What makes a cancer a cancer? The hallmarks of cancer.

Cancer – the ‘C word’ in far too many of our lives. Wherever you are, it’s unlikely you’ll be able to avoid the news reports and personal stories about people fighting against cancer. Understanding how the disease occurs and how it takes hold over the body is key for developing effective new treatments and managing patients in the clinic, and so huge amounts of money are invested in cancer research every year. But what actually is cancer and how does it develop?

Many people often think of cancer as unwanted growth – which is exactly right. Cancer is a disease of cell growth and division, where cells continue to grow and divide in an uncontrolled and indefinite manner. In solid tumours, the growing mass can be seen or felt as lumps and masses, whereas with non-solid cancers like leukaemia the cells aren’t in a single mass but are instead spread throughout the body, often in the blood.

Normal cells have a wide number of intrinsic defences against becoming cancerous, and so many changes need to occur before they start to grow uncontrollably to form cancer. In January 2000 a landmark paper outlining how cells acquire a cancer-like phenotype was published and detailed 6 key changes or features that make a cancer a cancer: these are the hallmarks of cancer, and represent the fundamental basis of malignancy. These principles are thought to govern all malignancies, simplifying and unifying the huge variety of diseases that come under the umbrella term ’cancer’.

The 6 original hallmarks of cancer. (Hanahan and Weinberg, 2000).

The 6 original hallmarks of cancer. (Hanahan and Weinberg, 2000).

“Self-sufficiency in growth signals” and “insensitivity to anti-growth signals”

As a disease of uncontrolled cell division, cells must acquire the ability to continually grow in order to become cancerous. Cancer cells constitutively activate signalling pathways to become self-sufficient in providing their own growth signals, so that they are no longer dependent on external signals to prompt them to progress through the cell cycle. Cancers also become resistant to anti-growth signals, meaning they can ignore normal signalling that limits the growth of cells to prevent abnormal division.

“Evading apoptosis”

In the face of aberrant and potentially cancerous growth signalling, normal cells activate programmed cell death – apoptosis. This is also activated in the face of DNA damage and other cellular stresses, which can also be features of cancerous cells, and so apoptosis represents a crucial mechanism to avoid accumulation of damage and mutations that can culminate in cancer formation. Cancer cells acquire the ability to evade this induction of cell death, which is crucial for both maintaining tumour growth and allowing cancerous cells to form in the first stage of disease development.

“Enabling replicative immortality”

Nearly all cancers are thought to arise from a single cell of origin. To become a visible and palpable mass, that first cell must divide an almost unfathomable number of times. Most normal cells are unable to grow and divide indefinitely, as they are limited in the number of times they can reliably and effectively copy all of the cell’s DNA – this is because small amounts of DNA on the ends of the cell’s chromosomes are lost during every replication cycle. These end sequences are called telomeres, and are simply repetitive DNA sequences. As a cell divides more and more its telomeres shorten, which eventually causes the cell to enter a permanent non-replicative state known as ‘senescence’. This mechanism that limits cellular replicative potential is known as the ‘end replication problem’.

Cancer cells must find ways of avoiding inducing cellular senescence to allow them to divide indefinitely and form tumours. This often involves finding ways of repairing or lengthening the telomeres to prevent them from shortening, allowing indefinite replication. Telomerase is an enzyme which adds more telomere sequences to the ends of chromosomes to avoid the end replication problem; some normal cells express telomerase, for example embryonic stem cells (the very first cells at conception from which the entire foetus is made), which allows them to replicate indefinitely – but normal adult cells do not express this immortalising enzyme.

Many tumours have been found to contain mutations that lead to reactivation of telomerase, facilitating replicative immortality. Another method of maintaining telomeres is ALT (alternative lengthening of telomeres), which doesn’t require telomerase, and instead resembles a mechanism of DNA repair. ALT has also been observed in some cancers.

