The Hallmarks of Cancer
Encyclopedia
"The Hallmarks of Cancer" is a seminal peer-reviewed article published in the journal Cell
in January 2000 by US 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 cancer
s share six common traits ("hallmarks") that govern the transformation of normal cells to cancer (malignant or tumor) cells.
Those hallmarks are: (1) cancer cells stimulate their own growth; (2) they resist inhibitory signals that might otherwise stop their growth; (3) they resist their own programmed cell death (apoptosis
); (4) they stimulate the growth of blood vessels to supply nutrients to tumors (angiogenesis
); (5) they can multiply forever; and (6) they invade local tissue and spread to distant sites (metastasis
).
By November 2010, the paper had been referenced over 10,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007. As of March 2011 it was Cells most cited article.
In 2011, Weinberg and Hanahan proposed 4 new hallmarks: (1) abnormal metabolic pathways; (2) evading the immune system; (3) chromosome abnormalities and unstable DNA; and (4) inflammation.
Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis
).
Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit cell suicide (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.
All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical proteins must be damaged in each of those mechanisms. These proteins are damaged when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, which Hanahan and Weinberg call hallmarks.
Normal cells require external growth signals (growth factors) to grow and divide. These signals are transmitted through receptors that pass through the cell membrane. When the growth signals are absent, they stop growing.
Cancer cells can grow and divide without external growth signals. Some cancer cells can generate their own growth signals. For example, glioblastomas can produce their own platelet-derived growth factor (PDGF), and sarcomas can produce their own tumor growth factor α (TGF-α).
Receptors themselves can be overexpressed. For example, the epidermal growth factor receptor (EGF-R/erbB) is overexpressed in stomach, brain and breast cancers, while the HER2/neu receptor is overexpressed in stomach and breast cancer. Or, mutated receptors can send signals without any growth factors at all.
The growth of normal cells is kept under control by growth inhibitors in the surrounding environment, in the extracellular matrix and on the surfaces of neighboring cells. These inhibitors act on the cell cycle clock, by interrupting cell division (mitosis) in the interphase.
Ultimately, the growth inhibitor signals are funneled through the downstream retinoblastoma protein (pRB), which prevents the inappropriate transition from (G1) to S. If pRB is damaged through a mutation in its gene, or by interference from human papillomavirus, the cell can divide uncontrollably, which can lead to cervical cancer.
Apoptosis can be triggered by an overexpressed oncogene, and this may be the primary means by which such mutant cells are continually removed. Conversely, cancer cells must overcome apoptosis to progress.
The apoptotic machinery can be divided into sensors, which monitor the cell for abnormal behavior, and effectors, which cause apoptosis.
The sensors include survival signals and their receptors, which monitor the cell for DNA damage, oncogene overexpression, and low oxygen (hypoxia). They monitor survival signals from the cell matrix and neighboring cells.
Sensors include IGF-1/IGF2 and their receptor IGF-1R; and IL-3 and its receptor.
The effectors include FAS ligand and its receptor, and TNF-α and its receptor.
The p53 tumor suppressor protein elicits apoptosis in response to DNA damage, and is a major mechanism of cancer control. In order for cancer to progress, it must overcome p53, and p53 is mutated in >50% of cancers.
Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60-70 doublings, at which point they reach a stage of senescence.
This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10-7) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.
The counting device for cell doublings is the telomere, which loses DNA at the tips of every chromosome during each cell cycle. Many cancers involve the upregulation of telomerase, the enzyme that maintains telomeres.
Cancer cells initially lack angiogenic ability, limiting their ability to expand. In order to progress, they must develop a blood supply. Angiogenesis is balanced by inducers and inhibitors.
Inducers include vascular endothelial growth factor (VEGF) and acetic and basic fibroblast growth factor (FGF 1/2), which bind to transmembrane tyrosine kinase receptors displayed on endothelial cells. An inhibitor is thrombospondin-1, which binds to CD36. Thrombospondin-1 is regulated by p53, so loss of p53 can allow angiogenesis.
Angiogenesis is involved in the growth of cervix, breast and melanoma tumors.
Anti-VEGF antibodies slowed the growth of tumors in mice. So this and other anti-angiogenesis compounds are under investigation as drugs to treat cancer.
Primary tumor masses spawn "pioneer cells" that invade adjacent tissues, and may then travel to distant sites, and establish metastases.
The newly formed metastases arise as amalgams of cancer cells and normal supporting cells conscripted from the host tissue.
