Kurzgesagt – In a Nutshell
Sources – Cancer vs. Immune
We thank the following experts for their support and critical reading:
James Gurney
Georgia State University, USA
Kimberly Luddy
Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, USA
Anna Obenauf
IMP, Research Institute of Molecular Pathology, Austria
DISCLAIMER: Cancer is a very complex disease, so are its interactions with the immune system. In addition, the textbook information is constantly changing thanks to the heavy research in this area in the last two decades. In this video, we are simplifying a lot by reducing this complexity down to a few basic cell types and interactions. We had to leave out many other cell types and mechanisms involved, further information is beyond what we can fit into the video. Our purpose is not to give a full account of the disease and immune system surveillance, but to give a pointer to the interested audience for further reading.
– The vast majority of cancer cells you develop will be killed without you ever noticing.
First, this doesn’t mean that we have cancer cells all the time in our bodies. There are a multitude of things that have to go wrong for a normal cell to become cancerous and even more for that one cell to develop into a clinical stage cancer. Here we refer to early stages, when mutated cells can still be eliminated by the immune system, before they become clinically visible. As far as current research goes, eliminative power of the immune system decreases as the cancer progresses, as it is demonstrated in the following figure.
#Gonzalez, Hagerling and Werb.Roles of the immune system in cancer: from tumor initiation to metastatic progression. 2018.
http://genesdev.cshlp.org/content/32/19-20/1267.full.pdf+html
Immune systems’ mechanisms fighting with cancer are collectively called immunosurvelliance. Though we are talking mainly about Natural Killer Cells and T Cells in this video, there are more players and even more mechanisms comprising the immune system's efforts against cancer. The paper cited above is an extensive review of the topic.
#Dersh et al. A few good peptides: MHC class I based cancer immunosurveillance and immunoevasion. 2020
https://www.nature.com/articles/s41577-020-0390-6
Quote: “Although our lifetime risk of cancer is approximately 40%, it is perhaps surprising that it is not higher. The 10^13 nucleated cells in our body replicate approximately 3 × 10^9
base pairs per cell division with an intrinsic mutation rate of approximately 10^–4.5 per base pair, with additional mutations generated from the daily barrage of chemical carcinogens and radiation. DNA quality control pathways repair much of the damage, but it is increasingly clear that the immune system plays an important role in limiting oncogenesis — the concept of immunosurveillance. Indeed, tumours evolve myriad mechanisms to evade immunity, a process termed immunoediting1”
– Cancer is when corrupted cells multiply uncontrollably.
Here we try to cover the definition of an otherwise much more complex disease with a single sentence. Even though it is true in the most basic sense, we had to leave out a lot to simplify it since a full account of mechanisms giving rise to cancer is beyond the scope of this video.
For a basic explanation on how cancer arises, one can refer to the following article:
#Nature Education. Normal Controls on Cell Division are Lost during Cancer. 2014.
https://www.nature.com/scitable/ebooks/essentials-of-cell-biology-14749010/122997842/
Quote: ”Cancer cells are cells gone wrong — in other words, they no longer respond to many of the signals that control cellular growth and death. Cancer cells originate within tissues and, as they grow and divide, they diverge ever further from normalcy. Over time, these cells become increasingly resistant to the controls that maintain normal tissue — and as a result, they divide more rapidly than their progenitors and become less dependent on signals from other cells. Cancer cells even evade programmed cell death, despite the fact that their multiple abnormalities would normally make them prime targets for apoptosis. In the late stages of cancer, cells break through normal tissue boundaries and metastasize (spread) to new sites in the body.”
For a more in depth characterization of cancer, one can refer to the following review paper.
#Hanahan & Weinberg. Hallmarks of cancer: the next generation. 2011.
https://pubmed.ncbi.nlm.nih.gov/21376230/
Quote: ”The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list— reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire 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.”
– It can emerge from basically every type of cell in your body, so there is not a single type of cancer but hundreds.
#Cooper GM. The Cell: A Molecular Approach. The Development and Causes of Cancer.
https://www.ncbi.nlm.nih.gov/books/NBK9963/
Quoter: “Cancer can result from abnormal proliferation of any of the different kinds of cells in the body, so there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment.”
Following is an online directory where one can find a comprehensive list of different types and related information on each.
#NIH, National Cancer Institute. Cancer Types.
– Cancer cells stop being part of the collective and become individuals again.
In the following paper, researchers compared the gene expression patterns from genomes of seven types of solid tumors, in search of how these patterns and corresponding processes compared to evolutionary history. They showed that genes conserved with unicellular organisms were strongly up-regulated in solid tumors, while genes of animal origin, therefore multicellularity, were downregulated. Also, the genes at the interface of the tightly controlled multicellularity and unicellularity processes are simply lost in tumors.
#Trigos et al. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. 2017
https://www.pnas.org/doi/10.1073/pnas.1617743114
Quote: ”Cancer has been suggested to result from an atavistic process, whereby the activation of primitive, highly conserved programs (2, 3) leads to molecular phenotypes and population dynamics (4) similar to those of unicellular organisms (5). Genes commonly involved in cancer associate with two major evolutionary events: the emergence of self-replicating cellular life and the appearance of simple multicellular organisms (6, 7). The disruption of genes and processes that appeared in early metazoan life to enhance intercellular cooperation is expected to be a recurrent driver of carcinogenesis, as implicated by the widespread occurrence of cancer across the tree of multicellular life (8, 9) and the common dysregulation of pathways that evolved to sustain multicellularity, such as Wnt and integrins (10, 11).”
– In principle, your body can handle a few rogue cells and even live in harmony together.
We mainly talk about how we have cancer in this script. However, how we manage to not have it, despite the existence of mutated cells, is a related but a slightly different question.
#Brown et al. Correction of aberrant growth preserves tissue homeostasis. 2007.
https://pubmed.ncbi.nlm.nih.gov/28783732/
Quote: “Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes1–3. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells.”
– Unfortunately some cancer cells are not content with doing their own thing but divide, again, and again, becoming a sort of new organism within you.
Since the cancerous cells stop regular communication with other cells and ignore the regulating signals, they start behaving somehow independently.
#Hanahan & Weinberg. Hallmarks of cancer: the next generation. 2011.
https://pubmed.ncbi.nlm.nih.gov/21376230/
Quote: “Arguably the most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. Normal tissues carefully control the production and release of growth-promoting signals that instruct entry into and progression through the cell growth-and-division cycle, thereby ensuring a homeostasis of cell number and thus maintenance of normal tissue architecture and function. Cancer cells, by deregulating these signals, become masters of their own destinies.”
– In a nutshell, your cells have a nucleus filled with DNA, the code of life. It consists of genes, which are instructions for building proteins, and a sort of manual which proteins to build at which time. These building instructions are copied and transferred to factories called ribosomes, where they are used to make proteins.
Producing proteins from genetic material is central to all life. From bacteria to us, all living organisms have ribosomes, and produce whatever protein is needed for their survival. In the following article, one can find the basics of the protein synthesis from genetic material.
