Cellular Hallmarks of Cancer: An Overview

Aman Singh
Post Graduate Student
Dr. D.Y. Patil School of Biotechnology & Bioinformatics

Special thanks to Isha Sharma for helping with this article.


i. List and understand 10 cellular hallmarks of cancer.
ii. Recognize how these cellular hallmarks distinguish between a cancer cell and a normal cell.
iii. Articulate, how these hallmarks make a cancer cell more fit for competing, surviving, and reproducing in the body.
iv. Understand recent developments in the field.

Hallmark No. 1: Replicative Immortality

Normal human cells have a finite ability to undergo mitosis due to end replication problems. This is largely due in parts to the end of chromosomes i.e Telomere shortening after each mitotic division. Once normal human cells have reached Hayflick’s limit, cells can enter senescence (Go Phase of the cell cycle). Cancer cells can prolong their Hayflick’s limit and ability to continue to undergo mitosis. They use an enzyme called telomerase. It can elongate the telomere after they get too short to sustain and proliferate.

Enzyme – It is a reverse transcriptase enzyme that can add nucleotides at the telomeric end.

Hallmark No. 2: Genomic Instability

They’re immortal and also they can pass on genes that are mutated. In normal cells, if they detect mutation which occurs in the gap phase of the cell cycle the cell can stop the cell cycle, repair the mutation, and re-enter the cell cycle. This is regulated by genes called tumor suppressor genes (TSG). Cancer cells are different and can have an abnormal amount of chromosomes per cell and can bear a mutation in their DNA with the ability to still undergo mitosis. Genes commonly lost or mutated are tumor suppressor genes. Genes that are promoted are known as oncogenes, which can cause the cell to proliferate uncontrollably. Notable gene alterations observed in cancer are point mutations, deletion of a region of chromosomes.

Hallmark No. 3: Evasion of growth suppression signals

Mitosis in a normal cell is a tightly controlled process wherein pro and anti-proliferation signals coordinate cell activities at the cell cycle level. However, due to genomic instability, most cancer cells circumvent normal growth suppressor signals in the G1 checkpoint to continue proliferating. A TSG called Retinoblastoma inhibits the normal cells’ passage through the restriction point in G1 phase of the cycle. Another TSG, p53, is lost. This allows the cell to go in the cell cycle and divide even though the DNA is damaged.

Hallmark No. 4: Resistance to cell death

Normal cells can undergo apoptosis in response to DNA Damage or mutation or other cellular stress. In contrast, cancer cells are generally less sensitive to DNA damage, growth factor deprivation, treatment, and similar stress and so they tend to avoid apoptosis. Pro- survival protein BCL (B cell lymphoma) – 2 is expressed in cancer cells. BCL – 2 has anti-apoptotic family members like BCL-2, BCL-X1, MCL-1, CED-9, A-1, BFL-1. Pro-apoptotic family members are BAX, BAK, BOK, BCL-X5, BIK, BIM, BAD, BID, EGL-1.

Hallmark No. 5: Sustained Proliferation

In Normal cells, growth factor signaling is also tightly controlled to allow for tissue and cellular homeostasis. Cancer cells can proliferate due to a lack of TSGs as well as over-expression of oncogenes such as RAS. Cancer cells can stimulate normal cells in the microenvironment to provide growth factors.

Hallmark No. 6 – Altered Metabolism

To fulfill energy requirements the cancer cells perform altered metabolism to carry out the uncontrolled proliferation. Cancer cells do this by finding & using alternate sources for energy & alternate metabolic pathway. Otto Warburg first described in the 1920s that cancer cells utilized higher levels of glucose in the presence of oxygen with an associated increase in lactate production. Normal cells break down glucose by glycolysis to pyruvate which provides energy to form ATP for the cells in Mitochondria. Cancer cells are very different; they can convert glucose to lactate irrespective of oxygen. This allows the cancer cells to divert metabolites for useful anabolic processes such as mitosis.

Hallmark No. 7 – Avoiding Immune Destruction

The immune system defends us against viruses, pathogens including viruses. B cells, T lymphocytes, Macrophages, Natural killer cells kill the antigen. Cancer cells can protect themselves by inhibiting T cells that would normally attack these cancer cells. Program Death Ligand (PDL) 1 & 2- These are proteins that are transmembrane, they are extracellular & intracellular. These proteins serve as a checkpoint if an antigen doesn’t have PDL-1 over its surface the T cells will attack them. But the Cancer cells are smart; they cover their membrane with PDL1&2 so that the T cells don’t attack them and they get suppressed.

Hallmark No 8 – Tumor – Promoting Inflammation

The tumor microenvironment is often inflamed by cells from the immune system that enable tumors to mimic inflammatory conditions seen in normal cells. Immune cells provide the tumor cells with essential factors that allow them to survive, move, proliferate & undergo epithelial to mesenchymal transition (EMT) & invade. The immune cells release cytokines & protease. Cancer cells can release chemokines against immune cells which triggers immune cells to release more cytokines. This results in cancer cell proliferation.

Hallmark No 9 – Induction to Angiogenesis

All tumors need blood supply & to do this they induce the formation of new blood vessels from pre-existing ones. Pro-angiogenic factors such as vascular endothelial growth factors (VEGF) become activated in tumor cells & signal endothelial cell proliferation & growth of blood vessels. Tumor cells grow faster than normal cells & outgrow their source of nutrients. They make new blood vessels to provide necessary nutrients & oxygen. Newly formed tumor vessels tend to be leaky. These new vessels provide a way for cancer cells to get into the main bloodstream & go to different places in the body.

Hallmark No 10 – Activation of Invasion and Metastasis

Here cell-to-cell and cell-to-extracellular matrix interaction is altered. Change in or loss of structural proteins (Integrins). Epithelial to Mesenchymal Transition (EMT) –
Epithelial Cells – Cuboidal, Intact, Stationary.
Mesenchymal Cells – Flat, No interaction, Floating
Loss of such genes such as metastasis suppressor genes (KAL1, CD82, NDRG1)

Invasion (Breaking through ECM) – Tumor cells are able to break out of the extracellular matrix during invasion & are able to migrate outwardly, away from their natural location.

Intravasation (Cancer cells get into the Blood) – Cancer cells enter their way through endothelial cells.
Actively – Cancer cells have the tendency to push their way through endothelial cells.
Passively – Cancer cells are shed from a tumor and they enter in new leaky blood vessels.

Survival during systemic circulation- Cells must transverse the venous system, lungs & arterial system. Tumors that are circulating in the bloodstream are called CTCs. During the process, cells must avoid various sources of cell death.

Extravasation- Cells begin growing in the secondary site into a metastatic tumor. These cells may not begin to divide immediately. They might go dormant & grow into tumors again.


Stress-induced mutation plays a role in genomic instability in cancer. Mutational clusters seen in cancer represent the molecular signature of a conserved stress-induced mutagenesis response. Understanding the parameters of this response will be key to maximizing the effectiveness of cancer treatment.

There is a limited number of studies supporting the involvement of ASCT2 and LAT1 in tumor development for each cancer model. These transporters have been associated with a variety of hallmarks of cancer, such as resisting cell death.

Bcl2 suppresses apoptosis (by phosphatase action when bound to calcineurin) as a defense against malignant tumorigenesis.

The discoveries in the field of immunology have driven the development of many novel therapeutics with immense potential for human cancer therapy. Although further research needs to be done to better understand the mechanisms of drug-induced toxicity, these new therapies have contributed to improved cancer treatments.

Reference (Feb-21-A7)

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