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Studying hallmarks of cancer

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                      ​Find the key markers and tools you need to study the hallmarks of cancer

                      Reviewed December 14 2020

                      In early 2000, Professors Hanahan and Weinberg proposed that when cells progress towards a neoplastic state, they acquire distinctive capabilities1. These were termed hallmarks of cancer and formed a useful framework in which to understand tumor pathogenesis. They include sustaining proliferative signaling, evading growth, suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. There were all underpinned by genome instability and mutation.

                      Later in 2011, they published an update to reflect advances in understanding, and to include reprogramming of energy metabolism, avoiding immune destruction, tumor-promoting inflammation, and evading immune destruction2.

                      Here we provide the relevant markers and tools to study these important hallmarks of cancer.

                      • Genome instability and mutation
                      • Enabling replicative immortality
                      • Evading growth suppressors
                      • Cell death
                      • Reprogramming energy metabolism
                      • Angiogenesis
                      • Avoiding immune destruction
                      • Tumor-promoting inflammation
                      • Sustaining proliferative signaling
                      • Activation of invasion and metastasis



                      Genome instability

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

                      Mechanism            Key markersFunction
                      Nucleotide excision repairERCC1-XPFERCC1 – XPF is an essential endonuclease for DNA damage repair. It is also involved in DNA interstrand crosslink and double-strand break repair.
                      XPAXPA is a Zinc finger protein responsible of DNA damage repair.
                      TFIIDTFIID is a complex that binds to the TATA box in the core promoter of the gene.
                      Base excision repairAPEX1/APEX2APEX are nucleases involved in DNA repair.
                      PNKPPNKP catalyzes 5’- kinase and 3’ – phosphatases activity
                      FEN1FEN1 is an endonuclease that removes 5’ overhanging flaps in DNA repair.
                      Double-strand break (DSB) repairGamma H2AXGamma H2AX is a component of histone octamer in the nucleosome. It is phosphorylated in DNA damage.
                      XRCC4                  XRCC4 functions together with DNA ligase IV and DNA dependent protein kinase to repair DNA DSB.
                      BRCA1                              BRCA genes are one of the widely studies tumor suppressor proteins that regulate DNA repair and cell cycle
                      53bp153bp1 binds to damaged chromatin and promotes DNA repair.
                      Kap1Kap1 is a key regulator of normal development and differentiation.
                      DNA mismatch repairMsh2/Msh6Msh2 and Msh6 form MutSα which binds to the site of mismatch base.
                      Msh2/Msh3Msh2 and Msh3 form MutSβ which participates in insertion/deletion loop repair.
                      PMS2Forms heterodimers with MLH1 to form MutLα.


                      ​
                      Enabling replicative immortality

                      Tumor cells can achieve unlimited replicative potential either by synthesizing high levels of telomerase enzyme 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 along with signaling pathways such as Wnt and HIPPO.

                      ​

                      MechanismKey markersFunction
                      Telomere maintenance and regulationhTERThTRET is the major component of telomerase activity. Telomerase has been identified as a diagnostic marker for various types of cancer.
                      TRF1/TRF2/POT1/
                      ​
                      TIN2/RAP1/TPP1
                      The Shelterin complex is a core of six proteins integral for telomere function.
                      p53 signalingTP53 (p53)p53 is called the “guardian of the genome” is the key regulator of gene expression.
                      MDM2MDM2 is a proto-oncogene and plays an important p53 regulation. It is the primary inhibitor of p53 transcriptional activation. MDM2 activity is tightly controlled by post-translational modifications. 
                      p14ARF/p19ARFp14ARF is a tumor suppressor gene that binds to the MDM2-p53 complex and prevents degradation of p53.
                      E2F-1E2F-1 is the transcription factor of the p53 pathway that regulates by initiating transcription of p14ARF.



                      Evading growth suppressors

                      To overcome growth inhibition from normal homeostatic signals, cancer cells lack response to external growth-inhibitory signals. Autophagy and apoptotic control are resisted by cancer cells. Both of these processes allow 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 these pathways include Bcl-2 and Caspases in apoptosis and proteasomal and lysosomal pathways, such as MAPK, ATG, and p62, in autophagy.


                      MechanismKey markersFunction
                      Tumor suppressorsRb1Retinoblastoma regulates the cell cycle and plays important role in cellular differentiation.
                      TP53 (p53)p53 is called the “guardian of the genome” is the key regulator of gene expression. It is also an established marker for cancer diagnosis.
                      APCAPC regulates tumor growth by suppressing Wnt signaling. It also plays an important role in cell adhesion and migration.
                      BRCA1,  BRCA2BRCA is one of the widely studies tumor suppressor proteins that regulate DNA repair and cell cycle
                      PTENPTEN is a key regulator of cellular activities. It regulates PI3K-AKT-mTOR signaling through its lipid phosphatase activity.
                      WT1, WT2Wilms tumor protein is a transcription factor important for normal cellular development and survival. WT1 plays both oncogenic role and tumor suppressor.
                      NF1, NF2Neurofibromin is a tumor suppressor that negatively regulates the Ras pathway.



                      Cell death

                      This 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 prevent 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.

