Why cancer cells waste so much energy
news.mit.edu
news.mit.edu
So tempting to go with analogies we are familiar with.
And hopefully that's a path to follow that will help treat/cure some types of cance? This all just barely makes sense to me, but my first question was "Does this help beat cancer in a new way?" and I guess the answer is... maybe?
You will force your own cells to do so: red blood cells, certain immune cells etc.
We already do something along those lines - reducing sugar input via diet and sugar neogensis via metformin.
Be all that as it may, the finding is astounding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474827/
This is known as "atavistic theory of cancer" and it is rather controversial, there are people who utterly hate it, not least because the original authors are not specialists in cancer treatment.
Part of this theory is that cancer cells "cannot help but switch to the previous single-celled metabolism, very inefficient compared to ours".
This is the track they are on, but given how shortlived they are, they never get the chance to do much evolution. They only have time to learn a few tricks. Simple things like turning stuff of or up/downregulating existing systems. It's a strange step to "cannot help but switch to the previous single-celled metabolism, very inefficient compared to ours".
Theory in article seems much more likely.
There is a very rare category of cancers for which this is not true, clonally transmissible cancers[1]. They can move from individual to individual like other pathogens. One example is the devil facial tumor disease[2] that has killed around 95% of Tasmanian devils.
1. https://en.wikipedia.org/wiki/Clonally_transmissible_cancer
2. https://en.wikipedia.org/wiki/Devil_facial_tumour_disease
Myers is very outspoken in his rejection of the idea, but even as an amateur I can see rhetoric sleights of hand in his argumentation. An example:
These “layers” don’t exist! When my car malfunctions, I don’t get a horse
Bad comparison, a car did not evolve from a horse, there is no mechanism for it to have a previous "horse layer".
Myers seems to hate the idea so much and return to it so often and with so many damnations and so few citations that it actually decreases his credibility in my eyes.
> and the original genes might carry on within our DNA until today
Luckily we don't need to resort to "might". Since the advent of genome sequencing we can just go ahead and take a look!
E.g. yeast (your standard single-celled organism) posesses ~6000 genes of which ~23% (= 1380 genes) are similar in function to those of humans. Of those genes most of them have been severely mutated, on average sharing 32% sequence similarity, which is a world of difference in terms of protein functionality.
The few highly preserved genes that remain are core parts of all eucaryotic life (ribosomes, proteins for amino acid metabolism, etc.) and are some of the most studied genes (regarding cancer and in general).
Suggesting that there are some genes hiding in there and have been overlooked due to narrow-mindedness of the whole life science community is a bit naive.
It's not close to even 'relatively' being new. I was giving cancer talks that made mention of it back when I worked in cancer bio, just about 16 years ago now. I didn't come up with it, and it wasn't new then. I used it in talks to laymen, to give a very abstract idea of how cancer worked. But it fell into the category of "lies we tell children," because it was only true in the most abstract way, and utterly incorrect once you dug into any details.
The reason cancer bio people dislike it is because it's only true at the 10,000-foot, highly abstracted level. When you start digging into the granular level, its testable predictions rank between 'falsified' and 'irrelevant'. It doesn't produce any alternative lines for thinking about treatment, causality, etc. Especially given that the progress of a single cancer tends to be all about their interaction with the multicellular milieu - e.g., developing immune evasion, which isn't at all an "atavistic" trait, although it's one of the core hextad that defines malignant development. (On the contrary, it comes built-in for normal cells - they're now developing a novel immune evasion, to hide their newly altered antigens from the immune system).
e.g., "Cannot help but switch to previous single-celled metabolism" doesn't follow in any meaningful way from the thesis of atavistic traits. In fact, it doesn't predict at all the relationship between tumor size, distance from vascular supply, and anaerobic metabolism. "Cells without controlled growth will outgrow their vascular supply, requiring a transition to anerobic metabolism" does, however, and predicted the relationships we see. It's not "cannot help but engage with less efficient metabolism", it's "transition to relying on the only metabolism afforded to a highly-dysregulated cell that is not responsive to environmental signals that normally trigger or withhold growth." Normal unicellular organisms are responsive to those signals.
Yeah, I don't hate it - it's a cute metaphor. It's a nice way of thinking of cancer at the 10K-foot level. It's just also wrong at any closer level of inspection than that, which is why people whose job is to be elbow-deep in all of the nitty-gritty details of cancer can't help but look at it and go "please stop wasting my time."
If cancer cells have high metabolic requirements, couldn't you attack them by:
1. lowering the caloric intake of the patient
2. Making the glucose the patient intakes mildly radioactive, say with a beta or an alpha emitter [1]. As the patient is strictly kept on a low caloric diet, the radioactive glucose is consumed and expelled quickly (i.e. doesn't accumulate in the adipose (?) tissue).
Not so radioactive that the person is harmed but radioactive enough to pack an extra punch to the metabolically starved, and therefore stressed, cancer cells (who are drawing more of the glucose to themselves).
