Mechanisms of Carcinogenesis3 Molecular Hallmarks of Cancer
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Mechanisms of Carcinogenesis3 Molecular Hallmarks of Cancer Cancer is a complex disease that is very variable the corresponding protein is behaving like a For the oncologist and the cancer patholo- for example, antibodies directed against cell- to the synthesis of new, abnormal proteins. in its presentation, development and outcome switch locked in the “on” position generating gist, cancer is best described as a progressive surface molecules expressed by cancer cells Such changes, whatever their size, are called 3.1 from one patient to the other. The same hetero- a permanent cell division signal. Mutations of disease. It starts as a small, inconspicuous lesion (such as trastuzumab, an antibody that inhibits “genetic alterations” or “mutations”. Significantly, Summary geneity and variability exist at the cellular and KRAS are common in many cancers, such as that generally remains confined to its tissue of a cell-surface receptor called HER-2 which is these changes can be detected by sequencing molecular level. Cancer is a multi-step process colorectal cancers (in 30–40% of the cases) origin and is considered as clinically benign often over-expressed in breast cancer) or drugs the DNA of cancer cells. > Cancer is a multi-step process in which during which cells undergo profound metabolic or adenocarcinomas of the lung (in 20–30% since, when detected at an early stage, it may that block the activity of enzymes activated in cells undergo metabolic and behavioural and behavioural changes, leading them to of the cases). Such an activated gene is called be completely resected and may not cause the cancer cells (such as imatinib, which blocks an The way DNA is read and copied is critically changes, leading them to proliferate in proliferate in an excessive and untimely way, an “oncogene” because it promotes cell prolif- patient’s death. Sometimes, these small lesions enzyme activated in many tumours of the gas- dependent upon the way in which DNA is an excessive and untimely way to escape surveillance by the immune system, eration. In contrast, some genes contribute to appear within a tissue area that is affected by a trointestinal stroma, or erlotinib, which inhibits compacted, packaged and organised. There and ultimately to invade distant tissues to form cancer development when they are inactivated. chronic inflammatory disease, such as cirrhosis the enzyme activity associated with the recep- are “closed” DNA areas (which are locked for > These changes arise through modifica- metastases [1]. These changes arise through This is, for example, the case of the TP53 gene. in the liver, gastritis in the stomach or intestinal tor of the epidermal growth factor. Thus, the editing and copying) and “open” ones (which tions in mechanisms that control cell the accumulation of modifications in the genetic This gene encodes a protein that naturally acts metaplasia (Barrett’s oesophagus) in the lower notion of time and progression is critical in car- the cell can copy, read, and use to produce proliferation and lifespan, relationships programmes that control cell proliferation and like an “emergency brake” to avoid inappropri- oesophagus. These chronic diseases that repre- cinogenesis. This concept has been confirmed RNA and proteins). Thus, another way to with neighbouring cells, and capacity to lifespan, relationships with neighbouring cells, ate cell division. Mutation in this gene disrupts sent a favourable terrain for cancer occurrence in studies using laboratory animals. These change the programme of cells, aside from escape the immune system and capacity to escape the immune system. the protein, which becomes unable to stop the are called “precursor diseases”. When unde- have shown that the development of cancer in DNA mutation, is to modify the overall packag- This process results in the formation of a mass proliferation of cells when needed. Mutations in tected at an early, benign stage, cancer has a mice or rats exposed to carcinogens occurred ing in order to shut down genes that lie in open > Modifications that lead to cancer include of deregulated cells, which can be qualified as TP53 are found in almost every kind of cancer. chance to develop and progress not only in size through different steps, with “initiation” (during areas or to switch on those that lie in closed genetic changes that modify the DNA “outlaw” because they do not obey the rules Such a gene that contributes to cancer devel- but also in its capacity to interfere and perturb which the carcinogen creates mutations in the areas. Such changes cannot be detected just sequence. Another way to change the that control normal cell growth and behaviour. opment through loss of its function is called a neighbouring cells. Such cancers will not be DNA of normal cells), being followed by “pro- by sequencing DNA. They require the analy- programme of cells is to modify the Such a mass may be asymptomatic for a long tumour