The Hallmarks of Cancer

The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.

They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis.

In addition to cancer cells, tumors exhibit another dimension of complexity: they incorporate a community of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

An expanding tumor requires new blood vessels to deliver adequate oxygen to the cancer cells, and thus exploits these normal physiological processes for its benefit.

It assists in the development of a functioning circulatory network during embryogenesis and is essential for repairing damaged tissue and wounds in adulthood.

In order to ensure appropriate vascular growth without excessive or inadequate blood vessel production, pro-angiogenic and anti-angiogenic factors usually interact constantly to maintain angiogenesis in balance.

This equilibrium becomes disrupted in cancer, as tumors are able to use and control the host's vascular system for their own advancement thanks to the angiogenic switch, a theory initially proposed by Folkman in 1971.

Our knowledge of the complexity of this network has grown as more molecules, including as platelet-derived growth factor (PDGF) and angiopoietins, have been linked to the angiogenic process in addition to VEGF and bFGF.

To enhance the angiogenic signal, for example, mesenchymal stem cells and cancer-associated fibroblasts (CAFs) in the tumor stroma may release pro-angiogenic cytokines.

Another strong inducer of angiogenesis is hypoxia, or oxygen deprivation in the tumor core, which stabilizes hypoxia-inducible factor-1α (HIF-1α), a transcription factor that promotes the production of VEGF and other angiogenic mediators.

[13] The function of exosomes, which are tiny extracellular vesicles released by tumor cells, in promoting angiogenesis has also been brought to light by recent studies.

[14] These exosomes involve microRNAs and angiogenic proteins that alter endothelial cell activity, promoting tube formation, migration, and proliferation.

Developing an understanding of these new processes opens up new therapeutic intervention options and offers important insights into the complex relationships between variables influencing tumor angiogenesis.

Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) to distant body parts.

This change enables cancer cells to detach from the primary tumor, invade surrounding tissues, and ultimately spread to distant locations in the body by entering the bloodstream or lymphatic pathways.

This is a hallmark of epithelial-to-mesenchymal transition (EMT), during which cancer cells acquire mesenchymal traits, such as increased motility and invasiveness.

pro- angiogenic factors like VEGF,[21] along with interactions between cancer calls and the vessel walls, make it easier for tumor cells to penetrate into the bloodstream or lymphatic system.

By gaining access to these transport networks, cancer cells increase their ability to spread and form new tumors in distant tissues.

The loss of E-cadherin disrupts cellular adhesion, allowing tumor cells to detach from the primary site and invade surrounding tissues.

This type of suppression is often mediated by EMT transcription factors such as ZEB1, Snail, and Twist, is then repress E-cadherin gene expression.

Furthermore, when E-cadherin is reduced, it facilitates interactions with the extracellular matrix (ECM) which in then enhances the ability of cancer cells to migrate and invade surrounding tissues.

By promoting these interactions, E-cadherin is able to support cellular motility and aid tumor cells navigate the tissue structures which drives metastasis.

Low levels of E-cadherin are often linked to poor clinical outcomes, therapy resistance and aggressive tumor phenotypes.

"[2] Most cancer cells use alternative metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis,[24][25] but only now gaining renewed research interest.

Mitochondrial membrane potential is hyperpolarized to prevent voltage-sensitive permeability transition pores (PTP) from triggering of apoptosis.

Tumor cells escape this aspect of the immune system by suppressing the expression of MHC I through various mechanism such as alteration of transcription factors and epigenetic modifications.

(See genome instability) Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer.

The ability to invade surrounding tissue and metastasise is a hallmark of cancer.
Signalling pathways are deregulated in cancer. Hanahan and Weinberg compared the signalling pathways to electronic circuits where transistors are replaced by proteins. The prototypical Ras pathway starts with an extracellular signal from growth factors (such as TGF-α). Other major extracellular signals are anti-growth factors (such as TGF-β), death factors (such as FASL), cytokines (such as IL-3/6)and survival factors (such as IGF1). Proteins inside the cell control the cell cycle, monitor for DNA damage and other abnormalities, and trigger cell suicide (apoptosis). Hanahan and Weinberg's signal pathway illustration is at Cell 100:59 [ 3 ]
The cell cycle clock. Cells do not divide in G 0 and are quiescent. After receiving growth factor signals, they prepare for division by entering G 1 , where everything within the cell except DNA is doubled. This doubling includes the size of the cell. The next phase of the cell cycle is S (synthesis) phase. It is the cell cycle phase where the chromosomes (DNA) are duplicated in preparation for cellular division. The transition from G 1 to S is a checkpoint. If the cell has damaged DNA or is expressing oncogenes or other inappropriate proteins, specialized checkpoint proteins, tumor suppressors such as p53 or pRB, will interrupt the transition to S phase until the damage is repaired. If the damage cannot be repaired, the cell will initiate apoptosis, often referred to as cellular suicide, which is programmed cell death. If the tumor suppressor genes incur loss-of-function mutations or are knocked out, the damaged cell can continue to divide unchecked – one of the hallmarks of cancer.
The hallmarks of cancer.