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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.
Nucleotide excision repair
ERCC1 – XPF is an essential endonuclease for DNA damage repair. It is also involved in DNA interstrand crosslink and double-strand break repair
XPA is a Zinc finger protein responsible of DNA damage repair
TFIID is a complex that binds to the TATA box in the core promoter of the gene.
Base excision repair
APEX are nuclease involved in DNA repair containing endonuclease, exonuclease, diesterase and phosphatase activities.
PNKP catalyzes 5’- kinase and 3’ – phosphatases activity
FEN1 is an endonuclease that removes 5’ overhanging flaps in DNA repair
Double strand break (DSB) repair
Gamma H2AX is a component of histone octomer in nucleosome. It is phosphorylated in DNA damage
XRCC4 functions together with DNA ligase IV and DNA dependent protein kinase to repair DNA DSB.
BRCA genes are one of the widely studies tumor suppressor proteins that regulates DNA repair and cell cycle
53bp1 binds to damaged chromatin and promotes DNA repair.
Kap1 is a key regulator of normal development and differentiation
DNA mismatch repair
Msh2 and Msh6 form MutSα which binds to the site of mismatch base.
Msh2 and Msh3 form MutSβ which participates in insertion/deletion loop repair
Forms heterodimers with MLH1 to form MutLα
Telomere maintenance and regulation
hTRET is the major component of telomerase activity. Telomerase has been identified as diagnostic marker for various types of cancer.
The Shelterin complex is a core of six proteins integral for telomere function
p53 is called the “guardian of the genome” is the key regulator of gene expression.
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 is a tumor suppressor gene that that binds to the MDM2-p53 complex and prevent degradation of p53.
E2F-1 is the transcription factor of the p53 pathway that regulates by initiating transcription of p14ARF.
Retinoblastoma regulates cell cycle and plays important role in cellular differentiation.
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 regulates tumor growth by suppressing Wnt signaling. It also plays an important role in cell adhesion and migration.
BRCA are one of the widely studies tumor suppressor proteins that regulates DNA repair and cell cycle
PTEN is a key regulator of cellular activities. It regulates PI3K-AKT-mTOR signaling through its lipid phosphatase activity.
Wilms tumor protein is a transcription factor important for normal cellular development and survival. WT1 plays a both oncogenic role and tumor suppressor.
Neurofibromin is a tumor suppressor that negatively regulates Ras pathway.
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.
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.
HIF is a heterodimeric DNA binding transcription factor that regulate broad range of cellular systems to hypoxia.
CAIX is a mediator of hypoxia-induced stress response in cancer cell.
GLUT1 levels can be elevated in hypoxia and can be used to indicate the degree of hypoxia.
TOM20 and GAPDH have been shown to be upregulated in in various types of cancer and it is necessary to metabolize glutamine
V-ATPase expression is shown to be upregulated in cancer cells.
GAPDH and Tom20 have been shown to be upregulated in in various types of cancer and can be used as marker
COX IV is used as a marker for the inner mitochondrial marker
VDAC1/Porin is used as a marker for outer mitochondrial marker
Beta subunit has a crucial role in the structural and functional maturation of Na+/K+-ATPase.
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.
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.
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 is part of the IKK complex which is a negative regulator of transcription factor NF-κB.
Tumor associated macrophages
CD68 is a key marker to recognize both M1 and M2 macrophages in tumor tissue
CD163 is a scavenger receptor upregulated in macrophages in an anti-inflammatory environment
iNOS is one of the major markers of M1 tumor associated macrophages.
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.
Hyaluronan is glucoseaminoglycan found in the extracellular matrix (ECM). HA is dramatically increased in most malignancies
Versican is either expressed by cancer cell or stromal cells and plays a wide role in invasion and metastasis
Collagen IV is essential for tumor angiogenesis by modulating cell growth and proliferation.
CEACAM1is down-regulated in several cancers. L-Form CEACAM1 has tumor suppressive function and dysregulation is found in early carcinogenic process.
DCC is a transmembrane receptor for netrins. It promotes apoptosis in the absence of netrin ligands.
E-Cadherin regulates morphogenic process like cell-cell recognition, cytoskeleton regulation, and surface adhesion
Tenascin C interacts with ECM proteoglycans it can interfere with tumor suppressor activity of fibronectin.
Fibrin deposits occur in stroma of many cancer types and affect the progression of tumor cells
Periostin is a secreted adhesion-related protein expressed in the periosteum and periodontal ligaments and plays a role in tumorigenesis
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).