#Nature Education. Ribosomes, Transcription, and Translation. 2010
https://www.nature.com/scitable/topicpage/ribosomes-transcription-and-translation-14120660/
Quote: “Cellular DNA contains instructions for building the various proteins the cell needs to survive. In order for a cell to manufacture these proteins, specific genes within its DNA must first be transcribed into molecules of mRNA; then, these transcripts must be translated into chains of amino acids, which later fold into fully functional proteins. Although all of the cells in a multicellular organism contain the same set of genetic information, the transcriptomes of different cells vary depending on the cells' structure and function in the organism.”
– What kind of proteins your cells make determine what they can do. The story of life really is the story of the dance of proteins – we made a whole video about it.
We explain the proteins and their working in detail in our video:
The Most Complex Language in the World
https://www.youtube.com/watch?v=TYPFenJQciw
– The important thing here is that a corrupt gene means you get a corrupt protein, which will get important later. Your DNA gets a tiny bit corrupted – it mutates – tens of thousands of times each day. Most of the time without any special cause, just by being alive. Almost all of these mutations are fixed very quickly or are not problematic. Still, over time as your cells make copies of themselves, damage is accumulating.
DNA replication mechanism generally work with high fidelity and there are mechanisms in place to correct the mistakes. However, it is still not a perfect process and some mistakes go uncorrected.
#Huntington, Cursons & Rautela. The cancer-natural killer cell immunity cycle. 2020
https://pubmed.ncbi.nlm.nih.gov/32581320/
Quote: “Each human cell is subject to approximately 70,000 DNA lesions per day31, the majority of these being single-stranded DNA breaks arising from natural oxidative damage, yet a fraction can be converted to more detrimental DNA double-strand breaks.”
#Bebenek & Ziuzia-Graczyk. Fidelity of DNA replication—a matter of proofreading. 2018.
https://link.springer.com/article/10.1007/s00294-018-0820-1
Quote: “Maintaining a low mutation rate is essential for cell viability and health. It was estimated that both in prokaryotic and eukaryotic cells, DNA is replicated with the very high fidelity with one wrong nucleotide incorporated once per 10^8–10^10 nucleotides polymerized. The accuracy of replication relies heavily on the ability of replicative DNA polymerases to efficiently select correct nucleotides for the polymerization reaction and excise mistakenly incorporated nucleotides using their intrinsic exonucleases.”
#Leslie A. Pray. DNA Replication and Causes of Mutation. 2008 Nature Education
https://www.nature.com/scitable/topicpage/dna-replication-and-causes-of-mutation-409/
Quote: “DNA replication is a truly amazing biological phenomenon. Consider the countless number of times that your cells divide to make you who you are—not just during development, but even now, as a fully mature adult. Then consider that every time a human cell divides and its DNA replicates, it has to copy and transmit the exact same sequence of 3 billion nucleotides to its daughter cells. Finally, consider the fact that in life (literally), nothing is perfect. While most DNA replicates with fairly high fidelity, mistakes do happen, with polymerase enzymes sometimes inserting the wrong nucleotide or too many or too few nucleotides into a sequence. Fortunately, most of these mistakes are fixed through various DNA repair processes. Repair enzymes recognize structural imperfections between improperly paired nucleotides, cutting out the wrong ones and putting the right ones in their place. But some replication errors make it past these mechanisms, thus becoming permanent mutations. These altered nucleotide sequences can then be passed down from one cellular generation to the next, and if they occur in cells that give rise to gametes, they can even be transmitted to subsequent organismal generations. Moreover, when the genes for the DNA repair enzymes themselves become mutated, mistakes begin accumulating at a much higher rate. In eukaryotes, such mutations can lead to cancer.”
In the following review paper one can find an extensive summary of the various sources of DNA damage and DNA repair mechanisms, as summarized in the figure from the paper.
#Chatterjee and Walker. Mechanisms of DNA damage, repair and mutagenesis. 2017
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474181/pdf/nihms862014.pdf
Quote: “In conclusion, DNA is continually being exposed to both endogenous and exogenous DNA damaging agents that chemically modify the DNA constituents. Unresolved DNA damages are implicated in human diseases and cancers. However, robust DNA repair and damage tolerance pathways help remove or tolerate the lesions to allow survival (Figure 4). An understanding of these pathways helps evaluate possible toxic exposures and design strategies to control deleterious consequences on human health.”
– You can increase DNA damage by doing things like smoking, drinking alcohol, by being obese, breathing in asbestos, by not using sunscreen or contracting a virus like HPV.
In addition to the mutations caused by errors in DNA replication, external factors can damage correctly copied DNA after replication. It is not possible here to give a full explanation of each and every factor causing damage, still in the following one can find relevant papers for the factors we mention.
Smoking:
#Li et al. Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene. 2017
https://www.pnas.org/doi/full/10.1073/pnas.1706021114
Quote: “Nucleotide excision repair is a versatile repair pathway that removes a variety of DNA damages, including UV- andbenzo[a]pyrene (BaP)-induced DNA damages. BaP, a widespread carcinogen, is the major cause of lung cancer (1). It is produced by incomplete combustion of organic materials and converted to the ultimate mutagen, BaP diol epoxide (BPDE), through enzymatic metabolism (2). BPDE preferentially forms bulky covalent DNAadducts at N2 position of guanines and causes mutations if these BPDE- deoxyguanosines (BPDE-dGs) are not efficiently elimi-nated by nucleotide excision repair (3). Various methods of varying resolutions have been developed for mapping DNAdamage and repair genome-wide (4–9). We previously reported a method, termed excision repair- sequencing (XR-seq), for mapping nucleotide excision repair (6). This method has been used to generate excision repair maps for UV-induced cyclobutane py-rimidine dimers (CPDs) and (6-4)pyrimidine-pyrimidone photo-products [(6-4)PPs], as well as cisplatin and oxaliplatin-inducedPt-d(GpG) diadducts for the human genome and CPDs for the Escherichia coli genome (10–12).”
Alcohol:
#Rumgay et al. Global burden of cancer in 2020 attributable to alcohol consumption: a population-based study. 2021.
https://www.thelancet.com/action/showPdf?pii=S1470-2045%2821%2900279-5
Quote: “Globally, about 741,000, or 4.1%, of all new cases of cancer in 2020 were attributable to alcohol consumption. About three-quarters of alcohol-attributable cancer cases were in males, and the cancer sites contributing the most attributable cases were oesophageal, liver, and breast (in females).”
#Gapstur et al. Alcohol and Cancer: Existing Knowledge and Evidence Gaps
Across the Cancer Continuum. 2022.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755600/pdf/nihms-1754531.pdf
Quote: “Numerous biological mechanisms may be involved in alcohol-related carcinogenesis. Alcohol drinking disorders can lead to liver fibrosis and cirrhosis (12)–an established cause of liver cancer. Ethanol in alcoholic beverages may enhance carcinogen diffusion into epithelial cells (13), and affect DNA repair, mitogen-activated protein kinases (MAPK), sex hormone regulation, immune function and inflammation, the absorption and metabolism of essential nutrients (e.g., vitamin A, folate), and the oral and gut microbiome (10).”