That should target cancer more specifically, and I guess it can be done in tandem with other techniques.
Is something similar done? I know that's how cancer is imaged, and the way I see it (I studied optics in a previous life) if you can image it, you should be able to destroy it.
[1] Say replacing the hydrogens in glucose with tritium. Hydrogen hopping will ensure that the water produced by metabolizing the sugar is homogeneously mixed, and therefore expelled with all the water loss mechanisms. According to wikipedia, TO2 has a half life of 12 days. I'd imagine you can lower that by pumping fluids into the patient.
That's part of the problem. Think you can come up with a synthesis of glucose that replaces the nonlabile hydrogens with tritium, is doable on the days scale, repurifiable for human consumption and mass producable on-site at a hospital?
For reference ($900/20Ci): https://www.perkinelmer.com/product/glucose-d-3-3h-hplc-puri...
(Not an endorsement of the idea)
At least that's my understanding. I'm not in the field.
Chlorine isn’t too bad in terms of toxicity, or it wouldn’t be added to drinking water and freely sold for all sorts of purposes.
But there’s absolutely no reason to ingest it (or any other route of administration).
I guess it’s exactly because of it’s ubiquity that those of a conspiratorial mindset like it so much: it fits with the idea that there are obvious and easy answers suppressed by that mighty cabal of Bill Gates/Soros/some other Jews.
It was used in a phase II clinical trial for ALS, and a subset of patients did not have any progression during the 6 month trial [0]. Something highly improbable.
Unfortunately this was not confirmed in a following phase III trial.
I wasn't sure what to make of what you said until you dropped this common fallacy used by MMS cultists.
All forms of oxidising bleach (chlorine gas, hypochlorite solution, chlorine dioxide, hydrogen peroxide, sodium perborate, etc) take effect by taking electrons from other matter. These reactions are able to "bleach" because pigments are often complex organic molecules which tend to decompose in presence of strong oxidizers.
The toxicity of chlorine dioxide is very well studied. Guess what, once absorbed it acts as a bleach/oxidizer in your blood, rupturing red blood cells and may lead to kidney failure as haemoglobin is released into the plasma.
The reaction is caused by the inhibition of glucose 6-phosphate dehydrogenase which is probably the tenuous link between consuming bleach and cancer treatment. While the enzyme is indeed a drug target that people have looked into, it is very unlikely to work by oral dosing because many healthy issue also rely on the enzyme to survive.
This, of course, has not stopped the MMS cult from claiming that their panacea cures every single ailment under the sun which has no medical basis whatsoever.
I'm not a doctor, but there seems to be some medical basis in some pathologies. If you are a doctor or scientist perhaps your input would be greatly appreciated in the following papers:
In vivo evaluation of the antiviral effect of ClO2 in chicken embryos inoculated with avian infectious bronchitis coronavirus https://www.biorxiv.org/content/10.1101/2020.10.13.336768v1
Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate https://pubmed.ncbi.nlm.nih.gov/7151767/
Mechanistic aspects of ingested chlorine dioxide on thyroid function: impact of oxidants on iodide metabolism https://pubmed.ncbi.nlm.nih.gov/3816729/
Efficacy and Safety Evaluation of a Chlorine Dioxide Solution https://pubmed.ncbi.nlm.nih.gov/28327506/
Also, CDS is not MMS.
>Also, CDS is not MMS.
Out of curiosity, do you acidify the ClO2 solution before quaffing it? It's a ritual very well associated with MMS proponents but probably does more harm than good if the goal is to deliver chlorine to the body.
> No evidence of thyroid effects were detected in the serum of human volunteers who ingested approximately 1 mg/l. of ClO2 in drinking water as a result of routine use in the community water treatment process.
I don't acidify the ClO2 solution.
I'm not a doctor but have a background in biomedical research. Just to point out that there are countless fringe medical theories and therapies out there with varying degrees of anecdotal and scientific evidence backing them up. However it's quite telling that many claim the same benefits whilst instructing people to do the exact opposite things. Even the more promising ones (resveratrol and fructose toxicity are the ones I have actually spent time working on) eventually turned out to be nothing but wishful thinking and sometimes just bad science. I wish you the best of health but at the end of the day, what seems to have worked for you does not mean that it will work for everybody else.
> what seems to have work for you does not mean that it will work for everybody else.
I agree with you on this. I just hope there was more funding or incentives for scientists studying this which, so far, has helped me and many people I know.
https://www.theverge.com/2020/5/26/21270290/youtube-deleting...
In fact for the average layperson, figuring out what's good information and what's bad information on YouTube or the internet in general is probably beyond their abilities. I know my dear mother, who I love, can't do it. I like to think I can, but I'm the least qualified person to judge that. I'm also not average.
But I want to point out that one of the main treatment options for cancer is Chemo, which is basically injecting/ingesting toxic substances in the effort to weaken or kill the cancer before killing the host. So chlorine could well work in the vein, but I wouldn't want to use myself as test subject A in an unregulated pre-clinical trial.
