The Hallmarks of Cancer

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The ability to invade surrounding tissue and metastasise is a hallmark of cancer.

"The Hallmarks of Cancer"[1] is a seminal[2][3] peer-reviewed article published in the journal Cell in January 2000 by the 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 ("hallmarks") that govern the transformation of normal cells to cancer (malignant or tumor) cells.

The traits ("hallmarks")that the authors highlight in the paper are (1) Cancer cells stimulate their own growth (Self-sufficiency in growth signals); (2) They resist inhibitory signals that might otherwise stop their growth (Insensitivity to anti-growth signals); (3) They resist their programmed cell death (Evading apoptosis); (4) They can multiply indefinitely (Limitless replicative potential) (5) They stimulate the growth of blood vessels to supply nutrients to tumors (Sustained angiogenesis); (6) They invade local tissue and spread to distant sites (Tissue invasion and metastasis).

By November 2010, the paper had been referenced over 15,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007.[4][self-published source?] As of March 2011, it was Cell's most cited article.[2]

In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways; and (2) evading the immune system.[5]

List of hallmarks[edit]

Signalling pathways are deregulated in cancer. Hanahan and Weinberg compared the signalling pathways to electronic circuits where transistors are replace by proteins. The prototypical Ras pathway starts with an extracellular signal from growth factors (such as TGF-α). Other major extracellular signals are anti-growth factors (such as TGF-β), death factors (such as FASL), cytokines (such as IL-3/6)and survival factors (such as IGF1). Proteins inside the cell control the cell cycle, monitor for DNA damage and other abnormalities, and trigger cell suicide (apoptosis). Hanahan and Weinberg's signal pathway illustration is at Cell 100:59[6]

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.

Self-sufficiency in growth signals[edit]

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.

Summary
Capability Simple analogy
Self-sufficiency in growth signals "accelerator pedal stuck on"
Insensitivity to anti-growth signals "brakes don't work"
Evading apoptosis won't die when the body normally would kill the defective cell
Limitless replicative potential infinite generations of descendants
Sustained angiogenesis telling the body to give it a blood supply
Tissue invasion and metastasis migrating and spreading to other organs and tissues

Insensitivity to anti-growth signals[edit]

Cancer cells are generally resistant to growth-preventing signals from their neighbours.
The cell cycle clock. Cells do not divide in G0 and are quiescent. After receiving growth factor signals, they prepare for division by entering G1, where everything within the cell except DNA is doubled. This doubling includes the size of the cell. The next phase of the cell cycle is S (synthesis) phase. It is the cell cycle phase where the chromosomes (DNA) are duplicated in preparation for cellular division. The transition from G1 to S is a checkpoint. If the cell has damaged DNA or is expressing oncogenes or other inappropriate proteins, specialized checkpoint proteins, tumor suppressors such as p53 or pRB, will interrupt the transition to S phase until the damage is repaired. If the damage cannot be repaired, the cell will initiate apoptosis, often referred to as cellular suicide, which is programmed cell death. If the tumor suppressor genes incur loss-of-function mutations or are knocked out, the damaged cell can continue to divide unchecked — one of the hallmarks of cancer.
The hallmarks of cancer.

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 papilloma virus, the cell can divide uncontrollably, which can lead to cervical cancer.

Evading apoptosis[edit]

Apoptosis is a form of programmed cell death (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 replicative potential[edit]

Non-cancer cells die after a certain number of divisions. Cancer cells escape this limit and are apparently capable of indefinite growth and division (immortality). 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[edit]

Angiogenesis 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[edit]

Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) 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 normal epithelial cell layers.

Updates[edit]

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 hypothesis,[7] but only now gaining renewed research interest.[8]
Evading the immune system
Cancer cells appear to be invisible to the body’s immune system.
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 inflammation in inducing many types of cancer.

Second review article[edit]

"The hallmarks of cancer" was published in 2000. In 2011, Douglas Hanahan and Robert A. Weinberg published in Cell an updated review article entitled "Hallmarks of cancer: the next generation".[5]

Cancer Hallmark Network Framework (2014)[edit]

Although cancer hallmarks represent the most important understanding of cancer over the past 50 years, they have been described only in text. In the cancer hallmark network framework, cancer hallmarks can be represented by molecular networks which can be quantified and modeled computationally.[9] The cancer hallmark traits can be represented by 9 molecular networks: Survival network, Mutating network, Dedifferentiation network, Angiogenesis-inducing network, Immune-escaping network, EMT (epithelial-mesenchymal transition) network, Genome duplication network, Metabolic network and Stroma-network. These networks interact each other during cancer cell evolution.

By applying a systems biology approach to the cancer hallmark network framework, Hallmark networks can be quantified and then computationally modeled to predict cancer evolutionary paths and clinical phenotypes, which is beyond the text-only description of the cancer hallmarks. 'Network operational signatures' have been proposed to quantify and model the measures of hallmark traits.[9] Some working examples are available.

Criticisms[edit]

An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours.[10] The only hallmark of malignant disease was its ability to invade and metastasize.[10]

Notes and references[edit]

  1. ^ Hanahan D, Weinberg RA (January 2000). "The Hallmarks of Cancer". Cell 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931. 
  2. ^ a b "Scientists Revisit 'Hallmarks of Cancer'". Science Daily. 16 March 2011. Retrieved 2011-04-04. 
  3. ^ "The Hallmarks of Cancer". Science Interviews. November 2010. Retrieved 2011-04-04. 
  4. ^ Hallmarks of Cancer, Cancer Research UK Science Update blog, November 2010
  5. ^ a b Hanahan, D.; Weinberg, R. A. (2011). "Hallmarks of Cancer: The Next Generation". Cell 144 (5): 646–674. doi:10.1016/j.cell.2011.02.013. PMID 21376230.  edit
  6. ^ Cell 100:59
  7. ^ O. Warburg, K. Posener, E. Negelein: "Ueber den Stoffwechsel der Tumoren" Biochemische Zeitschrift, 152, pp. 319–344, 1924. (German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930.
  8. ^ "Targeting tumour metabolism". Nature Reviews Drug Discovery 9 (7): 503–504. 2010. doi:10.1038/nrd3215. ISSN 1474-1776. PMID 20592733. 
  9. ^ a b Wang, E; Zaman, N; McGee, S; Milanese, J. S.; Masoudi-Nejad, A; O'Connor-Mccourt, M (2014). "Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data". Seminars in cancer biology. doi:10.1016/j.semcancer.2014.04.002. PMID 24747696.  edit
  10. ^ a b Lazebnik Y (April 2010). "What are the hallmarks of cancer?". Nat. Rev. Cancer 10 (4): 232–3. doi:10.1038/nrc2827. PMID 20355252. 

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