Medical Education Research Worldwide. Cancer review

BIOLOGY OF CANCER KEVIN J HARRINGTON

Abstract

Cancer is caused by aberrant patterns of gene expression. In general, the genes affected can be divided into two groups: oncogenes and tumour suppressor genes. Oncogenes undergo activation and are phenotypically dominant, while tumour suppressor genes undergo inactivation and are phenotypically recessive. Oncogenic activation can occur by specific point mutations within the sequence of a gene, by amplification of the numbers of copies of the gene or by translocation of DNA to a site where transcription is more active or where the formation of the new fusion gene generates a protein with enhanced biological activity. Tumour suppressor genes are inactivated by mutations that destroy the function of the protein encoded by the gene. Germline mutations of tumour suppressor genes can account for hereditary cancer syndromes. The biological behavior of cancer can be considered in the terms of six specific hallmarks: growth factor independence, insensitivity to anti-growth signals, avoidance of apoptosis (programmed cell death), sustained angiogenesis, cellular immortalization, and tissue invasion and metastasis.

Cancer is a genetic disease that occurs when the information in cellular DNA is corrupted leading to abnormal patterns of gene expression. As a result, the effects of normal genes that control cell growth, survival and spread are enhanced and those of genes that suppress these effects are repressed. The main mechanism by which this corruption of the genetic code occurs is through the accumulation of mutations, although there is increasing recognition of the role of non-mutational (epigenetic) changes in the process. Aberrant gene expression leads to a number of key changes in fundamental biological processes within cancer cells-the so-called hallmarks of cancer.


Structure and function of DNA

The genetic code is contained in the form of deoxyribonucleic acid (DNA) that is packaged in the chromosomes in the cellular nucleus. DNA molecules consist of a sugar phosphate backbone (deoxyribose sugars joined by phosphate linkage) with each sugar bearing one of four nucleotide bases (the purines: adenine (A) and guanine (G), and the pyrimidines: thymine (T) and cytosine (C)). Two DNA strands twist around one another to form a double-helix with the bases forming hydrogen bonds with the specific partners in the opposite strand: A pairs only with T and C pairs only with G. The helix is wound around nucleosomes, consisting of histone proteins, and is further condensed to form chromatin. The entire genetic code consists of approximately 3.2 x 10^9 bases and contains approximately 30,000 genes, which account for only 1% of the genome. The DNA sequence within a gene comprises both exons and introns. The exons represent the protein-coding regions that are translated at the ribosome, whereas the introns are non-encoding and are edited out.
The function of the genes is to make proteins. This process occurs in two steps. First, the DNA code is copied into messenger ribonucleic acid (mRNA) by the process of transcription. RNA differs from DNA in two ways:

1. The sugar backbone contains ribose (not deoxyribose).
2. Thymine is replaced by uracil (U).

The process by which a gene is transcribed into mRNA and then translated into a cellular protein is complex and subject to multiple levels of control. Regulation of transcription is the key initiating event in this process and is mediated by the interaction between enhancer/promoter elements in the DNA and the specific proteins (>100 individual sub-units) that bind to them. At the transcription start site, a DNA-dependent RNA polymerase II is recruited and begins to synthesize mRNA complementary to the coding strand of DNA, such that the DNA sequence CGTA becomes GCAU in the mRNA. Post – transcriptional modifications of mRNA include splicing out of introns and processing to make the mRNA ready for export from the nucleus. Alternate splicing of transcripts of many eukaryotic genes (approximately 60% of human genes) allows a corresponding set of different proteins to be produced from the same gene. The mRNA can be degraded by cellular small interfering RNA molecules (siRNA) before translation occurs. If the mRNA reaches the ribosome, its three-base (triplet) code of bases is translated into the specific protein molecules. It is these protein products of genes that mediate the phenotypic changes that we recognize as cancer.