As to Radioactivity, I’m not sure if your model would work: higher usage does not necessarily mean “more contact with”. Does the fish that drinks more have more exposure to water than his friend?
That said, radioactivity is obviously used, because cells at the proliferation stage are specifically susceptible to it. The same is true for most chemotherapy, I. e. they target the mechanisms of cell division.
The carbon and oxygen in glucose used as fuel doesn't stay in the cell - it becomes lactic acid (or carbon dioxide and water), which leaves the cell.
You could make a weaponised version of something which does get retained in the cancer cell. For example, nucleosides, which are the raw material for DNA, and which are needed in volume to support cancer cells' rapid proliferation. These drugs are called nucleoside analogues, and are used to treat cancer and viruses:
The keto diet is actually recommended for certain types of cancer patients for this reason. While almost all human body cells can adjust to using ketones, most types of cancer cells cannot.
1. We do attempt to attack cancers by reducing their available energy. That's why, at one point, a major field of research in cancer therapeutics was interfering with angiogenesis, because cancers will secrete messengers that help grow them dedicated (if crappy, low-quality) blood vessels. The issue with "starving" them more starkly is that they're very good at getting a share (e.g., forcing the body to supply them with blood vessels), so you're going to be hitting other labile tissues as fast or faster (skin, GI mucosa, blood and immune cells.)
Another way of targeting their rapid metabolism is pointing our therapy at cells with high replication rates. A number of our cancer therapeutics are aimed directly at cells that are currently replicating, which should selectively hit cancer cells (though again, it hits skin, GI mucosa, blood and immune cells, etc. because they're also high-turnover cells.)
We use methotrexate to interfere with DNA synthesis, thus reducing the rate of replication altogether (in cancer cells, as well as.... above).
The problem is, besides the dose-limiting toxicities of all of these things (because targeting metabolism hits all high-metabolism cells), is that cancer cells are really good at developing resistances. So, for instance, if you starve them of blood supply, they'll switch to anaerobic metabolism of glucose. If you starve them of glucose, well, you can't really - I'll discuss that below. If you give them methotrexate or other nasty drugs, they alter the cells' native drug-efflux pumps to target those drugs better and pump them right out of the cell. Cancer cells have a broken mechanism for protecting DNA - the result is really high rates of cell death among cancer cells, and also really rapid evolution.
In terms of starving cells of glucose: glucose is the least common denominator of cellular metabolism. It's the primary food source for the brain. Different cells have different receptors for absorbing it, with different levels of affinity. If you're running low, pretty much every cell in the body that can will kick up metabolic products to the liver to turn into glucose it can share with the bloodstream - because the best receptors in the bloodstream for picking up glucose belong to the brain. You'll starve, or poison, the brain long before you manage to starve out a cancer. (Yes, Ketone bodies are a thing, but that happens alongside your body mobilizing everything it can to feed the brain, not instead of.)
We also can't 'see' all the tumor. The way cancers actually develop is you have an abnormal cell A, which grows into a tiny nest. These are below detection in any practical clinical way, and we don't want to treat them because they're ridiculously common - your immune system wipes them up. If we tried to detect and treat them all, we'd kill everyone with side effects long before we prevented a fatal cancer.
Out of the bunches of these that develop and die, or develop and go permanently quiet, one gets active enough to start seeding tumor cells into the blood stream. Most of those cells will die, too, because blood is rough for cells not built to withstand it. Most of these are going to be undetectable in any way, and do nothing to people.
(Every time I say something is undetectable, I mean "Except for high precision laboratory experiments used to detect just such things").
Eventually a tiny pre-pre-tumor will start seeding cells into the blood stream that can survive the blood. These will get seeded effing everywhere. Most of these are permanently quiescent and do nothing, ever. They exist at the level of single cells - we can't see them. They don't do anything, metabolic activity very low, so we can't target them.
Once in a blue moon you get one seeded that is actually metabolically highly active. Or maybe it mutates into metabolic activity later. Most of those die.
Once in a blue moon, one of these will live enough to start replicating for real. Most of those get wiped out.
And once in a blue moon, they start replicating for real, and develop immune evasion, and you have something that becomes a cancer, maybe. Or it gets triggered by something external and becomes a cancer. There's a "seed and soil" element here. It'll often start seeding back into the blood stream.
By the time you have a detectable mass, your entire body has been seeded with these cells, most of them both un-image-able and un-selectively-treatable. Luckily, the overwhelming majority of these cells - lots of nines - won't do jack. Of the trillions that will seed your body, if we stimulate them just right, you might get a couple of new tumors, or none at all.
We know this because we learned that tumors benefit from circulating inflammatory markers early in modern oncology. When a surgeon took out a tumor, not infrequently, a patient would come in a year later with a new one or two that weren't previously detectable. We eventually learned that the inflammatory growth signals that come with surgical trauma can provoke an otherwise sleepy tumor cell into metabolic activity.