Obesity:
Oxidative stress and inflammation are commonly seen in obesity and can cause DNA damage and inhibit DNA repair mechanisms.
#Harris et al. Obesity: a perfect storm for carcinogenesis. 2022
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470699/
Quote: “Obesity has been associated with an increased risk of cancer in a wide range of tissues [5] and absence of body fatness lowers risk of several cancers including breast (post-menopausal), bowel, endometrium, oesophagus, ovary, liver, gastric cardia, gallbladder, pancreas, kidney, meningioma, multiple myeloma and thyroid [6]. While this epidemiological data merely demonstrates an association, different cancers appear differently affected, with causality in some cases backed by evidence from model systems. Supporting a causal relationship, we see that reduction of body mass following bariatric surgery is associated with a reduced cancer risk, particularly in obesity related cancers [7]. And by 2035, it is estimated that~40% of endometrial,>25% oesophageal,>20% renal and~20% liver cancers globally will be attributable to having a high body mass index (≥25 kg/m2) [8]. Furthermore, obesity in general is associated with worse prognosis in patients with cancer, although the jury is still out in certain tumour types [9].”
#Włodarczyk & Nowicka. Obesity, DNA Damage, and Development of Obesity-Related Diseases. 2019.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429223/pdf/ijms-20-01146.pdf
Quote: “In people with obesity, a broad range of DNA lesions such as double strand breaks (DSB), single strand breaks (SSB) or oxidized bases and about 2-times higher DNA damage in lymphocytes than in normal weight subjects have been observed and a correlation between body–mass index (BMI) and DNA damage was also found [5,30,31]. A significant difference in levels of DNA damage measured by H2AX phosphorylation was also observed in children with overweight and obesity compared to lean controls [32]. Lymphocytes from people with obesity had more mitomycin C-induced DNA damage compared to cells from normal weight subjects [33]. However, available data regarding the relationship between obesity and levels of oxidized bases in DNA such as 8-oxodG and 8-OHdG are inconsistent [34–37].”
Asbestos:
Asbestos is a fibrous silicate mineral and has different types of fibers that have been used in various industries from construction to fire blankets. Currently, commercial use of several types is regulated in most developed countries. Asbestos has been shown as the main cause of mesothelioma, a specific type of cancer of the linings of the internal organs especially lungs.
#Upadhyay & Kamp. Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis. 2003.
https://pubmed.ncbi.nlm.nih.gov/12773695/
Quote: “Asbestos causes asbestosis and various malignancies by mechanisms that are not clearly defined. Here, we review the accumulating evidence showing that asbestos is directly genotoxic by inducing DNA strand breaks (DNA-SB) and apoptosis in relevant lung target cells. Although the exact mechanisms by which asbestos causes DNA damage and apoptosis are not firmly established, some of the implicated mechanisms include the generation of iron-derived reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), alteration in the mitochondrial function, and activation of the death receptor pathway. We focus on the accumulating evidence implicating ROS. DNA repair mechanisms have a key role in limiting the extent of DNA damage. Recent studies show that asbestos activates DNA repair enzymes such as apurinic/apyrimidinic endonuclease (APE) and poly (ADP-ribose) polymerase (PARP). Asbestos-induced neoplastic transformation may result in the setting where DNA damage overwhelms DNA repair in the face of a persistent proliferative signal. ”
UV:
#Sinha & Häder. UV-induced DNA damage and repair: a review. 2002
https://link.springer.com/article/10.1039/b201230h
Quote: “DNA is certainly one of the key targets for UV-induced damage in a variety of organisms ranging from bacteria to humans. UV radiation induces two of the most abundant mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) and their Dewar valence isomers.”
HPV:
#Moody & Laimins. Human papillomavirus oncoproteins: pathways to transformation. 2010.
https://www.nature.com/articles/nrc2886
Quote: “The HPV oncoproteins E5, E6 and E7 are the primary viral factors responsible for
initiation and progression of cervical cancer, and they act largely by overcoming negative growth regulation by host cell proteins and by inducing genomic instability, a hallmark of HPV-associated cancers.”
There are many other carcinogenic environmental factors than we can fit here. Following paper provides a comprehensive account of these factors and compares the resultant mutation profiles.
#Kucab et al. A Compendium of Mutational Signatures of Environmental Agents. 2019
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506336/pdf/main.pdf
– But the simplest way to damage DNA and get cancer is to be alive long enough.
The longer you are alive, the more mutations accumulate in your tissues, which increases the probability of getting cancer. However, the relation between aging and cancer is more complicated than just that. Not only there are more mutations but also tumor suppression mechanisms might get worse with age. For example even the cancers that are known to be largely due to external factors, are more likely to come in old age. An example is smoking and lung cancer - it seems that smoking determines who gets cancer but age determines when it will happen.
#Laconi et al. Cancer as a disease of old age: changing mutational and microenvironmental landscapes. 2020.
https://www.nature.com/articles/s41416-019-0721-1
Quote: “The inextricable link between ageing and cancer is highlighted by a simple observation—the incidence curves for most common cancers are strikingly similar, rising after the age of 50 years (Fig. 1), despite the large variance in the numbers of driver mutations evident in these cancers and the fact that they originate in different stem cell pools with large differences in size and organisation.1”
– For many cancer cases, there is no cause other than bad luck.
We are aware that there is nuance to this statement. Here “bad luck” refers to the randomness of the errors made by DNA replication mechanisms. A research paper published in 2015 kindled a big discussion about the topic of the sources of the mutations causing cancer and to which extent each source contributes.
There can be mutations due to external factors (E) such as smoking, hereditary ones (H) and the ones that are due to intrinsic factors coming from the mistakes in the DNA replication mechanism during stem cell divisions(R ). R mutations are mainly due to the mistakes in the division of the cells in our bodies as we replace the old cells with the new ones, and these were the ones attributed to bad luck. Naming it luck attracted criticism due to the idea it might give to the public that most of the time there is nothing to do to prevent cancer no matter how healthy your lifestyle is. Besides, there were methodological problems in the initial paper. Authors addressed these issues in a second paper. In addition, this doesn’t include the further dissection of the causes of the errors in the replication mechanism, such as free radicals and oxidation. Also, binning the mutations in three groups might be problematic in itself, since a single mutation is not enough for the cancer to arise.
Bottomline is the reality about bad luck depends on the type of cancer, some cancers are mainly caused by external factors and some are more by random mutations. As more cancer genomes are sequenced and better informed statistical analysis done, we can have a more complete answer to the question of luck. You can find the relevant reading material and evidence in the following papers.
