Hallmarks of Cancer
In 2000, Douglas Hanahan and Robert Weinberg published the paper ‘The hallmarks of cancer’, conceptualizing six core rules which orchestrate the multistep transformation of normal cells into malignant cells. More than 20 years later, in the third update, ‘Hallmarks of cancer: new dimensions’, these six original hallmarks have expanded to 14. These hallmarks outline a set of criteria that explain how normal cells can develop into malignant tumors by identifying specific characteristics and describing how they interact with one another. These characteristics include: sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, limitless replicative potential, angiogenesis, and genomic instability. Together, these hallmarks allow cancer cells to evade the normal controls that regulate cell growth and division, enabling them to continue to divide and proliferate, forming a tumor that can invade nearby tissues and spread to other parts of the body. Below, you may find a summary of the respective hallmarks, as well as related resources (e.g. pathway illustrations) and research tools (i.e. antibodies, ELISA kits, recombinant proteins).
Hallmarks of Cancer
- Sustaining Proliferative Signaling
- Evading Growth Suppressors
- Resisting Cell Death
- Tumor Promoting Inflammation
- Enabling Replicative Immortality
- Senescent Cells
- Deregulating Cellular Metabolism
- Avoiding Immune Destruction
- Inducing or Accessing Vasculature
- Activating Invasion & Metastasis
- Unlocking Phenotypic Plasticity
- Genome Instability & Mutation
- Nonmutional Epigenetic Reprogramming
- Polymorphic Microbiomes
1. Sustaining Proliferative Signaling
The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. This refers to the ability of cancer cells to activate signaling pathways that promote cell growth and division. Normally, these pathways are tightly regulated, but in cancer cells, they are constantly activated, allowing the cells to continue to divide and proliferate even in the absence of normal growth signals. This can be the result of mutations in genes that encode proteins involved in these signaling pathways, leading to the activation of downstream signaling molecules that promote cell growth.
2. Evading Growth Suppressors
A highly complementary hallmark capability for sustaining proliferative signaling in cancer cells is the ability to evade growth suppression. Growth suppressor genes normally function to inhibit cell growth and division. Several tumor-suppressive protein-coding genes that operate in diverse ways to inhibit cellular growth and proliferation had been discovered. Prominent examples are the retinoblastoma protein (RB) or the human tumor suppressor p53. The transcription factor regulates the expression of genes involved in cell cycle control, induction of apoptosis, or DNA repair after DNA damage. In cancer cells, these genes are often inactivated, either through mutations that disable their function or by mechanisms that prevent them from being expressed. This allows cancer cells to avoid the normal constraints on cell growth and division, enabling them to continue to proliferate unchecked.
3. Resisting Cell Death
In addition to evading growth suppressors, cancer cells also have a high degree of resistance to cell death. Normally, cells undergo programmed cell death, or apoptosis, when they become damaged or no longer needed. The cancer cells may alter the mechanisms that detect the damage or irregularities, preventing proper signaling and apoptosis activation. Cancer cells may also introduce defects in the downstream signaling itself or the proteins involved, which would also prevent proper apoptosis. This can be the result of mutations in genes that regulate the apoptotic pathway, or it can be due to the activation of signaling pathways that promote cell survival.
4. Tumor Promoting Inflammation
Inflammation predisposes the development of cancer and promotes all stages of tumorigenesis. Pathways evolved to mediate immunity to infection and promote tissue homeostasis and are usurped by tumors for their benefit. Cancer cells, as well as surrounding stromal and inflammatory cells, form an inflammatory tumor microenvironment (TME). Additionally, inflammation induces the release of growth factors that support tumor growth.
There are several mechanisms of which the initial inflammatory responses may be induced. Examples are carcinogenic microbes, environmental pollutants, and low-grade inflammation associated with obesity, as well as epithelial barrier deterioration associated with commensal microorganisms. The timing of cancer-associated inflammation is variable as well. Relevant causes and stimuli are autoimmunities, infections, or malignant cells. The inflammation can even be triggered by anti-cancer therapy itself.
