The Hallmarks of Cancer
The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors that have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.
These hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. In addition to cancer cells, tumors exhibit another dimension of complexity: they incorporate a community of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
In an update published in 2011, Weinberg and Hanahan proposed two new hallmarks: abnormal metabolic pathways and evasion of the immune system, and two enabling characteristics: genome instability, and inflammation.
List of hallmarks
Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms.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 programmed cell death. 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 protein must malfunction in each of those mechanisms. These proteins become non-functional or malfunctioning when the DNA sequence of their genes is damaged through acquired or somatic mutations. This occurs in a series of steps, which Hanahan and Weinberg refer to as hallmarks.
| 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 |
Self-sufficiency in growth signals
Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signaling; by permanently activating the signaling pathways that respond to these signals; or by destroying 'off switches' that prevents excessive growth from these signals. In addition, cell division in normal, non-cancerous cells is tightly controlled. In cancer cells, these processes are deregulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor.Insensitivity to anti-growth signals
To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are orchestrated by proteins encoded by tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not. In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division, even when the cell has severe abnormalities. One of the most significant tumor suppressors is known as p53. It plays such a critical role in regulation of cell division and cell death that in 70% of cancer cells p53 is found either mutated or functionally inactivated. Often times tumors can not form successfully without deactivating critical tumor suppressors like p53. Another way cells prevent over-division is that normal cells will also stop dividing when the cells fill up the space they are in and touch other cells; known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings.Evading programmed cell death
Cells have the ability to 'self-destruct'; a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability; even though cells may become grossly abnormal, they do not undergo apoptosis. The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. This means that proper signaling cannot occur, thus apoptosis cannot activate. They may also have defects in the downstream signaling itself, or the proteins involved in apoptosis, each of which will also prevent proper apoptosis.Limitless replicative potential
Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide, or die. The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence.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 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 decreases in size during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres.
Sustained angiogenesis
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.A tumor requires new blood vessels to deliver oxygen to the cancer cells. The cancer cells orchestrate production of new vasculature by activating the "angiogenic switch." This allows them to control non-cancerous cells, present in the tumor so they can form blood vessels. Normal development and equilibrium depend on the physiological process of angiogenesis, which is strictly controlled. In order to balance vascular growth without excessive or inadequate blood vessel production, pro-angiogenic and anti-angiogenic factors usually interact constantly to maintain angiogenesis in balance. Cancer disrupts this equilibrium.
Tissue invasion and metastasis
Intravasation is the process where tumor cells enter blood or lymphatic blood vessels, enabling travel to distant parts of the body. Pro-angiogenic factors like VEGF, along with interactions between cancer calls and the vessel walls, make it possible for tumor cells to penetrate into the bloodstream.Upon entering the bloodstream, cancer cells become known as circulating tumor cells. To protect themselves from being detected by the immune system, these cells cluster or cover themselves with platelets.
Extravasation happens when circulating tumor cells leave the bloodstream and invade new tissues. Integrins help the cells attach to their new environment. Cancer cells then form a metastatic niche that helps them grow a new tumor in a new location.
E-cadherin is an epithelial adhesion protein that plays an role in maintaining tissue structure by facilitating cell to cell adhesion. The loss of E-cadherin disrupts cellular adhesion, which allows tumor cells to detach from the primary site and invade other tissues. Low levels of E-cadherin are linked to poor clinical outcomes, therapy resistance, and aggressive tumor phenotypes.
Updates
In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation."Emerging Hallmarks
Computational and gene set–based extensions
Recent studies have extended the conceptual framework of the hallmarks of cancer by developing computational gene set–based approaches that enable quantitative functional enrichment analysis of hallmark-associated genes.The Cancer Hallmarks gene set integrates 6,763 genes derived from curated oncological databases, Gene Ontology biological processes, KEGG pathways, and prior hallmark-related studies. This integrated gene set allows the systematic mapping of user-defined gene lists—such as differentially expressed or mutated genes—to specific cancer hallmark processes, enabling statistical enrichment analysis and comparative evaluation across tumor types.
Such computational implementations provide a unified bioinformatic representation of the hallmarks of cancer and support downstream applications including biomarker discovery, survival analysis, and cross-cohort comparisons.