A Brief Understanding of the Cancer Hallmarks and Enabling Characteristics: Part 1
The write-up provides a summarized version of (i) the characteristics that enable a cell to become malignant, and (ii) the hallmarks needed for endless cell replication to form a neoplasm.
This article may be relevant for anyone who needs an initial understanding of the tumorigenesis process.
Introduction
A cancer cell is an immortal cell that keeps dividing, can form an organ-like mass, and invade healthy organs and tissues, ultimately leading to their malfunction or failure causing death. It involves a lot of strategic planning and resourcefulness by cancer cells to be successful in their malicious scheme. There are many levels to understanding the journey of a cancer cell from normalcy to malignancy. It’s not a surprise that cancer biology may be categorized as a logical and systematic science comparable to physics and chemistry. There are several types and subtypes of cancers, different cancer types in an organ, and different cancer cells within a tumor. The silver lining is that the heterogeneities of the disease can be unified by a set of hallmarks that are thought to be shared by most cancers.
(i) WHY and HOW does a normal cell turn cancerous when the body has dozens of protective mechanisms in place at different stages of cell growth, maintenance, and death? How does a cancer cell overcome protective barriers like DNA repair, apoptosis, senescence, and immune surveillance? What are the different types of capabilities it needs to gain to cross all these hurdles to form a mass, and in what order?
There are germline mutations (inherited by embryo) and somatic mutations (non-inherited); the latter can develop from environmental exposure like UV damage, tobacco smoke, chemicals, viral infections, and dietary or lifestyle factors. They can also accumulate as faulty cells continue to divide unchecked over time or age. The mutational rate in a cancer cell is high. It needs to undergo a series of mutations before it can form a malignant tumor. One mutation can lead to the acquisition of one hallmark or a combination of hallmarks. The order in which hallmarks are acquired differs for different cells within a tumor and between different tumors. The paths are different but endpoints, i.e., hallmarks are all the same. Apart from that genomic instability, epigenetic reprogramming, inflammation, phenotypic plasticity, microbiomes, and senescence can also aid tumorigenesis.
The different enabling characteristics are summarized below:
1. Genomic instability
§ This happens by a malfunction of loss of DNA sensing or repair genes and chromosomal segregation genes also called tumor suppressors e.g., p53.
o P53 or TP53 causes cell cycle arrest or apoptosis in response to DNA damage but it is lost in most tumors.
§ There may be defects in detecting DNA damage, repairing damage, and inactivating mutagens before DNA damage.
§ Genetic diversity may be added by apoptosis upon release of DNA on cell death which is incorporated by neighboring cells via phagocytosis.
2. Epigenetic reprogramming
§ Mediated by the microenvironment surrounding the cancer cells without any change in DNA sequence and adds to the intra-tumoral diversity.
§ These include changes in DNA methylation, histone modification, chromatin accessibility, post-translational modifications, and RNA translation
o E.g., Hypoxia or oxygen deficiency in the tumor microenvironment (TME) can cause changes in hypermethylation
§ Accessory or stromal cells do not have genetic instability and mutations but the carcinoma-associated fibroblasts (CAFs) and immune cells or endothelial cells have some epigenetic reprogramming upon their recruitment by cancer cells.
§ Paracrine signaling by soluble factors released by stromal cells can also contribute to epithelial-to-mesenchymal transition (EMT), invasiveness, and growth.
§ Pancreatic cancer has an interstitial pressure-driven fluid flow which drives EMT.
§ Tumor tissue ECM has increased cross-linking and density, enzymatic modifications, and altered molecular composition, as compared to normal tissue ECM, which aids in invasiveness and other hallmarks.
3. Tumor-promoting inflammation
§ Every tumor contains immune cells at different densities.
§ Inflammation can lead to several hallmarks by supplying growth factors, survival factors, matrix-degrading enzymes, proangiogenic factors, invasion, EMT, and metastasis.
§ Inflammation can release reactive oxygen species (ROS), which mutates cancer cells further diversifying them for increased malignancy and resistance.
4. Phenotypic plasticity
§ A fully differentiated cancer cell can dedifferentiate back into progenitor-like cell states.
§ It may shorten the differentiation process by maintaining a partially differentiated, progenitor-like state by blocking further differentiation.
§ May transdifferentiate in which one cell may switch to another cell, so lineage targeting therapies may not work.
5. Polymorphic microbiomes
§ Can both positively and negatively impact hallmarks.
§ The gut epithelium can be mutated by the release of DNA damaging bacterial toxins like that of E. Coli.
§ Bacteria can bind to the surface of epithelial cells mimicking the ligands stimulating proliferation.
§ Butyrate-producing bacteria are elevated in colorectal cancer, which can induce senescent epithelial and fibroblast cells.
o Release immunomodulatory factors like diverse cytokines and chemokines modulating adaptive/innate immune systems which affect cancer pathogenesis as well as therapy response.
§ Can break biofilms and mucus lining epithelia disrupting tight cell-cell junctions and integrity of intestinal barriers.
§ Bacteria are also present within tumors and antibiotics can impair tumorigenesis.
6. Senescence*
§ It has a dual role in cancer i.e., protective effects when cancer cells become transiently senescent but also tumor-promoting effects when senescent cells accumulate in the TME.