“Sustained Angiogenesis”

Like normal tissue, a tumour mass requires a blood supply. For a tumour to be able to grow bigger than around 1mm3 in size, it must induce the creation of its own blood supply. This process by which the host’s normal blood supply is extended and grows into the tumour is called angiogenesis. This is not a distinct change in the cells themselves, but rather a process which is encouraged by interactions between the tumour mass and its environment (the normal host tissue). Factors such as low oxygen levels and secretion of pro-angiogenic factors drive angiogenesis.

“Invasion and metastasis”

Ultimately, it is the invasion of the normal host tissue by the tumour, and the spreading of cancer to other sites in the body (metastasis), which ultimately kills cancer patients. Cancer cells must acquire the ability to become motile and migrate from the original tumour site: this is the acquisition of the invasive and metastatic phenotype. Changes promoting invasion happen at the cellular level, including changes in the expression of surface markers which allow the cells to adhere to the surrounding tissues.

Metastasis is a particularly complex process, but usually occurs by cancer cells invading blood vessels and hitchhiking through the circulatory system to other sites of the body. These processes are by no means comprehensively understood as yet, but are known to involve a large number of secreted factors which break down tissues to allow for invasion into blood vessels and then establishment of a new tumour (a metastasis) at the site of deposition.

Hallmarks of cancer: the next generation

Since the seminal paper published in 2000, the hallmarks of cancer have been revised to include four further malignant traits: evading immune destruction, altered cellular energetics, cancer-enabling inflammation, and cancer-enabling genetic instability. These are not discussed thoroughly here, but also work to promote the development, survival and evolution of the tumour mass and its constituent cells.

Knowledge of these cancer-driving features is pathing the way for new therapies, with each of the hallmarks now being a target for drug therapy, many of which are now being brought into the clinic and are making a real difference to the lives of people fighting against cancer.


Hallmarks of cancer: the next generation. There are now 10 established hallamarks of cancer, including the enabling factors: inflammation and genomic instability. (Hanahan and Weinberg 2011).

Hallmarks of cancer: the next generation. There are now 10 established hallamarks of cancer, including the enabling factors: inflammation and genomic instability. (Hanahan and Weinberg 2011).


For an in-depth discussion on the hallmarks of cancer, including the four additional hallmarks, see the papers references below. They’re long, but give excellent examples and explanations of each hallmark, as well as illustrating how they have been translated into new therapies.




Hanahan, D., & Weinberg, R. (2000). The Hallmarks of Cancer Cell, 100 (1), 57-70 DOI: 10.1016/S0092-8674(00)81683-9

Hanahan D, & Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell, 144 (5), 646-74 PMID: 21376230

In-text images are from the above referenced paper (Hanahan and Weinberg 2011). (http://www.cell.com/cell/pdf/S0092-8674(11)00127-9.pdf)

Featured image: photo credit: GDS Infographics via photopin cc


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6 responses to “What makes a cancer a cancer? The hallmarks of cancer.

  1. I went to a seminar by Dr Dominic D’Agustino a few months ago. One interesting point in his seminar was an experiment transplanting the cell nucleus from cancerous cells to normal cells (with normal mitochondria)–cells were no longer cancerous. Transplanting mitochondria from cancerous cells to normal cells–the cells became cancerous. He also pointed out that cancerous cells must have glucose for energy–all other cells can use ketone as an energy source.

  2. Paraganglioma and pheochromocytoma display nearly all these things, but unless they metastasize they are considered benign.

  3. “Metastatic disease due to PGL can only be diagnosed based on the presence of chromaffin tumors in locations where chromaffin cells are not usually present. Thus, the widely used term ‘malignancy’, that is spreading of a primary tumor by tissue and/or vascular invasion and/or metastazising, does not necessarily apply to PGL. While tissue and/or vascular invasion are sometimes observed in PGLs these observations don’t correlate well with the severity of the disease and a patient’s prognosis. Thus, in contrast to other malignancies, the development of metastases cannot be predicted or evaluated by high vascularization and mitotic rate, or vascular and/or tissue invasion. Despite huge efforts, currently no gene or protein has been identified as a definite marker or predictor for metastatic disease and no reliable cure has been developed yet.”

  4. Pingback: The Heterogeneity of Cancer and DNA as a Prognostic Marker: The Truth is in our Blood | Antisense Science·

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