We now define cancer as a disease involving changes or mutations in the cell genome. Successive rounds of mutation and selective expansion of these cells result in the formation of a tumor mass (FIG. 1.1 a & b). Changes in DNA sequences result in the cell slowly progressing to the mildly aberrant stage.
The initiation and progression of cancer depends both on external factors in the environment (tobacco, chemicals, radiation and infectious organisms) and on factors within the cell (inherited mutations, hormones, immune conditions and mutations occurring from metabolism). While genes are unevenly distributed among populations, they do not explain differences in the world's cancer incidence rates. In the late 18th century, Sir Percival Pott reported that scrotal cancer in chimney sweeps was linked to poor hygiene and the accumulation of cancer-causing agents from soot.
DNA mutations cause errors in the cell's regulatory circuits, disrupting the normal behavior of cell proliferation. The behavior of an individual cell is not autonomous and usually relies on external signals from surrounding cells in the tissue or microenvironment. Which of these circuits are broken within the cell and which of these are connected to external signals from neighboring cells in the tissue.
Immortality: Continuous cell division
We now know that the ticking counter that controls finite cell division lies at the end of all human chromosomes: the telomeres. Telomeres are hexanucleotide sequences of DNA (short repeats of 6 base pairs), and each end of a linear chromosome contains thousands of copies of these repeats. The best analogy is that telomeres are like aglets that protect the ends of shoelaces from fraying.
The importance of telomeres in cell division is determined by a unique DNA replication problem called. During cell division, DNA is replicated during the S phase of the cell cycle creating double the number of chromosomes. However, after each round of DNA replication, a short (50–100 base pairs) telomere sequence is lost from the ends of each chromosome.
This progressive shortening is because the enzyme responsible for DNA synthesis, DNA polymerase, is unable to replicate the 50-100 base pairs at the end of one strand of DNA (the 3' ends). As a result, each round of DNA replication results in the breakdown of these sequences and increasingly shorter chromosomes. Because each chromosome has a finite number of these telomere repeats, successive cycles of replication result in a steady erosion of the telomeres until they cause genetic changes, chromosomal end fusions and disorder, and ultimately cell death.
After each round of cell division, telomere lengths gradually shorten until it provokes the cell to stop dividing and go into senescence. Cancer cells, on the other hand, maintain their telomere lengths without loss of DNA base pairs. The main strategy that cancer cells use to maintain telomere lengths is by activating an enzyme called telomerase.
Additional evidence for the importance of telomerase in telomere maintenance comes from tumors that have spread to distant sites in the body (metastases), which also show high levels of telomerase expression and activity. However, there is some debate that senescence is an artifact of cell culture conditions and not a true representation of the phenotype in the body (in vivo).
Sustained growth signals (oncogenes*)
Normal cells (eg skin fibroblast cells) that have been cultured in a petridish in vitro will not divide and proliferate in the absence of growth factors found in serum. This autonomy from growth factor signaling leads to unregulated growth (such as in the absence of ideal conditions for cell division or stress) and increases the chances of acquiring additional mutations in the cell genome. There are three primary cellular strategies used by cancer cells to achieve growth factor autonomy, based on the growth factor signaling pathway as shown in FIG 3.1.
This triggers an autocrine signaling loop in which the cell generates its own growth factor signal leading to constitutive growth stimulation (FIG 3.2). PDGF normally binds to its PDGF receptor in the extracellular domain to stimulate intracellular cell proliferation pathways. Overexpression: GF receptors are often overexpressed in many cancers, causing the cancer cells to hyper-react to levels of GF that would not normally trigger cell division.
Ligand-independent signaling: GF-independent signaling can be produced either by gross overexpression of receptors or by structural changes in the receptor. For example, a truncated epidermal growth factor receptor (due to deletion in exons 2-7 of the extracellular domain) still sends growth-stimulating signals inside cells consistently and without any EGF binding (FIG. 3.3). Mutations in the Epidermal Growth Factor Receptor (EGFR) receptors result in persistent and ligand-independent stimulation of growth-stimulating intracellular pathways.
It is involved in the initiation and progression of certain types of breast cancers. Signaling molecules in the ECM enable the integrin receptors to transmit signals to the cytoplasm that influence cell behavior, which varies from quiescence in normal tissue. Introduction to Cancer Biology Sustained growth signals (oncogenes). c) Changes in intracellular signaling pathways that stimulate proliferation.
