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Studying hallmarks of cancer

The tools and techniques you need to study the hallmarks of cancer

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

Escaping cell death

Reprogramming energy metabolism

Angiogenesis

Avoiding immune destruction

Tumor-promoting inflammation

Sustaining proliferative signaling

Activating of invasion and metastasis

Hallmarks of Cancer



Genome instability and mutation

Mechanism            

Key markers

Function

Nucleotide excision repair


ERCC1-XPF

ERCC1 – XPF is an essential endonuclease for DNA damage repair. It is also involved in DNA interstrand crosslink and double-strand break repair

XPA

XPA is a Zinc finger protein responsible of DNA damage repair

TFIID

TFIID is a complex that binds to the TATA box in the core promoter of the gene.

Base excision repair

APEX1/ APEX2

APEX are nuclease involved in DNA repair containing endonuclease, exonuclease, diesterase and phosphatase activities.

PNKP

PNKP catalyzes 5’- kinase and 3’ – phosphatases activity

FEN1

FEN1 is an endonuclease that removes 5’ overhanging flaps in DNA repair

Double strand break (DSB) repair

Gamma H2AX

Gamma H2AX is a component of histone octomer in 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 regulates DNA repair and cell cycle

53bp1

53bp1 binds to damaged chromatin and promotes DNA repair.

Kap1

Kap1 is a key regulator of normal development and differentiation

DNA mismatch repair

Msh2/ Msh6

Msh2 and Msh6 form MutSα which binds to the site of mismatch base.

Msh2/Msh3

Msh2 and Msh3 form MutSβ which participates in insertion/deletion loop repair

PMS2

Forms heterodimers with MLH1 to form MutLα









Enabling replicative immortality

Mechanism

Key markers

Function

Telomere maintenance and regulation

hTERT

hTRET is the major component of telomerase activity. Telomerase has been identified as 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 signaling

TP53 (p53)

p53 is called the “guardian of the genome” is the key regulator of gene expression.

MDM2

MDM2 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/p19ARF

p14ARF is a tumor suppressor gene that that binds to the MDM2-p53 complex and prevent degradation of p53.

E2F-1

E2F-1 is the transcription factor of the p53 pathway that regulates by initiating transcription of p14ARF.

   


Evading growth suppressors

Mechanism

Key markers

Function

Tumor suppressors

Rb1

Retinoblastoma regulates 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

APC

APC regulates tumor growth by suppressing Wnt signaling. It also plays an important role in cell adhesion and migration.

BRCA1,  BRCA2

BRCA are one of the widely studies tumor suppressor proteins that regulates DNA repair and cell cycle

PTEN

PTEN is a key regulator of cellular activities. It regulates PI3K-AKT-mTOR signaling through its lipid phosphatase activity.

WT1, WT2

Wilms tumor protein is a transcription factor important for normal cellular development and survival. WT1 plays a both oncogenic role and tumor suppressor.

NF1, NF2

Neurofibromin is a tumor suppressor that negatively regulates Ras pathway.

    


Escaping cell death

Apoptosis is characterized by several features, including cell shrinkage, membrane blebbing, chromosome condensation (pyknosis), nuclear fragmentation (karyohexis), 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 inflammatory response. 

See our guide to autophagy



Reprogramming energy metabolism

Mechanism

Key marker

Function

Hypoxia

HIF1α/ HIF2a /  HIF1β

HIF is a heterodimeric DNA binding transcription factor that regulate broad range of cellular systems to hypoxia.

CAIX

CAIX is a mediator of hypoxia-induced stress response in cancer cell.

AP-1


GLUT-1

GLUT1 levels can be elevated in hypoxia and can be used to indicate the degree of hypoxia.

Glycolysis

Tomm20

TOM20 and GAPDH have been shown to be upregulated in in various types of cancer and it is necessary to metabolize glutamine

V-ATPase

V-ATPase expression is shown to be upregulated in cancer cells.

GAPDH

GAPDH and Tom20 have been shown to be upregulated in in various types of cancer and can be used as marker

Mitochondrial metabolism

COX IV

COX IV is used as a marker for the inner mitochondrial marker

VDAC1/Porin

VDAC1/Porin is used as a marker for outer mitochondrial marker

ATPase Beta

Beta 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 requires a sufficient supply of nutrients and oxygen, as well as a means of waste removal. This is achieved by angiogenesis and lymphangiogenesis, respectively.

Growth factors, such as VEGF, play a pivotal in angiogenesis, while several other angiogenic factors are linked to tumor aggressiveness.

Learn more about the role of VEGF in angiogenesis.



Avoiding immune destruction

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.

Here we outline various strategies used in immunotherapy

See our pathway that outlines the immune checkpoint pathway



Tumor-promoting inflammation

Mechanism

Key marker

Function

NF-κB signaling

NF-κB

NF-κB is a transcription factor play an important role in regulation of cytokines. Dysregulation of NF-κB is linked to inflammatory, autoimmune diseases, and cancer

IKK Beta

IKK beta is part of the IKK complex which is a negative regulator of transcription factor NF-κB.

Tumor associated macrophages

CD68

CD68 is a key marker to recognize both M1 and M2 macrophages in tumor tissue

CD163

CD163 is a scavenger receptor upregulated in macrophages in an anti-inflammatory environment

iNOS

iNOS is one of the major markers of M1 tumor associated macrophages.



Sustaining proliferative signaling

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 recent guide




Activating of invasion and metastasis

Mechanism

Key marker

Function

ECM

Hyaluronan

Hyaluronan is glucoseaminoglycan found in the extracellular matrix (ECM). HA is dramatically increased in most malignancies

Versican

Versican is either expressed by cancer cell or stromal cells and plays a wide role in invasion and metastasis

Collagen IV

Collagen IV is essential for tumor angiogenesis by modulating cell growth and proliferation.

Adhesion molecules

CEACAM1

CEACAM1is down-regulated in several cancers. L-Form CEACAM1 has tumor suppressive function and dysregulation is found in early carcinogenic process.

DCC

DCC is a transmembrane receptor for netrins. It promotes apoptosis in the absence of netrin ligands.

E-Cadherin

E-Cadherin regulates morphogenic process like cell-cell recognition, cytoskeleton regulation, and surface adhesion

Secreted factors

Tenascin C

Tenascin C interacts with ECM proteoglycans it can interfere with tumor suppressor activity of fibronectin.

Fibrinogen

Fibrin deposits occur in stroma of many cancer types and affect the progression of tumor cells

Periostin

Periostin 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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