"The Hallmarks of Cancer " is a seminal peer-reviewed article published in the January edition of Cellular Journal by cancer researchers Douglas Hanahan and Robert Weinberg.
The authors believe that the complexity of cancer can be reduced to a small number of underlying principles. The paper argues that all cancers share six common traits ("excellence") that govern the transformation of normal cells to cancer cells (malignant or tumor).
The characteristics ("excellence") that the authors highlight in the paper are (1) Cancer cells stimulate their own growth (self-sufficiency in growth signals); (2) They withstand signaling inhibitors that may stop their growth (insensitivity to anti-growth signals); (3) They reject programmed cell death (avoid apoptosis); (4) They can multiply indefinitely (limitless replikative potential) (5) They stimulate the growth of blood vessels to supply nutrients to the tumor (continuous angiogenesis); (6) They invade local tissue and spread to distant places (invasion of tissue and metastasis).
In November 2010, the paper was referenced more than 15,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007. In March 2011, it was the most quoted article.
In an update published in 2011 ("Signs of Cancer: Next Generation"), Weinberg and Hanahan propose four new advantages: (1) abnormal metabolic pathways; (2) avoid the immune system; (3) genomic instability; (4)) inflammation.
Video The Hallmarks of Cancer
Daftar keunggulan
Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that govern these control mechanisms (ie defects in homeostasis).
Normal cells grow and divide, but have a lot of control on that growth. They only grow when stimulated by growth factors. If they are damaged, the molecular brakes stop them from dividing until they are repaired. If they can not be repaired, they commit programmed cell death (apoptosis). They can only divide several times. They are part of the network structure, and stay where they are. They need a blood supply to grow.
All of these mechanisms must be addressed so that the cells can develop into cancer. Each mechanism is controlled by several proteins. Important proteins must function by not working in each of these mechanisms. These proteins become malfunctioning or damaged when their gene DNA sequences are damaged through mutated or somatic mutations (mutations that are not inherited but occur after conception). This happened in a series of steps, which Hanahan and Weinberg called excellence.
Independence in growth signals
- Cancer cells do not require stimulation of external signals (in the form of growth factors) to multiply.
Usually, the body's cells need hormones and other molecules that act as a signal for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are several ways in which cancer cells can do this: by generating these signals themselves, known as autocrine signaling; by permanently activating the signal paths that respond to these signals; or by destroying a 'switch' preventing the overgrowth of these signals (negative feedback). In addition, cell division in normal and non-cancer cells is strictly controlled. In cancer cells, these processes are regulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor.
Insensitivity to anti-growth signal
- Cancer cells are generally resistant to growth-preventing signals from their neighbors.
To control strict cell division, cells have a process in it that prevents cell growth and division. These processes are governed by a protein known as tumor suppressor gene. These genes pick up information from the cell to ensure that the cell is ready for division, and will stop the division if it does not (when DNA is damaged, for example). In cancer, these tumor suppressor proteins are altered so that they do not effectively prevent cell division, even when cells have severe abnormalities. Another way of preventing over-division cells is that normal cells will also stop dividing when cells fill their spaces and touch other cells; known as contact inhibition. Cancer cells have no inhibitory contact, and thus will continue to grow and divide, regardless of the environment.
Avoid programmed cell death
- Apoptosis is a form of programmed cell death (cell suicide), a mechanism in which cells are programmed to die if they become damaged. Cancer cells are characteristically capable of passing through this mechanism.
Cells have the ability to 'self-destruct'; a process known as apoptosis. It is necessary for the organism to grow and develop properly, to maintain body tissue, and also begins when cells are damaged or infected. Cancer cells, however, lose this ability; although cells can become very abnormal, these cells do not apoptose. Cancer cells can do this by changing the mechanisms that detect damage or abnormalities. This means that proper signaling can not occur, so apoptosis can not be activated. They may also have defects in the downstream signals themselves, or proteins involved in apoptosis, each of which will also prevent proper apoptosis.
Unlimited replication potential
- Non-cancer cells die after a number of divisions. Cancer cells run away from this boundary and seem to be able to develop indefinitely and division (immortality). But perennial cells have damaged chromosomes, which can become cancerous.
The body cells usually do not have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide (aging), or die (the crisis). The cause of this obstruction is primarily due to the DNA at the end of the chromosome, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short that it triggers aging, so the cells stop dividing. Cancer cells pass through this barrier by manipulating enzymes that increase telomere length. Thus, they can divide indefinitely, without starting aging.
Mammalian cells have an intrinsic program, the Hayflick limit, which limits their multiplication to about 60-70 fold, at which point they reach the stage of aging.
