Cancer

In 2000, Douglas Hanahan and Robert Weinberg published the paper ‘The hallmarks of cancer’, conceptualising 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 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.

Sustaining Prolifeerativae 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.

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 are type of gene that 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 (programmed cell death) 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.

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 in apoptosis, 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.

Tumor Promoting Inflammation

Limitless Replicative Potential

The potential to replicate without limitation is another key aspect in tumor development which is also recognized as 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.

Senescent Cells

Cellular senescence is a typically irreversible form of proliferative arrest, likely evolved as a protective mechanism for maintaining tissue homeostasis, ostensibly as a complementary mechanism to programmed cell death that serves to inactivate and in due course remove diseased, dysfunctional, or otherwise unnecessary 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. Majority of triggers mentioned above are associated with malignancy, particularly DNA damage as a consequence of aberrant hyperproliferation, so-called 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).

Deregulating Cellular Metabolsim

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 have the capability to modify, or reprogram, cellular metabolism to support neoplastic proliferation most effectively. Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter 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 first observed an anomalous characteristic of cancer cell energy metabolism.

Avoiding Immune Destruction

Some cancer cells adapt mechanisms to evade 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 destruction of the tumor cell and survival of the target cell. 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: 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 cell 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, amongst others.

Sustained Angiogenesis

An expanding tumor has an increased need for nutrients to sustain his 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 orchestrates 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.

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 complicates treatment by a big 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 which 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, the primary cancer adapts the secondary site of tumor colonization involving the tumor-stroma crosstalk.

Cytokeratins in Tumor Detection

Unlocking Phenotypic Plasticity

Relative to the huge amount of development and differentiation that occurs during organogenesis, mammalian cells are typically restricted in the extent to which they can differentiate. This restriction allows cells to remain organized and functional within their respective tissue. In cancer, however, cells undergo molecular and phenotypic changes that allow them to adopt different identities along a phenotypic spectrum referred to as cellular plasticity. This includes dedifferentiation from mature to progenitor states, blocked differentiation from progenitor cell states, and transdifferentiation into different cell lineages. The EMT and mesenchymal-to-epithelial (MET) transitions are well-characterized examples of developmental regulatory programs that resemble transdifferentiation. Changes in cellular phenotype are important to cancer progression because these changes can facilitate tumor initiation and metastasis, immune invasion, chemoresistance and many other aspects of tumor progression.

Genome Instability & Mutation

Genomic instability and thus mutability endow 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 usually very 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, so does telomerase.

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. Changes in gene and histone modification, in chromatin structure, and in the triggering of gene expression switches that are stably maintained over time by positive and negative feedback loops are summarized as epigenetic alterations. 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 alterions are demonstrably necessary for the maintenance of the phenotypic state.

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, multiple tissues and organs have associated microbiomes, which have 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, 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 as well as 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.