The initial paper that kindled the discussion is in the following:
#Tomasetti and Vogelstein. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. 2015
https://www.science.org/doi/10.1126/science.1260825
Quote: “Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.”
Another group of researcher found the external factors to be more crucial:
#Wu et al. Substantial contribution of extrinsic risk factors to cancer development. 2015.
https://www.nature.com/articles/nature16166
Quote: “Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the ‘bad luck’ hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10–30% of lifetime risk) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then show that intrinsic risk is better estimated by the lower bound risk controlling for total stem-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.”
Then the authors of the initial paper followed up on the topic with the following paper:
#Tomasetti, Li and Vogelstein. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. 2017
https://www.science.org/doi/10.1126/science.aaf9011
Quote: “Cancers are caused by mutations that may be inherited, induced by environmental
factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an
independent approach, based solely on cancer genome sequencing and epidemiological
data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the
fraction of cancers that can be prevented by changes in the environment. Moreover, they
accentuate the importance of early detection and intervention to reduce deaths from the
many cancers arising from unavoidable R mutations.”
For further reading, another recent paper addressed the contribution of R mutations to the variation in cancer risk using the same dataset in 2015 paper:
# Pénisson, Lambert, and Tomasetti. Evaluating cancer etiology and risk with a mathematical model of tumor evolution. 2022
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700699/
Quote: “Based on a mathematical model of tumor evolution, a re-analysis of Tomasetti et al.6 provided an improved fitting of the variation in cancer incidence across cancer types. The number of cell divisions, and the normal endogenous mutational processes (R) associated to it, explained about 4/5 of the variation in cancer risk across tissues. When combined with the comparison between the expected number of somatic mutations due to R versus the observed one, these results overall provide further evidence for the major role R plays in cancer etiology.”
Another group of researchers recently used a different method to address the same question:
#Cannataro, Mandell and Townsend. Attribution of Cancer Origins to Endogenous, Exogenous, and Preventable Mutational Processes. 2022
https://academic.oup.com/mbe/article/39/5/msac084/6570859?login=false
Quote: “Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches—revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies.”
This does not mean that it is all luck and we can't do anything to prevent it. Most cancers that are known to be largely due to external factors like smoking, being obese, being exposed to UV can be prevented.
#Madeline Drexler. The Cancer Miracle isn’t a Cure. It’s Prevention.
https://www.hsph.harvard.edu/magazine/magazine_article/the-cancer-miracle-isnt-a-cure-its-prevention/
Quote: “A 2018 study in Science—co-authored by Song, Giovannucci, and Harvard Chan’s Walter Willett, professor of epidemiology and nutrition—made an even more emphatic case for prevention. It noted that for cancers in which most of the driving genetic mutations are caused by the environment—such as lung cancers, melanomas, and cervical cancers—85 to 100 percent of new cases could be eliminated through smoking cessation, avoidance of ultraviolet radiation exposures, and vaccination against HPV, respectively.”
– We are simplifying, but roughly, there are three categories of genes involved in cancer protection – fail safes that protect your cells from becoming cancerous. And all of these need to be corrupted so cancer can arise.
Cancer genetics is wildly complicated and we are simplifying a great deal here. We just try to give a basic explanation of how a cell turns deadly. Otherwise, genetic alterations causing cancer unfortunately do not categorize themselves into three neatly distinguished groups. It is partly because there are genes involved in multiple pathways and mechanisms that carry out functions from multiple categories and this blurs the lines between groups. For example, the P53 gene is one of the most studied tumor suppressor genes (TSGs) and found to be mutated in many cancer genomes. It is involved both in cell-cycle control, in apoptosis, and in maintenance of genetic stability. So it can be classified as TSG for stopping the cell cycle, which in turn allows for DNA repair therefore making it a caretaker-gene. It can induce apoptosis to prevent mutations from being fixed within the population (TSG) but is also necessary to protect the fidelity of essential genes (caretaker). Another reason is that there is more and more research on cancer genomes, and as more genes and functions are discovered, the new data doesn't always fit in with the previous categories.
Some researchers classify in two main categories: tumor suppressors and oncogenes.
#Vogelstein & Kinzler. Cancer genes and the pathways they control. 2004..
https://www.nature.com/articles/nm1087
Quote: “Alterations in three types of genes are responsible for tumorigenesis: oncogenes, tumor-suppressor genes and stability genes (Tables 1 and 2). Unlike diseases such as cystic fibrosis or muscular dystrophy, wherein mutations in one gene can cause disease, no single gene defect ‘causes’ cancer. Mammalian cells have multiple safeguards to protect them against the potentially lethal effects of cancer gene mutations, and only when several genes are defective does an invasive cancer develop. Thus it is best to think of mutated cancer genes as contributing to, rather than causing, cancer.”
Some other researchers categorize into three groups under a different naming and collect tumor suppressors and oncogenes together in one group.
#Michor, Iwasa & Nowak. Dynamics of cancer progression. 2004.
https://www.nature.com/articles/nrc1295
Quote: “Cancer is a genetic disease 1. Although environmental and other non-genetic factors have roles in many stages of tumorigenesis, it is widely accepted that cancer arises because of mutations in cancer-susceptibility genes. These genes belong to one of three classes 1,2: gatekeepers, caretakers and landscapers. Gatekeepers directly regulate growth and differentiation pathways of the cell and comprise oncogenes and tumour-suppressor genes (TSGs). Caretakers, by contrast, promote tumorigenesis indirectly 3,4. They function in maintaining the genomic integrity of the cell. Mutation of caretakers can lead to genetic instability, and the cell rapidly accumulates changes in other genes that directly control cell birth and death. Landscaper defects do not directly affect cellular growth, but generate an abnormal stromal environment that contributes to the neoplastic transformation of cells5.”
Otherwise it takes a lot more to define a cancer cell and the framework is updated as more research accumulates. The following paper summarizes how the commonly accepted hallmarks of cancer have changed in the last two decades.
#Hanahan. Hallmarks of Cancer: New Dimensions. 2022.
Quote: “[Image caption] In essence: the Hallmarks of Cancer, circa 2022. Left, the Hallmarks of Cancer currently embody eight hallmark capabilities and two enabling characteristics. In addition to the six acquired capabilities—Hallmarks of Cancer—proposed in 2000 (1), the two provisional “emerging hallmarks” introduced in 2011 (2)—cellular energetics (now described more broadly as “reprogramming cellular metabolism”) and “avoiding immune destruction”—have been sufficiently validated to be considered part of the core set. Given the growing appreciation that tumors can become sufficiently vascularized either by switching on angiogenesis or by co-opting normal tissue vessels (128), this hallmark is also more broadly defined as the capability to induce or otherwise access, principally by invasion and metastasis, vasculature that supports tumor growth. The 2011 sequel further incorporated “tumor-promoting inflammation” as a second enabling characteristic, complementing overarching “genome instability and mutation,” which together were fundamentally involved in activating the eight hallmark (functional) capabilities necessary for tumor growth and progression. Right, this review incorporates additional proposed emerging hallmarks and enabling characteristics involving “unlocking phenotypic plasticity,” “nonmutational epigenetic reprogramming,” “polymorphic microbiomes,” and “senescent cells.” The hallmarks of cancer graphic has been adapted from Hanahan and Weinberg (2).”