CANCER GENES

Cancer is driven by two classes of genes, oncogenes and tumour suppressor genes, which each provide and essential function in normal cells.
Oncogenes are derived from mutated versions of normal cellular genes (called proto-oncogenes) that control cell proliferation, survival and spread. In normal cells, the expression of proto-oncogenes is very tightly regulated to avoid uncontrolled cell growth. In cancer, activating mutations of proto-oncogenes are responsible for uncontrolled cell division, enhanced survival (even in the face of anti-cancer treatment) and dissemination. Oncogenes are described as being phenotypically dominant (i.e. a single mutated copy of a proto-oncogene is sufficient to promote cancer) and are never responsible for inherited cancer syndromes. Oncogenes can be activated in three ways to cause cancers

1. Gene mutation involves the acquisition of a specific defect in the sequence of a gene such that the gene has enhanced function (e.g. Ras in pancreatic and colorectal cancers)
2. Gene amplification occurs when a gene retains its normal sequence but the gene is repeated in the chromosome (e.g. N-myc in neuroblastoma)
3. Gene translocation involves the gene being moved from its normal chromosomal position (locus) to a new position (usually on a different chromosome) where it comes under the influence of a new, more active promoter element (e.g. bcr-abl in chronic myeloid leukaemia).

Tumour suppressor genes (TSG) are normal cellular genes whose function involves inhibition of cell proliferation and survival. They are frequently involved in controlling cell cycle progression and apoptosis. TSG are phenotypically recessive (i.e. the function of both copies must be lost I order to promote cancer to promote cancer) and are responsible for inherited cancer syndromes. In familial cancer syndromes, individuals inherit a Germline mutation in one copy (allele) of a TSG such that every cell in the body is affected. It is, therefore, highly likely that at least one cell in the body will suffer complete loss of TSG function because only one copy has to be mutated (so-called loss of heterozygosity). As a result, hereditary cancer syndromes often give rise to multiple cancers at an early age.