Which is a roundabout way of saying "cancers are more metabolically varied than the late, aggressive stage of the process we usually refer to as 'cancer' would suggest."
That being said, if you could inject something directly into the tumor (rather than the bloodstream would prioritize sending said poison pill glucose to the brain or liver) and take advantage of its metabolism, that would be great. We do kind of do that: we implant radioactive pellets directly, with the added benefit that we know it won't affect much tissue outside of the immediate area.
I hope my answer was actually useful in providing some biological context? I'm afraid I might have just word-vomited instead of being helpful.
I'm enjoying all your comments in this thread. You're knowledgeable and you're doing a good job of translating it into lay terms. I've had cancer and I'm a nerd, so I've read a fair bit about it. Everything you're saying fits well into my understanding, and you've given me some new things to look into.
Yes, it was!
"These are below detection in any practical clinical way, and we don't want to treat them because they're ridiculously common - your immune system wipes them up. If we tried to detect and treat them all, we'd kill everyone with side effects long before we prevented a fatal cancer."
I suppose it would help, if this would be more common knowledge. That cancer cells are very common and nothing to be afraid of. Just that when things go very wrong, it becomes a problem. And that is mainly, when the immune system fails?
So I suspect the stress for the fear of getting cancer, might in some people lead to actual cancer, by lowering their immune system.
Could you agree to such a statement, or do you think it is far off?
It's fair to say that it's a "failure of immunity," though it's a bit more varied than that. You might have started with a failure of the immune system, in the sense that something like autoimmune proliferative syndrome means cells that should be committing suicide aren't, and so eventually you have cancer. More common is a "normal" immune system, and a cancer cell lineage that evolves to be invisible to it.
Either way, it's fair to say that normal cells and cancer cells are divided by the fence of "immunity," and cancer doesn't happen until the cancer cells hop the fence or the fence falls down.
I suspect the fear -> cortisol -> immune suppression -> cancer pathway is probably, quantitatively, pretty small.
Stress does have negative effects on the immune system, in the broad sense, but granularly it gets more complicated. For instance, one of the key cells involved in keeping cancer at bay is the CD8+ cell. While total CD4/CD8 t-cell counts seem to trend down when cortisol trends up, CD8 T-cell counts actually trend up.
We know that Natural Killer T-cell activity drops in response to cortisol, in isolation, but that it has differing effects on NK cells in different organs. In some organs, it had no impact at all, due to shielding by other inflammatory signals.
It's probably true that there are some people who, if they didn't stress out about getting cancer, wouldn't have gotten cancer. I suspect that number is very, very, very low, though, and I'd certainly never tell a patient (or believe about a patient) "if they'd had different thoughts, they wouldn't have cancer."
I can't rule it out as never having happened. It's not physically impossible. But, compared to all of the other things that play a role in cancer development, it's probably not worth mentioning.
(I feel like I should clarify on the first paragraph: in short, every cell is somewhere on the continuum between 'normal cell' and 'cancer cell'. The only difference between the two is time. Like that Palahniuk quote, "On a long enough timeline, everyone you love is dead"? Well, "on a long enough timeline, every cell is a cancer cell.")
Can you summarize them, if you haven't done so elsewhere?
Anyway thanks. And you should consider writing a book about it ..
So, this is just a conceptual schema, and not a hard-and-fast rule. It was first published by Robert A. Weinberg in 2000 as "the six hallmarks of cancer", as an attempt to distill down everything we knew about cancer genesis into something we could understand as a model. He's considered the grand high poobah of oncogenetics. There've been people fretting at the details of his model since then, so it's grown a bit.
Also worth noting that this model was basically built on solid tumors. Liquid cancer (cancers of the blood - e.g., leukemia) have a different, more poorly studied path, though the broad brush-strokes seem to be the same.
The original model was: -Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential
The version that I learned in grad school was up to 8 hallmarks. Apparently it's evolved a bit more since then, and the most recent version being bandied about is:
-Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti-growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential -Avoiding immune destruction -Tumor-promoting inflammation -Genome instability and mutation -Deregulated cellular energy metabolism
Honestly, I'm not sure the ten hallmark model really adds anything - I'd argue that the four additions fall neatly under the old six. But whatever - it's just a model, and doesn't change the granular reality at all.
To summarize each of the hallmarks in brief:
(1) Evading Apoptosis. Cells have a number of mechanisms that basically say "something's off here, I should kill myself now."
For instance, when DNA repair enzymes get upregulated, so does p53 - if p53 tips over a key value, it starts setting off the suicide pathway. So, "too much DNA damage" = "cell offs itself rather than propagating damaged DNA." There are actually a bunch of proteins in the cell see-sawing here, in response to internal and external signals, and if the "kill yourself" signal tips the see-saw, the cell dies.