Besides, each cancer is different and has a map of genetic mutation from which scientists started to find potential signature patterns. Researchers make these maps by sequencing the genomes from tumors of different types of cancers. Following is an example in which 21 breast cancer genomes are sequenced and patterns in somatic mutations are identified.
#Nik-Zainal et al. Mutational Processes Molding the Genomes of 21 Breast Cancers. 2012.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414841/
Quote: “Cancers carry somatic mutations. A small proportion are ‘‘drivers’’ that confer clonal advantage, are causally implicated in oncogenesis, and have been positively selected during the evolution of the cancer (Stratton, 2011; Stratton et al., 2009). Driver mutations occur in the subset of genes known as cancer genes. Through systematic sequencing of cancer genomes, considerable advances have recently been made in the identification of cancer genes, providing insights into mechanisms of neoplastic transformation and targets for therapeutic intervention (Stratton, 2011; Stratton et al., 2009). We have relatively limited understanding, however, of the DNA damage and repair processes that have been operative during the lifetime of the patient and that are responsible for the somatic mutations that underlie the development of all cancers in the first place.”
Lastly, we obviously don’t mean that only three mutations are found in all cancers. Following is an extensive review of the genetic alterations in cancer.
#Vogelstein et al. Cancer Genome Landscapes. 2013.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749880/pdf/nihms496129.pdf
Quote: “Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.”
– The first key mutation is in the appropriately named tumor suppressor genes, or TSGs. These genes are a bunch of things. For one, they produce control mechanisms that continuously scan your DNA for mistakes and copying errors and fix them right away. If TSGs become damaged themselves, your cells basically forget how to repair themselves and get more and more faulty as time goes on.
Following paper provides a summary of different functions of TSGs.
#Sun & Yang. Functional Mechanisms for Human Tumor Suppressors. 2010
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948218/pdf/jcav01p0136.pdf
Quote: “Tumor suppressors refer to a large group of molecules that are capable of controlling cell division, promoting apoptosis, and suppressing metastasis. The loss of function for a tumor suppressor may lead to cancer due to uncontrolled cell division. Because of their importance, extensive studies have been undertaken to understand the different functional mechanisms of tumor suppressors. Here, we briefly review the four major mechanisms, inhibition of cell division, induction of apoptosis, DNA damage repair, and inhibition of metastasis. It is noteworthy that some tumor suppressors, such as p53, may adopt more than one mechanism for their functions.”
– And then they keep normal cells from multiplying recklessly. When mutations disrupt the function of tumor suppressor gene products these protections are turned off and a cancer cell can reproduce unchecked.
In the following paper, the section “Suppression of Cell Division” provides a short summary of examples of TSGs involved in this function.
#Sun & Yang. Functional Mechanisms for Human Tumor Suppressors. 2010
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948218/pdf/jcav01p0136.pdf
Quote: “Suppression of cell division is the main mechanism for most tumor suppressors. The tumor suppressors that adopt this mechanism include retinoblastoma protein (Rb), adenomatosis polyposis coli (APC), alternate reading frame (ARF), RIZ1, p15, p16, p18, p19, p21, p27, and p53 (8, 9, 11-21). Rb, which is the first discovered tumor suppressor, inhibits the transcription of specific genes required for mitosis through binding to transcription factors such as E2Fs, which are key cell proliferation regulators (12, 13). Tumor suppressor p53, which can also bind to DNA, stimulates the expression of other genes, such as WAF1/CIP1 encoding p21 (8, 22). ”
– The second crucial mutation can happen in your oncogenes. When oncogenes are turned on the cell is told to multiply rapidly. They were super active when you were inside your mother’s womb. To turn a single original cell into trillions in months, it needs to divide and grow rapidly. These rapid growth genes are turned off when there is enough of you. When your oncogenes get corrupted, they basically turn on again.
#Kontomanolis et al. Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review. 2020
https://ar.iiarjournals.org/content/40/11/6009.long
Quote: ”In the normal cell, there are proto-oncogenes which are key regulatory factors of biological processes. Proto-oncogenes may function as growth factors, transducers of cellular signals and nuclear transcription factors (Table I). Mammalian and avian genomes contain a range of proto-oncogenes which control normal cell differentiation and proliferation (3). Changes to these genes that influence either the control of their behavior or the way that their encoded proteins are structured can show up in cancer cells as enacted oncogenes. When such oncogenes are formed, they go on to drive cell multiplication and assume a pivotal role in the pathogenesis of cancer.”
#Rachel C. West, Gerrit J. Bouma & Quinton A. Winger. Shifting perspectives from “oncogenic” to oncofetal proteins; how these factors drive placental development. 2018
https://rbej.biomedcentral.com/articles/10.1186/s12958-018-0421-3
Quote: “Typically, when one considers oncogenes it’s hard to ignore the profound effects these proteins have during normal homeostasis in adult tissues. These genes promote rampant cell proliferation in otherwise healthy tissues. Proliferative cells eventually begin to migrate towards other organ systems, invading into tissues to form metastatic tumors. However, to only consider oncogenes as “bad” fails to consider the original purposes of these genes. These oncogenic processes are essential during early embryonic, fetal, and placental development and any aberrant signaling by these genes can cause devastating effects on fetal growth. These proteins are responsible for the cancer-like processes that characterize early placental development. However, in direct contrast to carcinogenesis, the placenta uses these factors in a tightly controlled, highly regulated environment. This regulation exploits these factors so that they create a remarkably efficient organ in a short amount of time without the adverse consequences that often come with the expression of oncogenic proteins. Therefore, we propose that oncogenes instead be considered as oncofetal proteins.”
– So one mutation switches genes off that should be on, and another one activates some that should be off.
Following paper explains the play off between the TSGs and oncogenes in a simple way.
#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. The Molecular Basis of Cancer-Cell Behavior.
https://www.ncbi.nlm.nih.gov/books/NBK26902/
Quote: “Oncogenes and tumor suppressors—and the mutations that affect them—are different beasts from the point of view of the cancer gene hunter. But from a cancer cell's point of view they are two sides of the same target. The same kinds of effects on cell behavior can result from mutations in either class of genes, because most of the control mechanisms in the cell involve both inhibitory (tumor suppressor) and stimulatory (proto-oncogene) components. In terms of function, the important distinction is not the distinction between a tumor suppressor and a proto-oncogene, but between genes lying in different biochemical and regulatory pathways.”
– The third crucial mutation is in your cells’ suicide switch. Most cells are constantly recycled and refreshed. When cells amass too much damage, they usually notice and special genes trigger a controlled suicide called apoptosis. If the genes that control this process get damaged, cells are free to live on despite being dangerously corrupted.
