The hallmarks of cancer are biological traits that cancer cells gain as tumors develop. These traits were first identified as six in 2000 by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published in the journal Cell. Over time, scientists added two more traits, making a total of eight hallmarks. In 2011, Hanahan and Weinberg also identified two additional enabling traits that support the development of cancer.

These hallmarks help scientists understand the complex nature of cancer. The hallmarks include: (1) keeping cells growing continuously, (2) avoiding signals that stop growth, (3) avoiding cell death, (4) allowing cells to divide endlessly, (5) creating new blood vessels to supply tumors, and (6) spreading to other parts of the body. Two other traits, genome instability and inflammation, help cancer cells gain these hallmarks. Tumors also include normal cells that surround cancer cells, forming the "tumor microenvironment." These normal cells help cancer cells develop their traits.

In the 2011 update, Hanahan and Weinberg added two new hallmarks: (1) abnormal ways cells process energy and (2) avoiding detection by the immune system. They also identified two enabling traits: (1) genome instability and (2) inflammation.

List of hallmarks

Cancer cells have problems with the systems that control how often they divide and the systems that manage these controls (problems with balance). Normal cells grow and divide, but they have many controls that stop this growth. They only grow when signals called growth factors tell them to. If they are damaged, a stop signal prevents them from dividing until they are fixed. If they can't be fixed, they stop living (apoptosis). They can only divide a limited number of times. They stay in their correct place in the body and need blood to grow.

For a cell to become cancer, all these controls must be overcome. Each control is managed by several proteins. A key protein must stop working in each of these controls. These proteins stop working when the DNA in their genes is damaged through changes that happen after birth (somatic mutations). This happens in steps, which Hanahan and Weinberg call hallmarks.

Normal cells need signals like hormones to grow and divide. Cancer cells can grow without these signals. They do this by making their own signals (autocrine signaling), keeping their signal systems always active, or by removing the systems that stop signals from working too much (negative feedback). In normal cells, division is carefully controlled. In cancer cells, these controls are broken because the proteins that manage them are changed, causing more growth and division in the tumor.

Cells have processes that stop them from growing and dividing. These processes are controlled by proteins from tumor suppressor genes. These genes check if the cell is ready to divide and stop it if it isn’t (for example, if the DNA is damaged). In cancer, these proteins are changed so they can’t stop division, even when the cell has serious problems. One important tumor suppressor is p53. It is so important for controlling division and cell death that in 70% of cancer cells, p53 is either broken or not working. Often, tumors can’t form without turning off critical tumor suppressors like p53. Another way cells stop over-division is by stopping when they fill a space and touch other cells (contact inhibition). Cancer cells don’t have contact inhibition, so they keep growing no matter what.

Cells can "self-destruct" through a process called apoptosis. This is needed for proper growth, tissue repair, and to remove damaged or infected cells. Cancer cells lose this ability. Even if they become seriously abnormal, they don’t self-destruct. This happens because the systems that detect damage are changed, so signals can’t work properly. They may also have problems with the proteins involved in apoptosis, which also stops self-destruction.

Normal cells can’t divide forever. They can only divide a limited number of times before they stop dividing (senescence) or die (crisis). This is mainly because of structures at the ends of chromosomes called telomeres. Telomeres get shorter each time a cell divides until they are too short, causing the cell to stop dividing. Cancer cells avoid this by using enzymes called telomerase to make telomeres longer. This lets them divide forever without stopping.

Mammalian cells have a built-in limit called the Hay

Updates

In his 2010 NCRI conference talk, Hanahan introduced two new hallmarks and two enabling characteristics of cancer. These ideas were later summarized in an updated review article titled "Hallmarks of cancer: the next generation."

Recent research has expanded the understanding of cancer hallmarks by using computer-based methods that analyze groups of genes related to these hallmarks. These methods help scientists study how genes connected to cancer processes are involved in different types of cancer.

The Cancer Hallmarks gene set includes 6,763 genes collected from reliable sources such as oncology databases, Gene Ontology biological processes, KEGG pathways, and earlier studies on cancer hallmarks. This collection allows scientists to compare user-defined gene lists—such as genes that are changed or mutated in cancer—to specific cancer-related processes. This helps identify patterns and compare findings across different cancers.

These computational tools provide a clear way to represent cancer hallmarks using computer science and support further research, such as finding biomarkers, analyzing survival rates, and comparing results from different studies.

Most cancer cells use different ways to produce energy, a concept first proposed in the early 1900s with the Warburg hypothesis. This idea is now being studied again because it helps explain how cancer cells function. Cancer cells that show the Warburg effect increase glycolysis and lactic acid production in the cell’s cytoplasm while stopping mitochondria from completing normal energy production steps, such as breaking down pyruvate, the citric acid cycle, and the electron transport chain. Instead of fully breaking down glucose to make the most ATP, cancer cells use glucose to create building blocks for new cells. This process may cause mitochondria to stop working properly. Mitochondria become more charged to stop pores that could trigger cell death. Many scientists believe cancer is a metabolic disease. This research helps scientists understand cancer metabolism better, which may lead to new treatments that target metabolism and help overcome drug resistance in some cancers. The ketogenic diet is being tested as a possible treatment for certain cancers, like glioma, because cancer cells are not efficient at using ketone bodies for energy.

Although cancer cells increase inflammation and blood vessel growth, they also avoid being detected by the immune system. This happens partly because they lose a protein called interleukin-33. Cancer cells use various methods to escape the immune system. One way is by hiding from immune cells, defending themselves, or using stem cells to avoid being attacked.

Cancer cells avoid being destroyed by the immune system by hiding from detection. One common method is by producing a protein called programmed death-1 ligand (PD-L1) on their surface. This protein usually stops T cells from attacking healthy cells. Cancer cells make large amounts of PD-L1, which prevents T cells from attacking them. Another method is by reducing the production of MHC I. MHC I molecules on cell surfaces signal the immune system to detect infected cells. Cancer cells avoid this by lowering MHC I levels through changes in gene regulation and other processes.

The updated paper also described two enabling characteristics. These are called enabling because they help cancer cells develop the other hallmarks.

Cancer cells often have serious chromosome problems that get worse as the disease progresses. For example, HeLa cells have many extra chromosomes, including four copies of chromosome 12 and three copies of chromosomes 6, 8, and 17. These cells have 82 chromosomes instead of the normal 46. Small genetic changes may start cancer, but once cells enter a cycle called the breakage-fusion-bridge cycle, they change more quickly.

Recent discoveries show that long-term inflammation in specific areas of the body can cause many types of cancer. Inflammation increases blood vessel growth and immune activity. Breaking down the tissue around blood vessels makes it easier for cancer to spread to other parts of the body.

Criticisms

An article in Nature Reviews Cancer from 2010 noted that five of the "hallmarks" of cancer were also found in benign tumors. The only feature that distinguished malignant tumors was their ability to spread to other parts of the body.

An article in the Journal of Biosciences from 2013 stated that there is not enough evidence to support most of these hallmarks. It suggested that cancer is a disease affecting the entire tissue, and that characteristics based only on individual cells may be misleading.