Metastatic cells must mimic normal cell-cell interactions, through cell-cell adhesion molecules (CAMs) and integrins. N-CAM is normally adhesive, suppressing metastases, but it becomes altered and allows metastases in Wilm's tumor, neuroblastoma, and small cell lung cancer, and its expression is reduced in invasive pancreatic and colorectal cancers.
E-cadherin, which is expressed on epithelial cells, transmits antigrowth signals. E-cadherin is therefore a widely acting suppressor of invasion and metastasis by epithelial cells, which must be overcome by cancer cells to progress.
Integrins display substrate preferences, and changes in integrins are displayed by migrating cells.
Matrix-degrading proteases are also necessary to facilitate invasion into stroma, across blood vessel walls, and through noral epithelial cell layers.
Deregulated metabolism
Evading the immune system
Unstable DNA
Inflammation
in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. The only hallmark of malignant disease was its ability to invade and metastasize
.
Cell (journal)
Cell is a peer-reviewed scientific journal publishing research papers across a broad range of disciplines within the life sciences. Areas covered include molecular biology, cell biology, systems biology, stem cells, developmental biology, genetics and genomics, proteomics, cancer research,...
in January 2000 by US cancer researchers Douglas Hanahan
Douglas Hanahan
Professor Douglas Hanahan an American biologist, and director of the Swiss Institute for Experimental Cancer Research.In 1983 he developed Super Optimal Broth, a microbiological growth medium....
and Robert Weinberg
Robert Weinberg
Robert Allan Weinberg is a Daniel K. Ludwig Professor for Cancer Research at MIT and American Cancer Society Research Professor; his research is in the area of oncogenes and the genetic basis of human cancer. Weinberg is also affiliated with the Broad Institute and is a founding member of the...
.
The authors believe that the complexity of cancer can be reduced to a small number of underlying principles. The paper argues that all cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s share six common traits ("hallmarks") that govern the transformation of normal cells to cancer (malignant or tumor) cells.
Those hallmarks are: (1) cancer cells stimulate their own growth; (2) they resist inhibitory signals that might otherwise stop their growth; (3) they resist their own programmed cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
); (4) they stimulate the growth of blood vessels to supply nutrients to tumors (angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
); (5) they can multiply forever; and (6) they invade local tissue and spread to distant sites (metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
).
By November 2010, the paper had been referenced over 10,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007. As of March 2011 it was Cells most cited article.
In 2011, Weinberg and Hanahan proposed 4 new hallmarks: (1) abnormal metabolic pathways; (2) evading the immune system; (3) chromosome abnormalities and unstable DNA; and (4) inflammation.
List of hallmarks
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
).
Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit cell suicide (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.
All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical proteins must be damaged in each of those mechanisms. These proteins are damaged when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, which Hanahan and Weinberg call hallmarks.
Self-sufficiency in growth signals
- Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply.
Normal cells require external growth signals (growth factors) to grow and divide. These signals are transmitted through receptors that pass through the cell membrane. When the growth signals are absent, they stop growing.
Cancer cells can grow and divide without external growth signals. Some cancer cells can generate their own growth signals. For example, glioblastomas can produce their own platelet-derived growth factor (PDGF), and sarcomas can produce their own tumor growth factor α (TGF-α).
Receptors themselves can be overexpressed. For example, the epidermal growth factor receptor (EGF-R/erbB) is overexpressed in stomach, brain and breast cancers, while the HER2/neu receptor is overexpressed in stomach and breast cancer. Or, mutated receptors can send signals without any growth factors at all.
Insensitivity to anti-growth signals
- Cancer cells are generally resistant to growth-preventing signals from their neighbours.
The growth of normal cells is kept under control by growth inhibitors in the surrounding environment, in the extracellular matrix and on the surfaces of neighboring cells. These inhibitors act on the cell cycle clock, by interrupting cell division (mitosis) in the interphase.
Ultimately, the growth inhibitor signals are funneled through the downstream retinoblastoma protein (pRB), which prevents the inappropriate transition from (G1) to S. If pRB is damaged through a mutation in its gene, or by interference from human papillomavirus, the cell can divide uncontrollably, which can lead to cervical cancer.
Evading apoptosis
- ApoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
is a form of programmed cell deathProgrammed cell deathProgrammed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
(cell suicide), the mechanism by which cells are programmed to die in the event they become damaged. Cancer cells characteristically are able to bypass this mechanism.