In the following one can find a simple explanation of apoptosis.
#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. The Molecular Basis of Cancer-Cell Behavior.
https://www.ncbi.nlm.nih.gov/books/NBK26902/
Quote: “To achieve net cell proliferation, it is necessary not only to drive cells into division, but also to keep cells from committing suicide by apoptosis. There are many normal situations in which cells proliferate continuously, but the cell division is exactly balanced by cell loss. In the germinal centers of lymph nodes, for example, B cells proliferate rapidly but most of their progeny are eliminated by apoptosis. Apoptosis is thus essential in maintaining the normal balance of cell births and deaths in tissues that undergo cell turnover. It also has a vital role in the cellular reaction to damage and disorder. As described in Chapter 17, cells in a multicellular organism commit suicide when they sense that something has gone wrong—when their DNA is severely damaged or when they are deprived of survival signals that tell them they are in their proper place. Resistance to apoptosis is thus a key characteristic of malignant cells, essential for enabling them to increase in number and survive where they should not.”
Some researchers group apoptosis genes together with TSGs, but again, the borders of these classifications are rather blurry and there is no clear right or wrong.
#Nenclares and Harrington. The biology of cancer. 2019.
https://www.medicinejournal.co.uk/article/S1357-3039(19)30287-7/fulltext
Quote: “TSGs are normal cellular genes that function to inhibit cell proliferation and survival. They are frequently involved in controlling cell cycle progression and programmed cell death/ apoptosis.”
– So if for example, your oncogenes switch back on, they make oncogene proteins. Your immune system knows that they should not be present if you are an adult.
#Lu et al. Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis. 2001.
https://pubmed.ncbi.nlm.nih.gov/11549587/
Quote: “Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II.” (HCC is short for hepatocellular carcinoma)
– So to know which cells are corrupt and which are healthy, your immune system needs to know what proteins they are making inside. To solve this evolution came up with MHC class I molecules, a sort of display window that makes cells transparent.
Following paper explains this peptide representation mechanism in detail.
#Leone et al. MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells. 2013.
https://academic.oup.com/jnci/article/105/16/1172/942776
Quote: “The main function of class I molecules, which are expressed on the plasma membrane of most cell types, is to display these peptides to cytotoxic CD8+
T cells in support of their crucial activity of immune surveillance. Peptides derived from normal cellular (self) proteins are regularly ignored by CD8+ T cells, whereas those from mutated proteins and from the nonself proteins of viruses and other intracellular pathogens are not ignored but trigger an adaptive immune response through binding to the T-cell receptor (TCR).”
– Cells constantly take little samples of the proteins they make and put them into thousands of these MHC molecules, to showcase what they are doing. The selection is constantly refreshed, always giving an up to date picture.
#Dhatchinamoorthy, Colbert & Rock. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.636568/full
Quote: “To understand some of the mechanisms by which many cancers evade immune surveillance, it is necessary to first understand the MHC I pathway of antigen presentation (Figure 1). This pathway is the mechanism that allows CD8 T cells to identify cells producing “foreign” proteins, such as ones from viruses in infected cells or mutant genes in cancers. In this pathway, MHC I-presented peptides are generated as part of the normal catabolism of cellular proteins. All endogenously synthesized proteins are continuously degraded into oligopeptides by the ubiquitin-proteasome pathway (29). This catabolic pathway is responsible for making the initial cleavages, and particularly the proper C-terminal cut, needed for the generation of a majority of MHC I-presented peptides (29–32).”
There is a constant turnover of proteins in the cell, they are continuously degraded and new ones are made. Old proteins are handled differently depending on their way of death. Short-lived, regulatory proteins, viral proteins in infected cells or mutated proteins in cancer cells are chopped in small chunks and are represented to T cells by MHC class I molecules. Production, transport, preparation and presentation of these smaller chunks involve a concerted activity of organelles and protein complexes, which has been schematically summarized in the following image.
#Leone et al. MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells. 2013.
https://academic.oup.com/jnci/article/105/16/1172/942776
– There is a whole library of proteins that are highly dangerous and should not be made by healthy cells, and your immune system has them all on file. It has billions of specialized cells, called T Cells, made to recognize specific proteins. If a T Cell sees a forbidden protein in an MHC display window, it knows that the cell is corrupted and kills it immediately.
The “forbidden proteins” are the so-called non-self peptides for which T Cells were selected in thymus before they got into circulation. If a T Cell then encounters a matching sequence on a cell, it simply kills the cell.
We explained this process in a previous video: You Are Immune Against Every Disease https://www.youtube.com/watch?v=LmpuerlbJu0
Still you can refer to the following papers for further reading:
#Messerschmidt et al. How Cancers Escape Immune Destruction and Mechanisms of Action
for the New Significantly Active Immune Therapies: Helping Nonimmunologists Decipher Recent Advances. 2016.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746082/pdf/theoncologist_15282.pdf
Quote: “Negative selection occurs when T-cell receptors recognize self-proteins presented by self-MHCs and elicit a higher affinity binding and T-cell activation response. Signaling then occurs to induce these higher binding (to self) T cells to start the process of self-apoptosis [25]. Conservation of germline-specific sequences within the variable regions are critical to MHC binding and peptide recognition. MHC binding is the integral first step in TCR binding to a presented antigen.The CD3 region of the TCR then contacts the presented peptide and must be recognized as self by these conserved sequences. If the location of the conserved sequences are recognized, no distortion in the CD3 will result, and the TCR and the T cell will be positively selected.
The newly rearranged positively selected T cells then exit the thymus and circulate via the blood and lymphatic vessel system.Thymocyte gene rearrangements, followed by positive and negative selection of these rearranged TCRs, results in approximately 2.5 x 10^8 (250 billion) different TCRs in the periphery of humans. Through constant recirculation, these lymphocytes continually search the human organism. Most of the time, they do not encounter their antigen and continue to move throughout the body looking for a match (Fig. 1) [26].”
#Messerschmidt et al. How Cancers Escape Immune Destruction and Mechanisms of Action
for the New Significantly Active Immune Therapies: Helping Nonimmunologists Decipher Recent Advances. 2016.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746082/pdf/theoncologist_15282.pdf
Quote: “Random gene rearrangements within these cells produce millions of different sequences, one per cell, that then are transcribed to produce the specific T-cell receptor surface complex (TCR) in the specific pre-T cell or the immunoglobulin (Ig) produced by the specific pre-B cell. Because the rearrangement process is random, some gene rearrangements will produce Igs or TCRs that recognize normal host proteins/sequences. Cells that randomly produce Igs or TCRs to “self” sequences are regulated through a process known as self-tolerance, either by deletion (central tolerance) or by suppressing their activation in the periphery (peripheral tolerance). Specificity is critical for T cells. Effector T cells are capable of killing normal and cancer cells if they are recognized as non-self. Most peripheral T cells never encounter a foreign antigen to which they can respond specifically. However, all T cells must be able to recognize self-peptides and self-MHC (abbreviated as self-pMHC) and demonstrate only low-affinity interactions to
avoid autoimmune reactions and maintenance of homeostasis once they leave the thymus and enter the peripheral circulations for their lifespan.”
