The hallmarks of cancer.

Genome instability and mutation

Cancer cells are highly proliferative. This feature means that these cells have an increased tendency for genomic changes and mutations that affects cell division and tumor suppression genes. This instability promotes further cancerous adaptations in cells. Changes may arise through direct DNA mutations or epigenetic modifications that can alter protein expression levels and affect genomic integrity.

Precision cancer therapies have been targeted to checkpoint kinases of the cell cycle, such as Chk1 and Chk2 proteins, and DNA damage repair enzymes, such as BRCA and 53BP1.

Enabling replicative immortality

Tumor cells can achieve unlimited replicative potential by synthesizing high telomerase enzyme levels or via a recombination-based mechanism. This prevents telomere shortening, which leads to senescence and apoptosis. However, many cancer cells have been shown to possess short telomeres.

Key targets include the telomere maintenance machinery and signaling pathways, such as Wnt and Hippo.

If you need a cell proliferation or cell cycle assay, please refer to our in-depth guide.

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Evading growth suppressors

To overcome growth inhibition from normal homeostatic signals, cancer cells lack response to external growth-inhibitory signals. Cancer cells resist apoptotic control that allows tight control over cell death and proliferative cell growth.

Apoptosis allows the removal of cells undergoing excessive proliferation to limit cell number and remove diseased cells, while autophagy is a cellular recycling system that removes abnormal proteins and cytoplasmic contents and promotes regeneration. Cancer cells resist apoptotic signaling to prevent cell death and promote autophagy to increase growth and overcome nutrient-limiting conditions.

Key targets for the apoptosis pathways include Bcl-2 and Caspases.

Resisting cell death

The resisting cell death hallmark refers to cancer cells preventing apoptosis through intrinsic mechanisms rather than a lack of response to external stimuli. Cancer cells may contain mutations that prevent damage detection or apoptotic signaling within the cell.

Apoptosis is characterized by several features, including cell shrinkage, membrane blebbing, chromosome condensation (pyknosis), nuclear fragmentation (karyorrhexis), DNA laddering, and the eventual engulfment of the cell by phagosomes.

Autophagy is essential in allowing cells to survive in response to multiple stress conditions. Tumor cells exploit this autophagic mechanism to overcome nutrient-limiting conditions and facilitate tumor growth. Autophagy can modulate the tumor microenvironment by promoting angiogenesis, supplying nutrients, and modulating the inflammatory response.

Caspases, Bcl-2, and p53 are among the key apoptotic signaling proteins frequently downregulated, mutated, or bypassed in cancer cells. Key autophagy targets include proteasomal and lysosomal pathways, such as MAPK, ATG, and p62.

To learn more about apoptosis, check out our resources: our in-depth guide to apoptosis, apoptosis in cancer signaling poster, and our protocol for induction of apoptosis in cells.

To learn more about autophagy, see our guide to autophagy.

Deregulating cellular metabolism

Due to their excessive growth, cancer cells require high levels of energy and nutrients with the ability to survive in hypoxic environments, as tumors can be poorly vascularized. To meet these needs, many of the cellular metabolic pathways are altered in cancer. The Warburg effect concerns the altered glycolytic metabolism in cancer cells, where pyruvate is diverted from the Krebs cycle to lactate production under oxygen conditions. Cancer cells can also increase glutamine metabolism to promote cell proliferation.

Key targets for controlling the hypoxic tumor environment include HIF-1α and AMPK, which switches to a tumor promoter acting to protect against metabolic, oxidative, and genotoxic stress.

To find the right assay for studying metabolism, explore our cellular metabolism assays.

Inducing angiogenesis

Growth of the vascular network is important for metastasis as cancer cells require a sufficient supply of nutrients and oxygen, as well as a means of waste removal. This is achieved by angiogenesis and lymphangiogenesis, respectively.

Aberrant growth factor signaling ligands, such as VEGF, fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF), play a significant role in promoting tumor angiogenesis.

Avoiding immune detection

The human immune system protects against foreign pathogens and diseases, but it also plays an important role in clearing the body’s unhealthy and ailing cells. As such, the immune system can also recognize and eliminate cancer cells.

T cells can selectively recognize and kill pathogens or unhealthy cells by orchestrating a coordinated immune response that encompasses innate and adaptive responses.

Immune checkpoint targets, such as PD1/PD-L1, TIM3, and LAG3, are all critical checkpoint molecules that have revolutionized cancer immunotherapy.

Explore our resources on cancer immunotherapy: an overview of various strategies used in immunotherapy, and our immune checkpoint pathway.

Tumor-promoting inflammation

Signaling within the tumor microenvironment (TME) operates to hijack the immune cells to promote tumor survival. The immune cells in the TME secrete factors that allow growth and metastasis rather than recognizing and destroying the cancerous cells.

Important inflammatory mechanisms corrupted by the tumor include NF-κB, immune checkpoint signaling, and inflammasome signaling. The inflammasome promotes the cleavage of caspase-1 and subsequent cleavage of pro-inflammatory cytokines IL-1β and IL-18.

Sustaining proliferative signaling

Normal cells depend on tightly-regulated cell cycle control to proliferate and maintain tissue homeostasis. This cycle is disrupted in cancer. Cancer cells release and respond to growth factors to stimulate growth, such as epidermal growth factor (EGF/ EGFR signaling).

This self-sufficiency in cell proliferation is driven via three main signaling pathways: Akt, MAPK/ERK, and mTOR.

Cell proliferation can be used to assess normal cell health, to measure responses to toxic insults, or as a prognostic and diagnostic tool in several cancers. The available markers typically look at DNA levels or synthesis, cellular metabolism, or proliferation-specific proteins.

Activating invasion and metastasis

Tissue invasion is the process of allowing tumor cells to expand into nearby tissues. Metastasis is the process of tumor cells migrating from the primary tumor site to a new distant location and establishing secondary tumors. The well-documented epithelial-to-mesenchymal transition is a key process in these mechanisms, allowing uninhibited cell division and metabolic adaptations that enable cell survival under nutrient-limiting and stress conditions.

These cancer mechanisms involve extensive changes to cell-cell and cell-matrix interactions and cellular transformation to allow invasion and migration, including targets such as Collagen and CEACAM1.

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