Apoptosis can be triggered by an overexpressed oncogene, and this may be the primary means by which such mutant cells are continually removed. Conversely, cancer cells must overcome apoptosis to progress.
The apoptotic machinery can be divided into sensors, which monitor the cell for abnormal behavior, and effectors, which cause apoptosis.
The sensors include survival signals and their receptors, which monitor the cell for DNA damage, oncogene overexpression, and low oxygen (hypoxia). They monitor survival signals from the cell matrix and neighboring cells.
Sensors include IGF-1/IGF2 and their receptor IGF-1R; and IL-3 and its receptor.
The effectors include FAS ligand and its receptor, and TNF-α and its receptor.
The p53 tumor suppressor protein elicits apoptosis in response to DNA damage, and is a major mechanism of cancer control. In order for cancer to progress, it must overcome p53, and p53 is mutated in >50% of cancers.
Limitless reproductive potential
- Non-cancer cells die after a certain number of divisionsHayflick limitThe Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....
. Cancer cells escape this limit and are apparently capable of indefinite growth and division (immortalityBiological immortalityBiological immortality refers to a stable rate of mortality as a function of chronological age. Some individual cells and entire organisms in some species achieve this state either throughout their existence or after living long enough. This requires that death occur from injury or disease rather...
). But those immortal cells have damaged chromosomes, which can become cancerous.
Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60-70 doublings, at which point they reach a stage of senescence.
This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10-7) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.
The counting device for cell doublings is the telomere, which loses DNA at the tips of every chromosome during each cell cycle. Many cancers involve the upregulation of telomerase, the enzyme that maintains telomeres.
Sustained angiogenesis
- AngiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
is the process by which new blood vessels are formed. Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients.
Cancer cells initially lack angiogenic ability, limiting their ability to expand. In order to progress, they must develop a blood supply. Angiogenesis is balanced by inducers and inhibitors.
Inducers include vascular endothelial growth factor (VEGF) and acetic and basic fibroblast growth factor (FGF 1/2), which bind to transmembrane tyrosine kinase receptors displayed on endothelial cells. An inhibitor is thrombospondin-1, which binds to CD36. Thrombospondin-1 is regulated by p53, so loss of p53 can allow angiogenesis.
Angiogenesis is involved in the growth of cervix, breast and melanoma tumors.
Anti-VEGF antibodies slowed the growth of tumors in mice. So this and other anti-angiogenesis compounds are under investigation as drugs to treat cancer.
Tissue invasion and metastasis
- Cancer cells can break away from their site or organOrgan (anatomy)In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
of origin to invade surrounding tissue and spread (metastasizeMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
) to distant body parts.
Primary tumor masses spawn "pioneer cells" that invade adjacent tissues, and may then travel to distant sites, and establish metastases.
The newly formed metastases arise as amalgams of cancer cells and normal supporting cells conscripted from the host tissue.
Metastatic cells must mimic normal cell-cell interactions, through cell-cell adhesion molecules (CAMs) and integrins. N-CAM is normally adhesive, suppressing metastases, but it becomes altered and allows metastases in Wilm's tumor, neuroblastoma, and small cell lung cancer, and its expression is reduced in invasive pancreatic and colorectal cancers.
E-cadherin, which is expressed on epithelial cells, transmits antigrowth signals. E-cadherin is therefore a widely acting suppressor of invasion and metastasis by epithelial cells, which must be overcome by cancer cells to progress.
Integrins display substrate preferences, and changes in integrins are displayed by migrating cells.
Matrix-degrading proteases are also necessary to facilitate invasion into stroma, across blood vessel walls, and through noral epithelial cell layers.
Updates - 2010
In his 2010 NCRI conference talk, Hanahan proposed four new hallmarks:Deregulated metabolism
- Most cancer cells use abnormal metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesisWarburg hypothesisThe Warburg effect is the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen....
, but only now gaining renewed research interest.
Evading the immune system
- Cancer cells appear to be invisible to the body’s immune systemImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
.
Unstable DNA
- Cancer cells generally have severe chromosomal abnormalities, which worsen as the disease progresses.
Inflammation
- Recent discoveries have highlighted the role of local chronic inflammationInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
in inducing many types of cancer.
Criticisms
An article in Nature Reviews CancerNature Reviews Cancer
Nature Reviews Cancer is a monthly review journal covering the field of oncology....
in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. The only hallmark of malignant disease was its ability to invade and metastasize
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.