Example 1 - Cell cycle related kinase (c-crk): These small adapter proteins (~60 amino acid residues) were first identified as a conserved sequence in the non-catalytic part of several cytoplasmic tyrosine kinases such as Abl and Src and have subsequently also been identified in several others protein families such as phospholipase, PI3-kinase, ras GTPase-activating protein, adapter proteins, CDC24 and CDC25. Sharma, SV , Bell, DW , Settleman, J and Haber, DA (2003) Epidermal growth factor receptor mutations in lung cancer.
THE BEST MASTER
IN THE NETHERLANDS
- Bypass anti-growth signals (Tumour Suppressor Genes*)
- Avoidance of cell death (apoptosis)
- Ensuring blood vessel growth (angiogenesis)
- Spread to other sites (metastasis)
For example, the presence of proteins involved in DNA replication at the end of the G1 phase pushes the cell into the S phase, while severe DNA damage can trigger the cell to kill itself by apoptosis or enter a quiescent state. One well-studied example of a tumor suppressor protein is the retinoblastoma (Rb) protein, which is involved in the development of rare pediatric tumors found in the retina of the eye. Most mutations in the Rb gene involve large chromosomal changes in the 3kb coding region of the gene, and about a third tend to be single base change mutations.
For example, downregulation/disruption of receptors and signaling molecules upstream of the pRb circuit or loss of functional pRb due to mutations. Originally discovered by David Lane, Arnold Levine, and William Old in 1979, it has been dubbed the "guardian of the genome" because of its extremely critical role in the cell cycle. The convergence of two signaling pathways that regulate cell proliferation (proto-oncogene and tumor suppressor) dictates whether a cell progresses through the cell cycle, switches to quiescence, or enters a state of postmitotic differentiation.
For example, the sculpturing of human fingers or feet is due to apoptosis of cells between the digits. Sensory pathways monitor the cell's internal and external environment to detect changes in environmental conditions that may affect the cell's fate (survival, division, or death). This receptor activation leads to activation of FADD, which in turn activates DED.
The most common method involves mutations of the p53 tumor suppressor gene resulting in the loss of proapoptotic regulators. More than 50% of all human cancers (and 80% of squamous cell carcinomas) show inactivation of the p53 protein. P53 is also known as the 'guardian of the cell' because of its central role in the cell's response to stress.
Disruption of the basement membrane allows activated endothelial cells—stimulated to proliferate by growth factors—to migrate toward the tumor. This ability of tumor cells to invade and metastasize is the last of the six hallmarks of cancer. Intravasation: The tumor cells move through the walls of the capillaries or the lymphatic system into the circulatory system.
Formation of micrometastasis: By extravasation, the cancer cells are now able to reactivate the cell proliferation pathways and form a small tumor mass, which either develops in the lumen of the capillary or through the vessel wall.
Arrest in capillaries in
Summary and some thoughts for the future
The six hallmarks of cancer described so far suggest that tumor progression occurs due to DNA mutations in genes involved in the regulation of cellular signaling and metastatic pathways. However, genomic integrity is carefully maintained by an army of surveillance and repair enzymes within the cell. One school of thought holds that mutations in 'caretaker' or guardian genes might be responsible for this increased mutability.
The most compelling evidence for this argument comes from mutations in the p53 tumor suppressor protein found in the vast majority of human tumors. It plays a central role in determining cell fate in response to DNA damage; must cell cycle arrest and repair pathways be switched on, or must the cell be allowed to die by apoptosis. Furthermore, other proteins involved in sensing and repair have also been found to be functionally lost in various cancers.
The genome instability generated as a result is perhaps another essential prerequisite required for tumor progression to all six biological features. The acquisition of the various mutations in the signaling circuit described so far is highly variable in terms of time and tissue type. Therefore, the order of expression of the six hallmarks of cancer can vary greatly across tumors of the same type and certainly in different tumor types.
Research into the biology of cancer has provided a wealth of information about cancer initiation and progression and has also resulted in dramatic new drugs in the fight against cancer. Simplifying and dissecting the pathways involved in each of these signaling pathways has been critical to understanding this process. On the other hand, the danger of simplification is that it reflects little of the biological reality of cancer progression in human patients in vivo.
New technologies have allowed us to identify epigenetic modifiers (agents that alter expression without changing the DNA sequence – such as microRNAs) located within the cancer cell or elsewhere in the body. It is very likely that in the near future the diagnosis of all cancers will depend on routine analysis of the expression profile of the set of underlying genetic mutations and/or their epigenetic modifiers.