suppressor, because in normal condi- confined any longer: they will spread within motion” (in which the initiated cells develop a sis of chemical modifications that regulate the conformation of chromatin, the structure time. However, it will ultimately grow to perturb tions its active products work as a brake to sup- the organ affected and then will disseminate growth advantage over their neighbours allow- accessibility and readability of DNA. These that wraps up DNA and regulates its physiological functions, giving rise to multiple press cancer growth [2]. to neighbouring organs. They also enter the ing them to produce a distinct lesion, and then changes are called “epigenetic”. access by DNA reading, copying and symptoms, depending upon the location and lymphatic vessels to spread into lymph nodes. by progression (in which tumours become more repair machineries. Such changes are Cellular origin and progression of and more aggressive through the accumulation The role of genetic changes in cancer has called “epigenetic” size of the mass, and of the spread of cancer Through the lymph or bloodstream, they can cells within the organism. cancer travel to distant organs and form colonies, the of supplementary genetic and epigenetic modi- been recognised for over 50 years and scien- > Among the 23 000 or so genes that metastases, in general located in bone, lung, fications). As a result, a number of oncogenes tists have now built a long catalogue of genes constitute the human genome, a few Cancer genes Many cancers arise from just one cell (or from liver or brain. Tumour dissemination is often and tumour suppressors are frequently altered that are mutated in cancer. In contrast, the role hundred are commonly targeted by a small number of cells) [3]. To become can- facilitated by the fact that cancer cells promote in many cancers, irrespective of the organ site of epigenetic changes has been recognised genetic or epigenetic changes. These The genetic programmes targeted by cancer cerous, this cell must acquire several changes in angiogenesis, that is, the synthesis of new small or the cause of the disease. The products of only relatively recently [6]. In describing the genes are parts of networks of genes that are present in scores of genes that are dis- oncogenes and tumour suppressor genes that blood vessels dedicated to tumour vascularisa- these genes are all part of a network of factors mechanisms of cancer, genetic and epige- regulate cell division, differentiation and persed throughout the human genome. It is will make the cell capable of proliferating well tion, thus improving tumour supply in oxygen that work together to control cell proliferation, netic changes have to be considered together, life span believed that human DNA contains about 23 beyond its normal limit. This process will result and nutrients. differentiation and survival as two sides of the same coin. They respond 000 genes. Several thousand of these genes in the formation of a clone of “outlaw” cells. If to each other and influence each other, gen- > The emergence of technologies for (3000–5000) encode proteins involved in such a clone is tolerated by the organism and Disseminated cancers are much more difficult How do genes become disrupted? erating pathways of sequential changes that genome-wide analysis of genetic and genetic programmes that are deregulated allowed to remain unperturbed, it may continue to treat. In addition to localised therapy tar- determine how a given cell will progressively epigenetic changes is advancing our in cancer. A dysfunctional gene can result in to proliferate and, during this process, the cells it geting tumour foci (surgery, radiotherapy) they Cancer may start when small changes called acquire the characteristics of a cancer cell. capacity to map patterns of alterations the production of abnormal levels of a critical contains will accumulate more and more modi- require systemic therapies using cytotoxic drugs mutations occur in the DNA sequence[5]. They Both genetic and epigenetic changes are uni- specific for each particular cancer, protein (either too much or too little), the pro- fications. In such a disrupted context, only the (chemotherapy). Chemotherapy is based on the can be limited to a single base change, thus versally present in human cancer: they induce paving the way to personalised medicine duction of an aberrant protein (with either gain fittest and the most aggressive cells will thrive, use of toxic substances that interfere with DNA changing one of the 3 bases that define a changes in gene expression that dividing cells based on molecular diagnosis or loss of function), or the complete absence taking the place of other, less disorganised and cell division to preferentially kill cancer codon and leading to the selection of a differ- can transmit to their daughters over many cell of the protein. For example, mutation in a gene cells. This is how tumours develop to become cells. This approach is based on the hypoth- ent amino-acid to be integrated into a protein.