This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, allowing them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disorder, and occasional (10 -7 ) which is immortalized that can be doubled indefinitely. Most of the tumor cells are immortalized.
Counters for cell multiplication are telomeres, which decrease size (loss of nucleotides at the end of a chromosome) during each cell cycle. Approximately 85% of cancer increases telomerase regulation to prolong their telomeres and the remaining 15% use a method called Telomere Alternative Extension.
Sustained angiogenesis
- Angiogenesis is the process by which new blood vessels are formed. Cancer cells seem to be able to start this process, ensuring that these cells receive a continuous supply of oxygen and other nutrients.
The normal tissues of the body have blood vessels flowing through them that deliver oxygen from the lungs. Cells must be close to the blood vessels to get enough oxygen for them to survive. New blood vessels are formed during embryonic development, during wound repair and during the female reproductive cycle. Widespread tumors require new blood vessels to provide sufficient oxygen to cancer cells, and thus exploit this normal physiological process for its benefits. To do this, the cancer cells gain the ability to regulate the production of new blood vessels by activating the 'angiogenic switch'. Thus, they control non-cancerous cells present in tumors that can form blood vessels by reducing the production of factors that inhibit the production of blood vessels, and increase the production of factors that increase blood vessel formation.
Network invasion and metastasis
- Cancer cells can break away from their original site or organ to invade surrounding tissue and spread (metastasize ) to distant parts of the body.
One of the most famous properties of cancer cells is their ability to invade neighboring tissues. That is what determines whether the tumor is benign or malignant, and is the reason for its spread throughout the body. Cancer cells must undergo many changes in order for them to gain the ability to metastasize. It is a multistep process that begins with a local invasion of cells into the surrounding tissue. They then have to attack the blood vessels, survive in the harsh environments of the circulatory system, get out of this system and then start dividing up in the new network.
Maps The Hallmarks of Cancer
Update
In the 2010 NCRI conference talks, Hanahan proposed four new advantages. This was later codified in an updated review article titled "The signs of cancer: the next generation."
Deregulation metabolism
Most cancer cells use an abnormal metabolic pathway to generate energy, a fact that has been appreciated since the early 20th century with the postulated Warburg hypothesis, but has only recently gained renewed research interest. Cancer cells that exhibit Warburg's effects increase the regulation of glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration (pyruvate oxidation, citric acid cycle, and electron transport chain). Instead of fully oxidizing glucose to produce as much ATP as possible, cancer cells prefer to convert pyruvate into building blocks for more cells. In fact, ATP is low: the ADP ratio caused by this effect is likely to contribute to mitochondrial deactivation. The potential of the mitochondrial membrane is hyperpolarized to prevent the pores of the transition of the voltage-sensitive permeability (PTP) from triggering apoptosis.
The ketogenic diet is being investigated as adjuvant therapy for some cancers, including gliomas, due to the inefficiency of cancer in ketone body metabolism.
Avoiding the immune system
Although cancer cells cause increased inflammation and angiogenesis, they also seem to be able to avoid interactions with the body through loss of the interleukin-33 immune system. (See cancer immunology)
Genomic Instability
Cancer cells generally have severe chromosomal abnormalities that worsen as the disease develops. HeLa cells, for example, are highly productive and have tetraploidy 12, trisomy 6, 8, and 17, and the number of capital chromosomes 82 (not the normal diploid number 46). Small genetic mutations are likely to initiate tumorigenesis, but after cells initiate a bridge-fusion-bridge cycle (BFB), they can mutate at a much faster rate. (See genomic instability)
Inflammation
Recent findings have highlighted the role of local chronic inflammation in inducing many types of cancer. Inflammation causes angiogenesis and more of an immune response. The degradation of the extracellular matrix needed to form new blood vessels increases the likelihood of metastasis. (See inflammation in cancer)
Criticism
An article in Nature Review Cancer in 2010 showed that five of these 'benefits' are also the hallmarks of benign tumors. The only characteristic of malignant disease is its ability to attack and metastasize.
An article in the Journal of Biosciences in 2013 states that the original data for most of these advantages is lacking. He argues that cancer is a tissue-level disease and the sign of this cell level is misleading.
Notes and references
Bibliography
- Hanahan D, Weinberg RA (January 2000). "Cancer excellence". Cell . 100 (1): 57-70. doi: 10.1016/S0092-8674 (00) 81683-9. PMID 10647931. .
- Hanahan D, Weinberg RA (March 2011). "The signs of cancer: the next generation". Cell . 144 (5): 646-74. doi: 10.1016/j.cell.2011.02.013. PMID 21376230. .
Source of the article : Wikipedia
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