5. Enabling Replicative Immortality
The potential to replicate without limitation is another key aspect of tumor development, which is also recognized as a hallmark of cancer. In contrast to human body cells, cancer cells can overcome the ‘Hayflick Limit’ and divide indefinitely, without undergoing the normal process of cellular aging. Normally cells entering the state of senescence or cell death, stop replication. This is mainly 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 the enzyme telomerase to increase the length of telomeres. Thus, they can divide indefinitely without initiating senescence.
6. Senescent Cells
Senescence can be induced in cells by a variety of conditions, including microenvironmental stresses such as nutrient deprivation and DNA damage, as well as damage to organelles and cellular infrastructure and imbalances in cellular signaling networks.
Cellular senescence has long been considered a protective mechanism against tumors whereby cancerous cells are induced to undergo senescence. The majority of triggers mentioned above are associated with malignancy —particularly DNA damage, as a consequence of aberrant hyperproliferation, also known as oncogene-induced senescence due to hyperactivated signaling. However, new publications question this linear relationship. In certain contexts, senescent cells variously stimulate tumor development and malignant progression. The principal mechanism by which senescent cells promote tumor phenotypes is thought to be via senescence-associated secretory phenotypes (SASP).
7. Deregulating Cellular Metabolism
For unhindered growth, tumors not only benefit from deregulated control of cell proliferation, but also corresponding adjustments of energy metabolism to fuel cell growth and division. They can modify or reprogram cellular metabolism to efficiently support neoplastic proliferation. Under aerobic conditions, normal cells process glucose first to pyruvate via glycolysis in the cytosol and secondly to carbon dioxide in the mitochondria. Under anaerobic conditions, glycolysis is favored, and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria. Otto Warburg was the first to observe an anomalous characteristic of cancer cell energy metabolism.
8. Avoiding Immune Destruction
Some cancer cells adapt mechanisms to evade both immune surveillance and attack by the host's immune system. One way cells do this is by hijacking normal mechanisms of immune checkpoint control. Immune checkpoints refer to the built-in control mechanisms of the immune system that maintain self-tolerance and help to avoid collateral damage during a physiological immune response. Tumor-specific T cells must discriminate between the destruction of the tumor cell and the survival of the target cell. What is important for discrimination are proteins on both the T-cell and the target cell. Tumor cells express molecules to induce apoptosis or to inhibit T lymphocytes, for example, PD-L1 on the surface of tumor cells leads to suppression of T lymphocytes. FasL, on the other hand, may induce apoptosis of T lymphocytes. Some cancer cells also try to gain resistance against possible cytotoxic CD8+ T cells which are a fundamental element of anti-tumor immunity. They lower their MHC I expression and avoid being detected by the cytotoxic T cells. Disruption of the apoptotic signal pathway molecules also leads to successful immune evasion by the tumor. Caspase 8, Bcl-2, or IAP are key targets, among others.
9. Inducing or Accessing Vasculature
An expanding tumor has an increased need for nutrients to sustain its growth and spread. The tumor requires new blood vessels to deliver adequate oxygen to the cancer cells. To do this, the cancer cells acquire the ability to undergo angiogenesis, the process of forming new blood vessels. Cancer cells orchestrate the production of new vasculature by releasing signaling molecules that activate the 'angiogenic switch'. By exploiting the switch, non-cancerous cells that are present in the tumor are stimulated to form blood vessels.
10. Activating Invasion & Metastasis
The ability to invade neighboring tissues is what dictates whether the tumor is benign or malignant, and it renders cancer a mortal threat. Metastasis enables their dissemination around the body and complicates treatment by a large margin. The cancer cells must undergo a multitude of changes in order for them to acquire the ability to metastasize. The metastatic cascade represents a multi-step process that includes local tumor cell invasion, invasion of blood vessels followed by the exit of carcinoma cells from the circulation, and colonization in the new tissue. At the earliest stage of successful cancer cell dissemination, primary cancer adapts to the secondary site of tumor colonization involving the tumor-stroma crosstalk.