– What if a cancer cell mutates and finds a way to circumvent this process? All it needs to do is to stop making MHC Class I molecules, and boom, it’s invisible.
#Dhatchinamoorthy, Colbert & Rock. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.636568/full
Quote: “Cancers are often genetically unstable and can lose expression of non-essential molecules through gene loss or epigenetic silencing. MHC I molecules and most of the other molecules of the MHC I antigen presentation pathway are not essential for cell viability or growth (see below). Consequently, cancers can down-regulate or lose MHC I antigen presentation, and thereby become less stimulatory or even invisible to CD8 T cells, without impairing their ability to grow and metastasize.”
From trimming the proteins into peptides to presenting them to T Cell, there are many steps carried out by many organelles and protein complexes, which are collectively called the MHC class I antigen processing and presentation machinery (APM). Anything going wrong in any of these may avoid MHC class I molecules to do their job, and indeed several of these components have been found to be defected in tumors.
Following paper provides a list of mutations in APM found in various cancer types.
#Leone et al. MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells. 2013.
https://academic.oup.com/jnci/article/105/16/1172/942776
Quote: “Defects in the expression and function of APM components have been found in various solid and hematologic tumors. They occur individually or in combination, and the frequency and nature of the defect vary substantially according to tumor type (Table 1). The
molecular mechanisms underlying these defects have been partly identified for some components only and seem to take place at the genetic and epigenetic levels (Table 2). There is also some evidence that transcriptional and post-transcriptional defects may occur.”
– In this second, hundreds of millions of Natural Killer Cells patrol your body looking for cells that have already turned into cancer or are corrupted by a virus.
#Huntington, Cursons & Rautela. The cancer-natural killer cell immunity cycle. 2020
https://pubmed.ncbi.nlm.nih.gov/32581320/
Quote: “A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. ”
#Caligiuri. Human natural killer cells. 2008.
https://ashpublications.org/blood/article/112/3/461/25260/Human-natural-killer-cells
Quote: “NK cells are believed to be relatively short-lived, and at any one time there are likely more than 2 billion circulating in an adult.”
#Imai et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. 2000.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)03231-1/fulltext
Quote: “Our results indicate that medium and high cytotoxic activity of peripheral-blood lymphocytes is associated with reduced cancer risk, whereas low activity is associated with increased cancer risk suggesting a role for natural immunological host defence mechanisms against cancer.”
– Natural Killer Cells move through your body right now, going from cell to cell to check for one thing: Does a cell have MHC class I molecules? Does it have a display window and is doing its duty of showing off what is going on inside itself.
Natural Killer Cells carry out their function through the battery of inhibitory and activating receptors they carry. They differentiate healthy cells from unhealthy ones by measuring the sum of activating and inhibitory signals. Therefore it is not only the absence of MHC class I molecules but also the presence of activating ligands on viral or cancer cells that turn the killing mode on NK cells.
#Leone et al. MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells. 2013.
https://academic.oup.com/jnci/article/105/16/1172/942776
Quote: “MHC class I molecules also function in the innate immune system by serving as ligands of inhibitory killer cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells. NK cells have the unique ability to recognize and nonspecifically kill cells lacking self MHC class I molecules. Because all healthy nucleated cells express self MHC class I molecules, inhibitory KIRs ensure that NK cells do not attack normal cells but eliminate infected and tumor cells (which may have reduced MHC class I molecule expression) (9). Because not all infections or cancers reduce MHC class I expression, the role of these proteins in the adaptive immune response is fundamental.”
#Paul and Lal. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. 2017
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01124/full
Quote: “Natural killer cell stimulation and effector function depend upon the integration of signals derived from two distinct types of receptors—activating and inhibitory receptors (Table 1). Normal healthy cells express MHC class I molecules on their surface which act as ligands for inhibitory receptors and contribute to the self-tolerance of NK cells. However, virus-infected cells or tumor cells lose surface MHC class I expression, leading to lower inhibitory signal in NK cells. Simultaneously, cellular stress associated with viral infection or tumor development such as DNA damage response, senescence program or tumor suppressor genes upregulate ligands for activating receptors in these cells. As a result, the signal from activating receptors in NK cell shifts the balance toward NK cell activation and elimination of target cells directly through NK cell-mediated cytotoxicity or indirectly through secretion of pro-inflammatory cytokines (10) (Figure 1) ”
– This is so amazing because it covers all of your bases: While T Cells look for the presence of the unexpected, something that should not be here, Natural Killer Cells look for the absence of the expected, the absence of something that should be here.
The ability of Natural Killer Cells to detect the target based on the absence of a signal rather than the presence of it as thought initially. This mechanism is called the Missing Self Theory and it is the guiding principle of NK cell target recognition for more than 20 years.
#Ljunggren & Kärre. In search of the ‘missing self’: MHC molecules and NK cell recognition. 1990.
https://www.sciencedirect.com/science/article/abs/pii/016756999090097S
Quote: “T cells recognize nonself antigens in association with MHC molecules, for example on transformed or virus-infected cells 1-3. Such is the sensitivity of recognition that single amino acid substitutions in an MHC class I molecule or a peptide antigen can be sufficient to create a foreign determinant detected by cytotoxic T cells (CTL) 4,5. NK cells can also discriminate between aberrant and normal cells. They can reject transformed, virus-infected and nonsyngeneic hemopoietic cells and thereby protect an animal from death 6-9. However, it has been difficult to define minimal changes that determine whether an NK cell will lyse or spare an aberrant cell from lysis.
The 'missing self' hypothesis Soon after the discovery of NK cells 10, it became clear
that they could kill certain tumor lines in spite of the fact that they expressed no, or only low amounts of, MHC class I molecules 11-16. We have suggested that NK cells kill such targets because they express reduced levels of 'self’ MHC class I gene products 17-19. According to this 'missing self' hypothesis, one function of NK cells is to recognize and eliminate cells that fail to express self MHC class I molecules”
– What makes the Natural Killer Cell even more metal, is that it is always in murder mode. It patrolls your body, checking cell after cell with the intention of killing it. Your healthy cells have to convince it that they should not die today. And a way to do that is to have a lot of MHC class I molecules.
As mentioned above, Natural Killer Cells have a rather graded response than an ultimate killer mode. They integrate the competing signals they receive from the target cells and based on the net input of that signal they decide if the target cells should be killed or not.
#Vivier, Nunes and Vely. Natural Killer Cell Signaling Pathways. 2004.
Quote: “NK cells have been instrumental in revealing a general theme in cell
activation, which is that effector cell function results from a dynamic equilibrium
between multiple and sometimes opposing pathways that can be simultaneously engaged (1, 2). Integration of these numerous inputs culminates in a graded NK cell response—in other words, cytotoxicity and/ or cytokine production.”
