Major Development: The Number of Cancer Cell Hallmarks Reaches 14

“What are the fundamental differences between cancer cells and normal cells?” received its first comprehensive answer in 2000, when 6 hallmarks of the multistep process by which normal cells become cancerous were defined.

These 6 features were called “Hallmarks of Cancer Cells.” In subsequent years, 4 new features were added, shedding more light on this complex process. In 2022, another 4 features were added to the 10 hallmarks of cancer. We now know 14 hallmarks of cancer.

Scientists greeted the news enthusiastically. Many shared their excitement on Twitter at seeing their own research fields recognized among the fundamental features of cancer biology.

In the original paper published in 2000, cancer research pioneers Robert Weinberg of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology and Douglas Hanahan of the Swedish Federal Institute of Technology organized the latest knowledge about cancer into a logical framework of fundamental traits shared by most, if not all, human cancers, summarizing the extraordinary complexity of the disease.

Douglas Hanahan later became the name most closely associated with the Hallmarks of Cancer. Considered a milestone, this work quickly became a major resource for cancer researchers by providing a comprehensive foundation for understanding and studying cancer biology. Further hallmarks were added in subsequent years.

Today, cancer medicines are developed by targeting the hallmarks of cancer.

2000: The First Known Hallmarks of Cancer

The original framework reported 6 hallmarks of cancer:

1. Self-Sufficiency in Growth Signals: Normal cells depend on external growth signals to proliferate, whereas cancer cells can greatly reduce or eliminate their dependence on external stimuli and generate most growth signals themselves. It was later also found that cancers are complex tissues that influence surrounding normal cells to provide the necessary growth signals, making them active collaborators rather than passive bystanders.
2. Evading Growth-Suppressing Signals: Multiple antiproliferative signals maintain homeostasis in normal tissues by pushing cells out of the cell cycle into temporary rest or a differentiated state. Cells becoming cancerous evade these signals by disrupting the mechanisms that control the cell cycle, for example by impairing the pRb pathway and overexpressing growth-stimulating factors such as c-myc.
3. Activating Tissue Invasion and Metastasis: Metastasis causes more than 90% of cancer deaths. The ability to invade, settle in and grow in distant tissues is therefore a hallmark of cancer. It relies on changes in how cancer cells interact with their surroundings through E-cadherin, integrins and other adhesion molecules, and on the production of matrix-degrading proteases. Invasion means a tumor spreading deeper into tissue from where it began.
4. Unlocking Unlimited Replicative Potential: For a tumor to grow, cancer cells must proliferate indefinitely. Normal cells have limited replicative potential and eventually stop dividing when cultured in the laboratory, whereas cancer cells have lost this restriction mechanism governed by telomere shortening. To become immortal, they rely on the telomerase enzyme to maintain telomere length above a critical threshold that allows continued division.
5. Triggering New Blood Vessel Formation (Angiogenesis): A growing tumor's oxygen and nutrient requirements increase. To keep growing, it must therefore create new blood vessels for itself by sending proangiogenic signals. When the authors described this hallmark, tumors had been found to undergo an “angiogenic switch” that allowed them to grow from microscopic to macroscopic lesions.
6. Developing Resistance to Programmed Cell Death: Because immortality is another way cancer cells continue to increase in number, apoptosis (programmed cell death) is an important anticancer barrier, and cancer cells can evade its mechanisms. Cancer researchers are intensively investigating programmed cell death mechanisms to discover new medicines.

2011: The Hallmarks of Cancer Increase to 10

In 2011, Weinberg and Hanahan published an account of progress made over 10 years through the 6 distinguishing cancer traits described in 2000. They also announced two emerging hallmarks:

1. Reprogramming Energy Metabolism: Normal cells use glucose and oxygen to generate energy, whereas cancer cells can switch to aerobic glycolysis (energy production without oxygen) even when oxygen is present. This is known as the Warburg effect. Although less efficient, this mechanism is faster and generates several intermediate precursors that cancer cells use as building blocks for proteins, DNA and fats to support rapid proliferation.
2. Evading the Immune System: The ingenious ways cancer cells evade the immune system are among their most discussed and studied characteristics today. Medicines that prevent cancer cells from hiding from immunity, or, conversely, activate the immune system against cancer, are called immunotherapy. Hanahan and Weinberg considered studies in mouse models showing that cancers grew faster in mice with absent immunity, especially those lacking cytotoxic and helper T cells or natural killer cells, together with observations that human tumors with high immune infiltration had better outcomes. They reviewed this evidence in support of the immune system's central role as a barrier to tumor formation.
3. Tumor-Promoting Inflammation: In 2011, they also identified tumor-promoting inflammation as a new enabling characteristic. Immune cell infiltration into tumors had historically been regarded as a sign of an immune response against them, but the second publication clarified the tumor-promoting effects of certain inflammatory cells. It examined how inflammation supports many hallmarks by providing growth, survival and proangiogenic factors and releasing chemicals such as reactive oxygen species that can cause further mutations in nearby cancer cells. It also included a paragraph on the tumor microenvironment (TME), which became the subject of extensive research over the following decade, showing that tumor biology must be studied by considering both cancer cells and the microenvironment they create around them.
4. Genomic Instability and Accumulating Mutations: Accumulation of DNA damage is the most important cause of cancer development. Loss of function in enzymes responsible for DNA repair also promotes further disruption of gene structure.

2022: Expanding the Boundaries of Cancer Biology—New Hallmarks

After 10 years, Hanahan again focused on cancer hallmarks, considering the substantial advances enabled by big data and reaffirming the framework's influence in conceptualizing discoveries, to “help turn this complexity into an increasingly logical science.” In the latest paper, the two hallmarks emerging in 2011 were firmly established as hallmarks because research over the preceding 10 years had largely confirmed the importance of metabolic reprogramming and evading immune destruction. Hanahan also proposes further emerging hallmarks:

1. Phenotypic Plasticity and Disrupted Differentiation: Terminal differentiation in normal cells is associated with permanently stopping proliferation. Increasing evidence suggests that cancer cells evade differentiation and unlock “phenotypic plasticity” to keep growing. In other words, they can change their identity into something more prone to proliferation. This can occur in different ways:
   • Cells approaching full differentiation can dedifferentiate.
   • Cancer cells originating from an undifferentiated cell can halt differentiation and remain in a partially differentiated, stem-cell-like state.
   • Cells committed to one differentiation type can change developmental programs or differentiate to acquire traits unrelated to their stem cells.

Hanahan says that, like other hallmarks, cellular plasticity is not something cancer cells have “newly invented.” Rather, it involves cancer-associated changes to existing mechanisms that certain normal cells can activate to repair and regenerate normal tissues.

2. Nonmutational Epigenetic Reprogramming: Epigenetics means beyond genetics and studies how genes behave and are regulated. Epigenetic mechanisms do not alter DNA or gene structure but determine whether a gene is active; gene expression therefore changes without a mutation. The best-known epigenetic changes are DNA methylation and histone modification. Global changes in the epigenetic landscape are recognized as a common feature of many cancers. Cancer cells can reprogram gene networks through epigenetic mechanisms to support their development.
3. The Microbiome: Our bodies are colonized by a wide variety of microorganisms living in and on us, approximately 40 trillion cells. Their profound contributions to human health and disease are now better understood. Researchers have found, for example, that some can have protective or harmful effects on cancer development, progression and treatment response.
4. Senescent Cells: This new paper on the 14 hallmarks of cancer also emphasizes the importance of senescent cells as contributors to the tumor microenvironment. In the 2000 paper, when the authors examined senescence as a barrier to cancer medicines, they did not consider the possibility of it being a pile of cellular fragments rather than a real cell. More than twenty years later, the role of cellular senescence in tissue homeostasis and cancer is well understood, and important associated morphological and metabolic characteristics have been identified. Research has also shown how senescent cells can promote tumor development and carcinogenesis in certain contexts. Hanahan therefore suggests including senescent cells as important components of the tumor microenvironment.

• Related topic: How does an aging microenvironment support cancer development and progression?

In closing, Hanahan says that although some hallmarks are now well established, the newest additions proposed as emerging hallmarks are intended as “trial balloons” to stimulate debate in the cancer research community and inspire further research to improve our understanding of cancer biology.

Here is to many more discoveries in the next decade…