11. Unlocking Phenotypic Plasticity
Relative to the immense differentiation and development that takes place during organogenesis, mammalian cells usually have limited capacity for differentiation, ensuring that they remain organized and functional within their respective tissues. However, in cancer, cells undergo molecular and phenotypic changes that enable them to take on different identities along a phenotypic spectrum, which is known as cellular plasticity. The epithelial–mesenchymal transition (EMT) and mesenchymal-to-epithelial (MET) transitions are examples of developmental regulatory programs that resemble transdifferentiation. Alterations in cellular phenotype are crucial to cancer progression because they can facilitate tumor initiation and metastasis, immune invasion, chemoresistance, and numerous other aspects of tumor progression.
12. Genome Instability & Mutation
Genomic instability and thus mutability impose cancer cells with genetic alterations that drive tumor progression. Certain mutant genotypes give subclones of cells a selective advantage and enable them to spread and eventually dominate in a local tissue environment. The genome repair machinery in mammalians detects and resolves defects in the DNA and ensures that rates of spontaneous mutation are low during each cell generation. In order to increase the number of mutant genes needed to orchestrate tumorigenesis, cancer cells try to increase the rates of mutation. Increased sensitivity to mutagenic agents and breakdown of the genomic maintenance machinery in several components are main drivers to increase the mutability. Defects in the DNA-maintenance machinery—often referred to as the ‘caretakers’ of the genome—positively correlate with human cancer development. The so-called ‘guardian of the genome’, p53, plays the central role in the machinery along with telomerase.
13. Nonmutional Epigenetic Reprogramming
In the big picture of hallmarks of cancer, ‘nonmutational epigenetic reprogramming’ is viewed as an emerging characteristic. It is an additional—apparently independent—mode of genome reprogramming that involves purely epigenetically regulated changes in gene expression. Epigenetic alterations can be summarized as changes in gene and histone modifications, chromatin structure, and the triggering of gene expression switches that are stably maintained over time by positive and negative feedback loops. They regulate gene expression in developmental and adult cells. Growing evidence supports the proposition that analogous epigenetic alterations can contribute to the acquisition of hallmark capabilities during tumor development and malignant progression.
Nonmutational epigenetic reprogramming is key for enabling the hallmark capability of phenotypic plasticity mentioned above. The epigenetic reprogramming results in dynamic transcriptomic heterogeneity, a feature of cancer cells populating malignant TMEs. ZEB1, master regulator of the EMT, is a good example for nonmutational epigenetic reprogramming. It induces expression of a histone methyltransferase, SETD1B, that in turn sustains ZEB1 expression in a positive feedback loop that maintains the (invasive) EMT regulatory state. Similarly, upregulation of the transcriptions factor SNAIL1 due to chromatin landscape alterations induces EMT build up. The chromatin modifiers responsible for the alterations are demonstrably necessary for the maintenance of the phenotypic state.
14. Polymorphic Microbiomes
As studies mount, there is more and more evidence that the ecosystems created by resident bacteria and fungi—the microbiomes—have profound effects on health and disease. The gut microbiome has been the pioneer of this new frontier as multiple tissues and organs have associated microbiomes with distinctive characteristics in regard to population dynamics and diversity of microbial species and subspecies. In relation to cancer, there is increasingly strong evidence that polymorphic variability in the microbiome between individuals in a population can influence the cancer phenotype. Microorganisms, principally—but not exclusively—bacteria, may be directly carcinogenic. They also impact host immune responses to promote malignancy and may be key effectors in determining the efficacy of anticancer therapy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
Butyrate-producing bacteria are an example for specific bacterial species promoting tumorigenesis. Studies indicated that mouse models and patients with colon carcinogenesis populated with butyrate-producing bacteria, developed more tumors than mice lacking such bacteria. The production of the metabolite butyrate has complex physiologic effects, including the induction of senescent epithelial and fibroblastic cells.
Further Reading