                      See our guide to apoptosis

                      Autophagy has an important role in allowing cells to survive in response to multiple stress conditions. Tumor cells exploit this autophagic mechanism as a way to overcome nutrient-limiting conditions and facilitate tumor growth. Autophagy can modulate the tumor microenvironment by promoting angiogenesis, supply nutrients, and modulate the inflammatory response. 

                      See our guide to autophagy

                      Caspase-8, Bcl-2 and, p53 are among key apoptotic signaling proteins that are known to be mutated in many cancers.​


                      Reprogramming energy metabolism

                      Due to their excessive growth, cancer cells require high levels of energy and nutrients with the ability to survive in hypoxic environments, as they are not completely vascularized. To meet these needs, many of the cellular metabolic pathways are altered in cancer. The Warburg effect concerns the altered glycolytic metabolism that occurs in cancer cells, where pyruvate is diverted from the Krebs cycle to lactate production under oxygen conditions. Cancer cells are also known to increase glutamine metabolism to promote cell proliferation.

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

                      MechanismKey markerFunction
                      HypoxiaHIF1α/ HIF2a / HIF1βHIF is a heterodimeric DNA binding transcription factor that regulates a broad range of cellular systems to hypoxia.
                      CAIXCAIX is a mediator of hypoxia-induced stress response in a cancer cell.
                      AP-1/c-junThe AP-1 transcription factor family is known to play an important role in tumor progression and development.
                      GLUT-1GLUT1 levels can be elevated in hypoxia and can be used to indicate the degree of hypoxia.
                      GlycolysisTomm20TOMM20 and GAPDH have been shown to be upregulated in various types of cancer and it is necessary to metabolize glutamine.
                      V-ATPaseV-ATPase expression is shown to be upregulated in cancer cells.
                      GAPDHGAPDH and Tom20 have been shown to be upregulated in various types of cancer and can be used as a marker.
                      Mitochondrial metabolismCOX IVCOX IV is used as a marker for the inner mitochondrial marker.
                      VDAC1/PorinVDAC1/Porin is used as a marker for the outer mitochondrial marker.
                      ATPase BetaBeta subunit has a crucial role in the structural and functional maturation of Na+/K+-ATPase.



                      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, such as VEGF, fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF), is known to play a significant role in promoting angiogenesis of the tumor.

                      Learn more about the role of VEGF in angiogenesis

                      Avoiding immune detection

                      The human immune system protects against foreign pathogens and diseases, but it also plays a very important role in clearing the body’s own unhealthy and ailing cells. As such, the immune system is also capable of recognizing and eliminating cancer cells.

                      T cells have the capacity to selectively recognize and kill pathogens or unhealthy cells by orchestrating a coordinated immune response that encompasses but the 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.

                      Here we outline various strategies used in immunotherapy

                      See our pathway that outlines the 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 that are 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.


                      MechanismKey markerFunction
                      NF-κB signalingNF-κBNF-κB is a transcription factor that plays an important role in the regulation of cytokines. Dysregulation of NF-κB is linked to inflammatory, autoimmune diseases, and cancer.
                      IKK BetaIKK beta is part of the IKK complex which is a negative regulator of transcription factor NF-κB.
                      Tumor-associated macrophagesCD68CD68 is a key marker to recognize both M1 and M2 macrophages in tumor tissue.
                      CD163CD163 is a scavenger receptor upregulated in macrophages in an anti-inflammatory environment.
                      iNOSiNOS is one of the major markers of M1 tumor-associated macrophages.


                      Sustaining proliferative signaling

                      Normal cells depend on the growth signaling of a tightly-regulated cell cycle to proliferate and maintain tissue homeostasis. This cycle is disrupted in cancer. Cancer cells release and respond to their own growth factors to stimulate growth, overcoming the requirement for external growth factors, such as epidermal growth factor (EGF/ EGFR).

                      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 insult, 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.​

                      For a look at the most common methods to mark and score cell proliferation see our guide.

                      ​


                      Activation of invasion and metastasis

                      Tissue invasion is the process that allows 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.

                      Both of 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.


                      MechanismKey markerFunction
                      ECMHyaluronanHyaluronan is a glycosaminoglycan found in the extracellular matrix (ECM). HA is dramatically increased in most malignancies.
                      VersicanVersican is either expressed by cancer cells or stromal cells and plays a wide role in invasion and metastasis.
                      Collagen IVCollagen IV is essential for tumor angiogenesis by modulating cell growth and proliferation.
                      Adhesion moleculesCEACAM1CEACAM1is down-regulated in several cancers. L-Form CEACAM1 has tumor suppressive function and dysregulation is found in the early carcinogenic process.
                      DCCDCC is a transmembrane receptor for netrins. It promotes apoptosis in the absence of netrin ligands.
                      E-CadherinE-Cadherin regulates morphogenic processes like cell-cell recognition, cytoskeleton regulation, and surface adhesion.
                      Secreted factorsTenascin CTenascin C interacts with ECM proteoglycans it can interfere with tumor suppressor activity of fibronectin.
                      FibrinogenFibrin deposits occur in the stroma of many cancer types and affect the progression of tumor cells
                      PeriostinPeriostin is a secreted adhesion-related protein expressed in the periosteum and periodontal ligaments and plays a role in tumorigenesis.

                      References

                      1.  Hanahan, D. & Weinberg, R. A. The Hallmarks of Cancer. Cell 100, 57–70 (2000).

                      ​2.  Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell 144, 646–674 (2011).

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