#Backes et al. Natural killer cells induce distinct modes of cancer cell death: Discrimination, quantification, and modulation of apoptosis, necrosis, and mixed forms. 2018.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200954/pdf/zbc16348.pdf
Quote: “Whereas CTL recognize specific peptides presented by MHC-I using the T-cell receptor, NK cells analyze both activating and inhibitory ligands on the target cell with their germline–encoded receptor repertoire and integrate these signals. Upon activation, killer cells form a tight contact with the target called the immune synapse (IS) and polarize lytic granules (LG) as well as other organelles and molecules toward the contact site (11, 12). LG contain the pore-forming protein perforin, which, upon release, generates holes in the target cell membrane and allows serine proteases called granzymes to enter the cytosol of the target cell. If this local membrane disruption cannot be neutralized by the target cell, cell death by rapid swelling and lysis follows (necrosis). If membrane integrity can be restored, the injected granzymes induce cell death by caspase activation and subsequent caspase-dependent apoptosis (13). In addition to the granule-based killing pathway, another well-established killing mechanism involves the interaction of Fas ligand (FasL) on cytotoxic cells with Fas receptor (FasR)-positive target cells inducing target cell apoptosis (14).”
– Ok, but if your body is this prepared, why do we still get cancer?
Being a second line of defense does not make Natural Killer Cells the ultimate exterminator. Cancer cells still progress in most clinic cases despite NKCs.
#Dhatchinamoorthy, Colbert & Rock. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.636568/full
Quote: “Despite NK cells being a potential second line of defense against tumors that have lost MHC I, once such tumors become clinically evident, they almost always progress. In fact, as noted above, loss of MHC I is often a negative prognostic indicator. Moreover, there is no evidence that MHC I negative cancers are infiltrated with more NK cells than MHC I sufficient cancers (283). Therefore, for many MHC I low cancers, either they were never targets of NK cells or such tumors have evolved ways to evade control by NK cells.”
– Well, sometimes cancer cells mutate more and get much better at fighting back.
Here we just brushed the surface of a bigger concept called cancer immunoediting, which includes not only immunosurveillance but the broader range of interactions between the immune system and tumor. Immune system not only protects against cancer but also shapes it. Cancer cells are not a lump of idle cells but they engage with the immune system which genetically sculpts the cancer in a way. By eliminating the cancer cells that are easier to catch, the immune system selects for the more resistant cancer cells that are better at fighting with the defenses of the immune system.
Essentially, our current understanding is that the race between the immune system and cancer is a three step process. So far we talked about the first one, the elimination phase and specifically the role of the Natural Killer Cells in it. However, the elimination phase is not always complete and if the cancer cells survive; they take it to a second phase called equilibrium where lymphocytes keep the tumor contained but are not able to get rid of it. Under the selective pressure of the immune system, new variants of the tumor cells with resistance to immune defense arise. And the last step, Escape Phase, variants that can not be detected or eliminated by the immune system take over which leads to the clinically observable cancer. Each phase involves a complex network of interactions between the immune cells and the tumor and there is still much to be uncovered about each mechanism. Tumor is not a lump of uniform cells, it is a dynamic tissue with different types of cells that interact with each other and immune cells.
#Dunn et al. Cancer immunoediting: from immunosurveillance to tumor escape. 2002.
https://www.nature.com/articles/ni1102-991
Quote: “We envisage cancer immunoediting as a result of three processes: elimination, equilibrium and escape. We call these the three Es of cancer immunoediting (Fig. 1). Immunosurveillance occurs during the elimination process, whereas the Darwinian selection of tumor variants occurs during the equilibrium process. This in turn can ultimately lead to escape and the appearance of clinically apparent tumors.”
– Right now a number of new anti cancer therapies are beginning to show amazing promise, from new cancer fighting vaccines, to Immunotherapie, that use engineered and improved T Cells and even Natural Killer cells that have been buffed to eliminate this disease – we will look at these therapies in future videos.
Immunotherapy simply involves all methods that harness the immune system’s tools to fight cancer. Cancer vaccines, adoptive cell therapies (engineering T or NK cells), monoclonal antibodies, cytokine therapies, oncolytic viruses, and inhibitors targeting immune checkpoints fall under immunotherapy. Accounting for all methods is beyond the scope of this video but the following paper reviews the recent advances.
#Mishra et al. Emerging Trends in Immunotherapy for Cancer. 2022
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498256/
Quote: “Recent advances in cancer immunology have enabled the discovery of promising immunotherapies for various malignancies that have shifted the cancer treatment paradigm. The innovative research and clinical advancements of immunotherapy approaches have prolonged the survival of patients with relapsed or refractory metastatic cancers. Since the U.S. FDA approved the first immune checkpoint inhibitor in 2011, the field of cancer immunotherapy has grown exponentially. Multiple therapeutic approaches or agents to manipulate different aspects of the immune system are currently in development. These include cancer vaccines, adoptive cell therapies (such as CAR-T or NK cell therapy), monoclonal antibodies, cytokine therapies, oncolytic viruses, and inhibitors targeting immune checkpoints that have demonstrated promising clinical efficacy. Multiple immunotherapeutic approaches have been approved for specific cancer treatments, while others are currently in preclinical and clinical trial stages. Given the success of immunotherapy, there has been a tremendous thrust to improve the clinical efficacy of various agents and strategies implemented so far.”
In the following you can find further information for the three specific methods we mentioned.
On cancer vaccines:
#Runwal. Cancer vaccines are showing promise. Here’s how they work. 2022.
On engineering T Cells:
#Sterner & Sterner. CAR-T cell therapy: current limitations and potential strategies. 2021.
https://www.nature.com/articles/s41408-021-00459-7
Quote: “Chimeric antigen receptor (CAR)-T cell therapy has been revolutionary as it has produced remarkably effective and durable clinical responses1. CARs are engineered synthetic receptors that function to redirect lymphocytes, most commonly T cells, to recognize and eliminate cells expressing a specific target antigen. CAR binding to target antigens expressed on the cell surface is independent from the MHC receptor resulting in vigorous T cell activation and powerful anti-tumor responses2. The unprecedented success of anti-CD19 CAR-T cell therapy against B cell malignancies resulted in its approval by the US Food and Drug Administration (FDA) in 20173,4,5. However, there are major limitations to CAR-T cell therapy that still must be addressed including life-threatening CAR-T cell-associated toxicities, limited efficacy against solid tumors, inhibition and resistance in B cell malignancies, antigen escape, limited persistence, poor trafficking and tumor infiltration, and the immunosuppressive microenvironment. “
On engineering NK Cells:
#Xie et al. CAR-NK cells: A promising cellular immunotherapy for cancer. 2020.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30351-0/fulltext#%20
Quote: “Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for treating haematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including: (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogenic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for ‘off-the-shelf’ manufacturing. CAR-NK cells could be engineered to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, and ultimately achieve an effective anti-tumour response.”