Key Markers and Tools to Explore the Hallmarks of Cancer

Introduction

During early 2000, professors Weinberg and Hanahan proposed that cells acquire distinctive capabilities when they advance towards a neoplastic state1. These were called hallmarks of cancer and created a useful framework to gain insights into tumor pathogenesis. These include:

  • Sustaining proliferative signaling
  • Evading growth
  • Suppressors
  • Resisting cell death
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Activating invasion and metastasis

They were all fortified by genome instability and mutation.

Later in 2011, an update was published by Weinberg and Hanahan that reflects advances in their understanding. The following were also included by them as hallmarks of cancer:

  • Reprogramming of energy metabolism
  • Avoiding immune destruction
  • Tumor-promoting inflammation
  • Evading immune destruction2

This article provides the relevant tools and markers to investigate these key 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.

 

TFID

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

Base excision repair

APEX1/APEX2

APEX are nucleases involved in DNA repair

 

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.a

 

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.

 

Cell death

The following are the key characteristics of apoptosis:

  • Cell Shrinkage
  • Chromosome condensation (pyknosis)
  • Membrane blebbing
  • DNA laddering
  • Nuclear fragmentation (karyohexis)
  • Eventual engulfment of the cell by phagosomes

 

Autophagy plays a key role in allowing the survival of cells in response to multiple stress conditions. This autophagic mechanism is exploited by cancer cells as an approach to overcome nutrient-limiting conditions and promote tumor growth. Autophagy can supply nutrients, modulate the tumor environment by facilitating angiogenesis, and modulate inflammatory response.

 

Reprogramming energy metabolism

Mechanism

Key markers

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/c-jun

The AP-1 transcription factor family is known to play an imortant role in tumor progression and development.

 

GLUT-1

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

Glycolysis

Tomm20

TOMM20 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

The growth of the vascular network is vital for metastasis which provides a sufficient supply of oxygen and nutrients required for cancer cell growth and it’s also a means for waste removal. This is completed by angiogenesis and lymphangiogenesis, respectively.

 

In angiogenesis, growth factors such as VEGF play an important role, whereas several other angiogenic factors are related to tumor aggressiveness.

 

Avoiding immune destruction

The immune system provides protection against diseases and foreign pathogens, but is also important for removing the body’s own ailing and unhealthy cells. As such, the immune system has the ability to identify and eliminate tumor cells.

 

T cells are capable of selectively recognizing and destructing unhealthy cells or pathogens by organizing a coordinated immune response that includes the innate and adaptive responses.

 

Tumor-promoting inflammation

Mechanism

Key markers

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 employed to measure responses to toxic insult, evaluate normal cell health, or it can be used as a prognostic and diagnostic tool for different types of cancer. The markers available on the market typically investigate DNA levels or synthesis, proliferation-specific proteins, or cellular metabolism.

 

Activating of invasion and metastasis

Mechanism

Key markers

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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Last updated: Jul 14, 2018 at 6:31 PM

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