Pretty much any mutation in the cell suicide pathway predisposes to cancer. For instance, an extrinsic trigger of apoptosis is binding of what's called the FAS Ligand to the FAS Receptor (a big part of how immune cells regulate their own suicide, to prevent auto-immunity.) A mutation in FAS Ligand, or FAS Receptor, or anything downstream of them, will predispose to autoimmune disease and cancer.
Another one is the anti-apoptotic protein BCL-2, which you'll find overexpressed in something like half of all cancers.
Since cancer development triggers so many "kill me now!" signals, turning this pathway off is a hallmark of cancer development. The cancer will usually do so through a combination of over-expressing anti-apoptotic proteins, and under-expressing pro-apoptotic proteins.
Do we make use of this knowledge for therapy? Sure do. One therapy is a BCL-2 inhibitor, Venetoclax. Methotrexate, which slows down cell proliferation, also causes adenosine accumulation that can trigger apoptosis. These drugs have varied benefits: when you target the specific broken pathway in the cell, they're excellent (e.g., BCL-2 in CLL). Cancers are good at evolving around these therapies though, so they're not used as mono-therapy.
(2) Self sufficiency in growth signals. Normal cells don't just grow on a whim - they require signaling from cells around them and from distant parts of the body, to ensure things are kept regulated. Once a cell starts generating its own growth signals, though - like an army in revolt, giving its own orders - then you're on the path to cancer. This is one of the key mutations that gives rise to the "atavistic cell" description of cancer - they've thrown off their shackles, and become wild cells again! Well, not really - even wild cells are careful about when to expend the resources to proliferate. Bacteria commonly depend on their neighbors - using whats called quorum sensing molecules - to control their growth. Heedless, runaway growth is not the norm even in 'wild' cells.
(3) Ignoring anti-growth signals. Most everything in the cell is the process of see-saw balances: there are always signals pushing in each direction, compensating biochemical pathways, and shifting balances. Growth is no exception: how the cell acts is in response to a whole bunch of pro- and anti-growth signals, and most of the time it moves in the direction that they're pressured to by the consensus.
Well, if one of the hallmarks of cancer is like an army giving itself orders (independence from external growth signals), another is the active refusal to heed anti-growth signals (shutting down lines of communication with the Joint Chiefs of Staff). This may be because key anti-growth receptors are broken; it may be because something downstream of those receptors is broken. The key is, though, that between "I'll tell myself when to grow" and "I don't care what anyone else says to the contrary," the cell is now positioned to grow and grow and grow.
(4) Autonomous Angiogenesis.
Tissues need oxygen and nutrients and stuff. However, that stuff really only travels a tiny distance from the smallest blood vessels - capillaries - because it has to leave the capillaries via diffusion, and the time for something to travel by diffusion increases as the square of the distance. So, going 4mm will take 4x longer than going 2mm. Forget about feeding tissues 1cm away from a capillary - it's not happening. Usually, outside of embryogenesis, blood vessel construction is rare - it happens when a blood vessel is damaged, and it secretes growth signals to build a new vessel. (In fact, in a well regulated environment, this is often followed by signals to kill some of the new vessels, too - which is why a fresh scar is red and angry, but an old one is pale and avascular. The blood vessels that came in to supply immune cells and fibroblasts actually regress.)
So, anyway, here's our tumor - replicating like wild, if it can, not caring if it grows too far from a capillary. One of the consequences is rampant cell death. Tumors aren't healthy, they're usually riddled with dying cells. Another consequence is shifting to anaerobic metabolism - which, yay, don't need blood supply so much. But it's also massively less energy-efficient than oxygen, so any tumor cells that can make use of oxygen supply will tend to outreplicate those that can't.
So what happens? Almost inevitably, they start secreting stuff like VEGF (vascular endothelial growth factor) to grow their own blood vessels. These vessels are messy and leaky and prone to breaking, but they're so much better than nothing, and our tumor is off to the races.
Do we target angiogenesis in therapy? Yeah, there's a shit-ton of drugs that inhibit angiogenesis (you might have heard about bevacizumab a lot lately - we've also given it to Covid patients at high risk of hospitalization, since nothing in the body ever only has one effect).
I'll continue in another post; I'm not sure if HN has length limits.
Solid cells generally sit on a foundation called basement membrane. Tissue invasion means "fuck basement membrane, I'm cutting through it and getting into the sewer pipes (blood vessels) below!"
This actually has two consequences. One is that, well, it's not really cancer until it can escape its original confines - then it's just a pre-cancerous growth. There are a lot of cellular proliferative conditions that will get big, but never go anywhere (e.g., uterine fibromas). These can still cause problems due to displacement of normal tissues, but not of the "I'm all over the body and munching happily away" variety.
The other implication of this step, though, is another type of immortality. Being detached from the basement membrane is one of those cell suicide signals we discussed earlier. So if you can successfully invade the membrane and dig into tissue, the implication is "I'm no longer sensitive to the basement membrane's cell-death signals." These signals overlap and tie into the cell-suicide signals mentioned above. None of these things are completely walled off from the others.