THE HALLMARKS OF CANCER

Hanahan and Weinberg described six keys changes that occurs in cancers and which can be seen as largely responsible for driving their malignant behavior the role played by each of these processes will be reviewed briefly below.
Growth factor independence. A general scheme for the function of growth factor receptors and their ligands in promoting cell growth and other effects. In this case binding of epidermal growth factor to its specific ligand binding domain on the extracellular component of the epidermal growth factor receptor (EGFR) leads to a signal being passed from the membrane such that the ligand binding on the cell surface alters the behavior of the cell. Under normal circumstances, activation of growth factor receptors is very tightly controlled- as is the synthesis and the release of ligand that stimulate them. Cancer cells frequently usurp normal growth factor signaling pathways and use them to promote unrestrained cell division.
Cancer cells exploits
Three main strategies for achieving self sufficiency in growth factors:
They manufacture and release growth factors which stimulate their own receptors (autocrine signalling) and those of their immediate neighbours (paracrine signalling)
They alter the number, structure or function of the growth factor receptors on their surface such that they are more likely to send a growth signal to the nucleus (even in the absence of the cognate ligand)
They deregulate the signalling pathways downstream of the growth factor receptor so that it is permanently turned on (constitutively active).
Insensitivity to anti growth signals. There are a number of normal anti growth signals that counteract the positively acting growth signals described above. Anti growth signals work either by forcing cells into quiescence such that they are permanently unable to re-enter the cell cycle. Anti – growth signallling is mediated by ligands e.g. transforming growth factor beta (TGF-β), that act on cellular receptors (e.g. TGF-β receptors) and send signals to the nucleus via secondary messengers. These pathways are mainly involved in controlling the cell cycle clock and mediate their effects through proteins that include retinoblastoma protein (Rb), cyclins, cyclins-dependent kinases (CDK) and their inhibitors (CDKi). Abnormalities in anti- growth signalling pathways are extremely common in the cancer and play a role in helping cancer cells to progress through the cell cycle. Therefore, loss of Rb and members of the CDKi family and over expression of certain cyclins and CDK has been shown to occur in a large number of tumour types.
Avoidance of apoptosis-normal cells continually audit their viability by assessing the balance of survival (anti-apoptotic) and death (pro-apoptotic) signals that they receive. In normal cells, DNA damage leads to a block in proliferation (cell cycle arrest) while the potential for repair is assessed. If the level of damage exceeds the capacity for repair, the balance of anti-and pro-apoptotic signals tips and the cell undergoes programmed cell death (apoptosis). This prevents maintenance of DNA damage and avoids the risk that mutations will be passed to the progeny of cell division. As such, this mechanism represents a very powerful barrier to the development of cancer.
Loss of normal apoptotic pathways signalling is an extremely common event in cancer. Indeed two of the best known cancer-associated genes (p53 (TSG) and bcl-2 (oncogenes)) are intimately involved in apoptosis. The two main mechanisms of apoptotic signalling (intrinsic and extrinsic pathways). Cancer cells are able to evade apoptosis through an ability to ignore signals sent through the extrinsic pathway or by re-setting the balance of intracellular pro- and anti-apoptotic molecules in the favour of inhibition of apoptosis. By circumventing apoptosis, cancer cells can sustain DNA damage without it causing cell death (unless the damage is to a gene that is absolutely necessary for cell survival). Therefore, cancer cells that have switched off their apoptotic pathway are more likely to be intrinsically resistant to anti- cancer treatments. In fact, the use of these treatments may promote the accumulation of other mutations that may have a negative influence on the biology of the disease.
Sustained angiogenesis-in normal tissue, the growth of new blood vessels (angiogenesis) is held very tightly in check by a balance between positive (pro-angiogenic) and negative (anti-angiogenic) signals. The growth of cancer deposits is intimately related to their ability to secure a blood supply. A small cluster of cancer cells can grow to 60-100μm by deriving a supply of oxygen and nutrients by direct diffusion, but beyond this size the fledgling tumour must acquire its own dedicated blood supply. Cancer acquires the ability to grow a new blood supply by subverting the balance between pro- and anti- angiogenic factors. Essentially, cancers switch to an angiogenic protein such as vascular endothelial growth factor (VEGF) and/or by downregulating production of anti-angiogenic protein such as thrombospondin-1.
Cellular immortalization- normal somatic cells can undergo only a finite number of cell division (Hayflick limit) before they enter a period of permanent growth arrest known as replicative senescence. This process occurs as a result of the cells’ inability to replicate the ends of their chromosomes (the telomeres) fully at each division. Therefore, over time the telomeres get progressively shorter, effectively acting as molecular clocks that count down the cells’ lifespan. In contrast, the stem cells and malignant cells have acquired immortality by maintaining the length of their telomeres. In most tumours, this occurs through upregulation of the enzyme telomerase, but in 10-15% of cases a different mechanism called alternative lengthening of the telomeres (ALT) is responsible. Telomerase enzymatic activity involves a large number of proteins, but its two main components are an RNA template (hTR) and a reverse transcriptase enzyme (hTERT): the reverse transcriptase uses the hTR RNA template as a guide in the resynthesis of the DNA sequence of the telomere. Therefore, tumours that have reactivated the expression of telomerase are able to rebuild the parts of their telomeres that they lose with each round of cell division and, so, are able to avoid being sidelined into replicative senescence.
Invasion and metastasis – distant metastasis cause 90% of cancer deaths. Invasion and metastasis involves careful orchestration of a series of complex biological processes:
Detachment from immediate neighbours and stroma at the local site.
Enzymatic digestion of the extracellular matrix followed by the specific directional motility.
Penetration (intravasation) of blood or lymphatic vessels and tumour embolization.
Survival in the circulation until arrival at the metastatic site that may be chosen on the basis of provision of a favorable supply of appropriate growth factors.
It adheres to the endothelium of blood vessels at its destination and extravasates from the vessel
It begins to proliferate and invade its new location and sets about recruiting a new blood supply.
The patterns of metastasis of different cancers to specific organs (e.g. breast cancer to liver, bone and brain; lung cancer to brain and adrenal gland) are not random, but appear to be driven by expression of Chemokine receptors by tumour cells that allow them to ’seek’ a suitable environment in which to establish a colony.






References
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
2. Rogers SJ, Harrington KJ, Rhys Evans P, O-Charoenrat P, Eccles SA. Biological significance of c-erbB family oncogenes in the head and neck cancer. Cancer Metastasis Rev 2005; 24: 47-69.
3. Muller A, Homey B, Soto H, et al. Involvement of Chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-56.

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