- damaging activity may be identified on the each tumour arises from a single cell. The nancy, and these may be exploited as an basis of defined protocols (sometimes development of a malignant tumour from early indicator in the context of carcino- called “short-term tests”, to emphasize a normal cell usually occurs over a con- gen testing [3]. Thus, wholly on morpho- their difference from chronic lifetime siderable fraction of our lifetime. Such a logical grounds, cancer may be perceived bioassay in rodents). Chemicals which long period is reflected, for example, by as the outcome of a complex biological exhibit mutagenic activity in short-term the difference between the age at which process. tests, which typically involve sensitive people start smoking and the age at bacterial strains and cell-free extracts to which diagnosis of lung cancer most Multiple steps are required for a can- catalyse metabolism of the test com- often occurs. The long “latent period” in cer to arise pound, are characterized as “genotoxic” lung cancer and almost all other malig- Animal “models” of cancer development, [5]. Genotoxic agents may be complete nancies is not explicable on the basis of a most commonly involving treatment of carcinogens, but can also act as “initiating single-step transition from a normal cell rodents with carcinogenic chemicals or agents”. After a single treatment with an to malignant one. Rather, the tumour is other cancer-inducing agents, have pro- initiating agent, tumour growth may be the outcome of an evolutionary process vided clear evidence that specific stages facilitated by chemicals (or treatments) involving successive generations of cells, in malignant transformation can occur dis- which stimulate cell proliferation, some- which are progressively further advanced cretely [4]. Chemicals which cause cancer times by inducing mild toxic damage in towards cancerous growth [1]. in animals without the need for other exposed tissue. These agents are termed Human histopathological observations treatment are sometimes called “com- “promoters” (Table 3.1). As well as these support this scenario, and a range of pre- plete carcinogens” (although “carcino- genotoxic chemicals, a range of non-geno- malignant lesions have been identified gens” would be appropriate). Most such toxic agents can cause cancer in humans [2]. Likewise, in experimental animals, carcinogens cause damage to DNA of and/or experimental animals [6]. 84 Mechanisms of tumour development WCR-S3.Q (composition) 29/01/03 13:58 Page 85 The stages in tumorigenesis have been designated “initiation”, which encom- passes damage to, and then division of Factor Cancer site/cancer exposed cells such that their growth potential is changed irreversibly, and Hormones Estrogens, progesterone Uterus, mammary gland “progression”, denoting multiple rounds Gonadotrophins Ovary, testis, pituitary of cell replication mediating the gradual Testosterone Prostate gland transition of an initiated cell towards Pharmaceutical Oral contraceptives Liver autonomous, cancerous, growth. Ultimate products Anabolic steroids Liver spread of malignant cells resulting in mul- Analgesics Renal pelvis tiple tumour sites has been termed “metastasis”. The unequivocal identifica- Miscellaneous Bile acids Small intestine tion by the mid-1970s of these various substances Saturated fatty acids Colon phases was one indication that carcino- Salt Stomach genesis is a multistage process. Arguably, Tobacco Oral cavity, lung, bladder etc. the greatest achievement of cancer Saccharin, uracil, melamine, Urinary bladder research during the last decades of the tetraphthalic acid and other 20th century has been the elucidation of xenobiotics causing urinary stones multistage carcinogenesis at the molecu- Dichlorobenzene, trimethylpentane Kidney (lead-free gasoline), perchloroethyl- lar genetic level. ene Butylated hydroxyanisole, propionic Stomach The molecular basis of tumour acid pathology Nitrilotriacetate Kidney In a seminal publication, Vogelstein and colleagues [7] provided evidence that Table 3.1 Promoting agents: non-genotoxic agents that facilitate carcinogenesis by stimulating cell division. the different stages in the cellular evo- Tobacco smoke also contains genotoxic carcinogens. lution of colon cancer in humans, histo- logically identified as hyperplasia, CHROMOSOME: 5q 12p 18q 17p early-stage adenoma, late-stage adeno- ALTERATION: Mutation Mutation Loss Loss ma etc., could be identified with specif- GENE: FAP KRAS DCC? p53 ic successive genetic changes (Fig. 3.2). The genetic changes included oncogene activation by mutation at DNA Other specific sites and loss of chromosomal hypomethylation alterations regions (necessarily involving multiple genes) which were subsequently shown to be the location of tumour suppressor Normal Hyperproliferative Early Intermediate Late Carcinoma Metastasis genes. Since that initial description, epithelium epithelium adenoma adenoma adenoma knowledge of the molecular genetic basis for human colon cancer has been Fig. 3.2 The original Vogelstein model for the genetic and histological evolution of colon cancer. massively extended (Colorectal cancer, (Colorectal cancer, p198). p198). For most tumours, the genetic changes are not inherited from our par- ents but arise in a previously normal Commonality and heterogeneity amplification) are common to a number cell. The progeny of this cell after cell The molecular biological basis of multi- of tumour types. However, each tumour division carry the same genetic change stage carcinogenesis initially described type is associated with a distinctive set but the surrounding cells remain nor- for colon cancer appears to have appli- of gene alterations. The genes in ques- mal. Because these genetic changes cation to all tumour types, although tion are discussed under the subhead- affect only the cancer cells, they are there is marked variation in the extent ing Pathology and genetics for each of not passed on to the children of cancer to which genes relevant to particular the tumour types included in Chapter 5. patients. However, in a minority of tumours have been identified [8]. Some Such enumeration of relevant genes cases some critical changes are inherit- genes, and the corresponding change necessitates a degree of simplification. ed, giving a familial predisposition to associated with tumorigenesis (muta- There is clear heterogeneity between colon or other cancers. tion, overexpression, deletion and/or individual tumours of the same type. In Multistage carcinogenesis 85 WCR-S3.Q (composition) 27/01/03 9:27 Page 86 Peutz-Jeghers polyp RER+ cancer (Replication Dysplasia in hamartoma Error Positive) Loss of mismatch repair Juvenile polyp Normal Early adenoma Intermediate adenoma Late adenoma Cancer Flat dysplasia Ulcerative colitis-associated colorectal carcinoma