(6) Limitless replicative potential.
Normal cells are limited in their ability to replicate. Every time they do, there is a bit of their DNA that degrades on the ends. In order to compensate, there's a little end-cap, like the plastic aglet on a shoelace, that is there to be sacrificed. Those are called telomeres. Cancers will develop runaway enzymes for restoring those telomeres, so that they never run out of runway for cell replication.
There are other mechanisms in there that make it more complicated, though - we know this because some creatures have much longer telomeres than we do, but not proportionately more cancer (rabbits, if memory serves.)
This also gives rise to some of the weirdness in cancer research. We need immortal cell lines to do standardized research (so everyone is using the same baseline), but by being immortal they are fundamentally abnormal. The HeLa (Henrietta Lacks) cell line of recent fame is one of these immortalized cell lines. (Worth noting: at least in my lab, it wasn't hard to immortalize a cell line if needed. HeLa was unique only in that it was used early enough to become ubiquitous and set a standard - not that there's anything otherwise noteworthy about that particular handful of cells. They're the USB of cells.)
(7) Avoiding immune destruction.
There's overlap between all of these categories. Some of the ways your immune system kills pre-cancer cells are the pathways we broke above: the immune system might trigger apoptosis directly or indirectly, for instance. A cell-killer (CD8+ cytotoxic cell) will attack with an enzyme called 'granzyme', that explicitly tries to trigger apoptosis!
But there are other ways for the immune system to kill, and to be evaded. For instance, cells all express what's called "MHC 1". It's like the inspection sticker on your car. It take samples of intracellular proteins and shoves them up onto the cell surface for inspection by the immune system. If they're unusual, the immune system binds to them and kills the cell. So, not surprisingly, there are some cancers that downregulate MHC 1 - parking your car in your driveway so no one sees the expired sticker. This is common, I believe, in lung cancers. You can also see defects in the machinery that gets proteins to MHC 1; you can increase expression of "come hither" signals for immune suppressing cells (e.g., Regulatory T Cells, and Myeloid-derived suppressor cells); or secretion of immune suppressing molecules directly (e.g., TGF-Beta, IL-10, and VEGF). If VEGF sounds familiar, I should point out it's the signal for growing new blood vessels above.
(That's not a coincidence. Healing a wound requires quieting the inflammation that preceded the healing.)
New research in cancer vaccines is focusing on how to either restore the immunogenic environment, or to use alternative pathways. For instance, the toll-like receptor pathway doesn't usually play much of a role in developing cancer, so it's usually intact - so one of the new strategies that's being worked on is how to activate that pathway in response to cancers. And, we have drugs that target some of the elements here! For instance, those T-Regs express the cell surface marker CD25, which we can hit with a drug called daclizumab (I hope I got that spelled right - small molecule and monoclonal names are all gibberish.)
(8) Tumor-Promoting Inflammation. This wasn't a separate hallmark when I was a wee baby: the inflammatory signals promote cell proliferation, they can make blood vessels leaky, they can make blood vessels dilate (the combination means lots of yummy blood to feed a tumor). Inflammation also brings in lots of tumor-killing signals. "Tumor-promoting inflammation" is basically "everything I described above." So, I don't know, maybe something unique has been found here over time that I missed out on as the field evolved? Or not - all of these have grey areas of overlap.
(9) Genome instability and mutation.
Cancer cells, by virtue of shedding their DNA-protecting mechanism (cell death if the DNA is damaged too much) and going into rapid division, break the absolute shit out of their DNA. Not just the run-of-the-mill "oh, mutations accrue" type of breakage. I mean chromosomes are breaking and reattaching and breaking again, centromeres are all over the place, it's a shit show. This is a normal karyotype (image of the chromosomes as a whole): https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.scienc...
This is the karyotype of a breast cancer cell: https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.resear...
This "genome instability" doesn't just allow for rapid evolution - the fact that it can exist without the cell suiciding is a great big flag that this cell has very serious immortality mechanisms in play already.
(10) Deregulated cellular energy metabolism.
All of the stuff regulated above? It regulates, and is regulated by, cellular energy metabolism (which also feeds into various other type of macromolecule metabolisms - so when energy is dysregulated, it's like saying "our entire supply-side market is broken.") Which means dysregulated growth, dysregulated proliferation, etc. This is also a really core pathway - you can't fuck with such elemental life-or-death metabolic pathways without breaking stuff or killing stuff. By the time a cell can dysregulate these pathways (excess free radical generation by way of energy pathways is one of those cell suicide triggers, for instance), it's already shed a lot of its suicide signals and it's just burning through energy without heed for the tissues around it.
I hope that helps.
Thanks!
Not really true, except in the grandest sense (“humanity is the cancer of Earth”).