§ The senescence secretory phenotype or SASP which consists of growth factors, immunomodulatory cytokines, chemokines, matrix proteins, etc., can promote different aspects of tumorigenesis like proliferation, angiogenesis, metastasis, immunosuppression.
§ SASP has both pro-tumorigenic and anti-tumorigenic effects.
*Senescence has been covered by me in detail in another article (https://medium.com/@narainradhika17/senescence-and-its-role-in-cancer-2644305c90d2)
(ii) How do cancer cells grow and replicate endlessly?
After the genetic and epigenetic reprogramming, the cell activates many tumor-supporting genes called ‘oncogenes’ like Ras and myc and inhibits ‘tumor-suppressor’ genes like p53 and pRB. The mutations, epigenetic changes, or even inflammation can help the cell acquire self-reliance in growth signaling, evade anti-growth signals and apoptosis, and attain limitless potential. A cancer cell overcomes the replicative limit as imposed on normal cells called Hayflick’s limit and enters a second stage called crisis marked by mass cell death. Due to telomerase upregulation, a cancer cell can cross the crisis stage to become immortal i.e., gain limitless replicative potential. It takes several generations of cells to accumulate mutations and then overcome the crisis stage. A cancer cell then divides relentlessly and starts forming a mass of cells.
The hallmarks needed for the proliferation of cancer cells are summarized below:
- Self-sufficiency in growth signals
§ A cancer cell generates many of its own growth factors, aided by oncogenes, and responds to its own growth factors by autocrine stimulation.
o E.g., TGFα by glioblastomas, and PDGF by sarcomas.
§ Growth factor receptors are overexpressed in many cancers, which is why even normal levels of those factors would trigger proliferation in cancer cells that otherwise would not.
§ The receptors are structurally altered such that they can constitutively fire.
o E.g., EGF receptor.
§ Cancer cells can switch to receptors that transmit pro-growth signals and of motility, apoptotic resistance, and entrance into the cell cycle.
o E.g., Expression of cell adhesion receptors like Integrins are lost which send anti-growth signals.
§ Some proteins get structurally activated without stimulation by upstream regulators.
o E.g., Ras.
§ Heterotypic signaling between cancer and other cells also drives proliferation in cancer cells by the release of growth signals by other cell types.
§ Mutations in downstream pathways like PI3K and Ras-MAPK and disruptions in inhibitory pathways like mTOR and loss of PTEN suppressor also aid growth.
2. Insensitivity to anti-growth signals
§ Cancer cells can avoid or turn off anti-growth signals present in the soluble form or immobilized form in ECM like integrins which can lead to quiescence or post-mitotic differentiation and favor pro-growth signals.
o E.g., One strategy involves c-myc oncogene.
§ Retinoblastoma protein or pRB inactivates proliferation in its hypophosphorylated form and stops progression from G1 to S phase of the cell cycle. pRB largely senses growth inhibitory extracellular signals and is disrupted in many cancers.
§ TP53 or p53 receives signals from intracellular stress like excessive DNA damage, nucleotide pools, growth-promoting signals, glucose, and oxygenation and causes cell senescence or death. Thus, p53 which senses intracellular stress signals is also disrupted in most cancers.
§ Cancer cells evade contact inhibition and suppress TGFβ signaling initially which has tumor-suppressive effects in the early stages.
3. Ability to evade apoptosis
§ Cancers express decoy Fas receptors to divert Fas ligands which are required for apoptosis.
§ P53 transmits apoptotic signals in response to hypoxia and oncogene hyperexpression is lost in many cancers.
o E.g. It upregulates the expression of pro-apoptotic Bax in response to DNA damage, stimulating mitochondria to release cytochrome C.
§ PI3 kinase-AKT/PKB pathway reduces apoptosis in tumors by activation of Ras oncogene or loss of pTEN tumor suppressor.
§ PI3K, AKT, and mTOR kinase pathways inhibit autophagy, which is a mechanism through which cell organelles like mitochondria and ribosomes are broken down for biosynthesis and metabolism to support survival in stressed and nutrient-limited environments like cancer.
§ Some cancer cells tolerate necrosis, which is cell death and explosion upon bloating and releases proinflammatory signals recruiting tumor-promoting inflammatory cells to aid proliferation, invasiveness, and angiogenesis.
4. Limitless replicative potential
§ Cells have a finite replicative potential given by Hayflick’s limit after which they turn senescence or stop growing but don’t die, but by disrupting the pRB and p53 tumor suppressors, the cells cross this divisional barrier until they enter a second stage called crisis.
§ Crisis leads to massive cell death and karyotypic disarray but some 1 in 107 variant cells can survive this stage and are immortalized, with limitless replicative potency.
§ Thus, cancer cells need to surpass not only Hayflick’s limit but also the crisis stage, requiring many generations of cells to produce cancer.
§ Telomeres protect the ends of chromosomes by shortening with each division and the telomerase enzyme adds repeat segments to the ends of telomeric DNA but cancers upregulate the telomerase enzyme which helps them with immortalization.
References:
- Hanahan D, Weinberg RA, “The hallmarks of cancer”, Cell (2000) 100(1):57–70.
- Hanahan D, Weinberg RA, “Hallmarks of cancer: the next generation”, Cell (2011) 144(5):646–74.
- Hanahan D, “Hallmarks of Cancer: New Dimensions”, Cancer Discov (2022) 12(1):31–46.