Which brings up a really interesting question - how can our reproductive system be so good at removing/restoring the effects of cancer & ageing? Why is sperm quality dropping with age but the effect resets after conception?
Some cells never divide, and so theoretically shouldn't become cancerous. They still happen though: myocardium tumors shouldn't happen, but hey, rhabdomyoma. In that case, it's more likely in youth / congenital, because it had to happen via inherited defect rather than one that accrued through cell replication in your lifetime. It is rare, though, and ridiculously rare in adults. Still, "on a long enough timeline...". I mean geeze, let a guy get a tiny bit poetic.
Other cells don't have DNA and don't reproduce, so they shouldn't be eligible (red blood cells.) They still fall into a grey area though: the RBC itself will be dead soon enough and never leave behind cancerous progeny. On the other hand, your bone marrow can absolutely lose its mind and pump out the equivalent of a red blood cell mass, a condition known as polycythemia. You can also have RBCs turn cancerous before they become fully mature and shed their DNA. The erythroblast stage - the late stage of RBC development, the last stage before it chucks its nucleus and becomes disposable - can develop into a leukemia.
Our reproductive system generally keeps its genetic payload cells in stasis for the lifetime, so it doesn't accrue replication errors, as well as sitting behind a protective wall (e.g., the Blood-Testis Barrier) similar to the one that protects the brain. Even in stasis, though, damage accrues - the age of the parent has a direct impact on the likelihood of various congenital disorders.
So does that mean for the off chance we live long enough for aging reversal to be developed and affordable we'd still die of cancer? :)
(a) True cancer cures will be more dynamic than cutting bits off, like very sophisticated immune therapies, or
(b) We'll get really good at replacing cut off bits.
Question:
> "you'll starve, or poison, the brain long before you manage to starve out a cancer. (Yes, Ketone bodies are a thing, but that happens alongside your body mobilizing everything it can to feed the brain, not instead of.)"
Layman here, but my understanding is that depriving the body of the ability to replenish glycogen stores that are normally used for energy forces the body to metabolize fat in order to produce ketones, which in a ketogenic state, the brain is entirely fine utilizing as a primary energy source. Thus, if in a ketogenic state (or on a strict ketogenic diet), the body isn't being starved, just consuming stored energy reserves.
Am I oversimplifying the concept?
You've got it essentially correct, it's just that every metabolic pathway is in a dynamic equilibrium. So let's say you do deprive the body of fresh glucose intake. While liver is turning fat into ketone bodies, and brain and skeletal muscle are digesting those ketone bodies, at the same time that TCA cycle that is now getting fed ketone bodies is going to push back upstream to tilt 'eat sugar' (glycolysis) a little bit more towards 'make sugar' (gluconeogenesis); meanwhile, other ketone bodies (dihydroxyacetone) are going to plug right into the gluconeogenic pathway.
The body will be making glucose where it can, because, if I recall correctly, red blood cells can't make use of ketone bodies, full stop. Some level of production must be maintained.
Which, in the body's parlance, is 'starvation'. If red blood cells are going hungry, from the body's perspective, there's a serious problem. But that's part of the difference between true ketosis and a ketogenic diet - the latter continues glucose intake, with a preference towards stimulating ketogenesis. The former is "oh fuck where's the glucose why can't I use the glucose aaaaaah!"
I gotta go refresh this now - you're painfully reminding me of how long it's been since I reviewed biochem.
The staging is just ("just") a reflection of the primary cancer mass, which is really predictive of outcomes. It's generally not directly related to whether these sorts of satellite tumors form, since the above advances. It's mostly at this point a historical point of "this is part of how we figured out how cancer works," and ties into the rationale for some of the now-standard treatments.
My IMHO, is that the only real cure to this disease(s) will be learning how to disrupt its immune response evasion tricks.
Tritium will be transferred to proteins and retained in the body. A low-calorie diet won't help: when the glucose enters the citric acid cycle, the 3H will end up everywhere. 18FDG, used for PET, is also concentrated in the kidneys and bladder, ruling it out for therapy. If it were that easy to find something uptaken only by tumors, we'd be using it.
In brachytherapy, we do something like this, except we put a solid radiation source inside the tumor. Nonetheless, the treatment has serious side effects.
The whole "genes that shouldn't be on being switched on" thing made me think about David Sinclair's work on aging, and his information theory of aging.
Has anyone been really looking into ways to avoid damaging (or ways to repair) epigenetic information as a potential solution to cancer?
>"Cannot help but switch to previous single-celled metabolism"
This line itself should immediately give anyone with a molecular bio line a pause. Molecules, cells and other small chemical phenomena are not humans. They do not act with intent.
Personifying these machines and systems may be helpful to make a system relatable, but it is a toy model, not an explanatory one.
He also mentions this "atavistic" view, but it is not central in his theory.
https://www.semanticscholar.org/paper/Cancer-tumors-as-Metaz...
Genes which are essential the the function of an organism are well conserved relative to silenced genes over long time spans.
This is because mutations happen randomly, and mutations to essential genes in the germline tend to get weeded out, while mutations to silenced genes can get corrupted without affecting the fitness of the offspring. This theory, from the way you've stated it, would require preservation of inactive genes for hundreds of millions of years, only to spring back to action in cancer cells.
If you're not already familiar with them, you might want to look up HeLa cells:
I assume no such thing.
I've read (but can't cite) that roughly 90% of our genes are related to construction and maintenance of the cell itself, and only about 10% are related to higher order organization. Just as it has been said that something like humans and tomatoes have 50% of our genomes in common, there is a significant but smaller percent that we have in common with single-celled life forms.
> HeLa
I read the book years ago.
You certainly do:
"This theory, from the way you've stated it, would require preservation of inactive genes for hundreds of millions of years, only to spring back to action in cancer cells."
This is only true if the genes for being single-celled are inactive in multi-celled creatures and would need to be re-actived to revert to being single-celled. But this is not the case. Milti-cellularity is a functional layer built on top of single-cellularity, so to revert to being single-celled you have to deactivate currently active genes, not activate inactive ones.
Someday we'll need to address the issue that talks, with their more extensive and accessible graphics and explanations, are less available to the public than papers.
[1] https://www.sciencedirect.com/science/article/pii/S109727652... [2] https://twitter.com/zhaoqili [3] https://biology.mit.edu/graduate/why-mit-biology/graduate-te...
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.1...
For anyone wishing to understand the fundamental features and survivorship bias that all cancer cells go through I highly recommend it.
I think this is an updated version: https://www.cell.com/fulltext/S0092-8674(11)00127-9
There’s also Emperor of All Maladies (and his other book Genes) from another author that may be of interest.
Author name's Siddhartha Mukherjee. Great book, focused more on history of oncology than the biology of cancer though.
[1] - https://www.youtube.com/watch?v=06e-PwhmSq8 [video]
On the other hand, a recent paper shows that NAD+ replenishment reverts tumor resistance to immunotherapy, so those therapies shouldn't be combined.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)...
A ketogenic diet can also be ideally coupled with intermittent fasting[2] in order to engage/enhance autophagy within the body.
[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842847/
But I'm very glad that whatever your decision, you're still among the living! Cancer is a terrifying diagnosis.
I've read it twice. Strongly recommended.
[0]: https://www.goodreads.com/book/show/23496164-tripping-over-t...
But worth noting is that there are cancers that feed on estrogen for example. And other users have noted that cancers don't just feed on ketones.
But it's really cool because keto seems to be a diet that truly works, also requires some will power.
It specifically found " Low-carbohydrate diets were associated with a significantly higher risk of all-cause mortality and they were not significantly associated with a risk of CVD mortality and incidence."
Perhaps you are on the "oh but the study does specifically say, "low carb, high fat" diet, so it obviously only looked at people eating low carb, low fat diets!" train? There seems to be some fantasy with the Keto crowd that these studies somehow only look at some mysterious section of the population in which eats a very low carb diet but also low fat? People don't eat a low carb diet by accident, when they do they often follow the horrible advice given by the many misguided keto diet proponents: eat low carb, high fat, medium protein.
You can find a near endless amount of longitudinal meta analysis and more focused studies that nearly universally find diets that are lowest in carbs (regardless of protein/fat ratio) produce the highest all-cause mortality.
https://www.acc.org/latest-in-cardiology/journal-scans/2019/...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555979/
https://academic.oup.com/eurheartj/article/40/34/2870/547549...
https://www.thelancet.com/journals/lanpub/article/PIIS2468-2...
And so on...
This is not remotely my anecdotal experience. The overwhelming majority of those I know that I have dabbled with low carb ran the bunless burger, chicken wings, bacon, and steak game and I would guess that their macro intake was high protein, medium fat (if that), low carb. The textbook versions are high fat, medium protein, low carb. And seemingly pretty hard to pull off without eating a lot of stuff like salads with a cup of olive oil.
Regardless the studies are quite clear. It doesn't matter the fat/protein ratio, the diets with the lowest carbs produce the highest amount of death.
Hi-protein is glucogenic and thus not ketogenic, so the ratio would seem to matter. So would the resolution between an avocado and a fistful of bacon, given the safe assumption that the materials and cooking of them rate to have different impacts on human health.
This is backed by other meta-analyses such as https://www.thelancet.com/journals/lanpub/article/PIIS2468-2... :
> Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50–55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality.
Stressing that both hi carb (contra your claim) and lo carb when specifically overindexed on animal protein had higher mortality, not just lo carb.
Pretty much every major study that has done this has found similar results. I linked 4 more large studies below.
There are also many diets that aren't keto so the population of people who felt compelled to lose weight but chose not to do a keto diet, but perhaps a low fat diet (which tends to be high carb) are well represented in the study, once again rebuffing your hypothesis.
In terms of your vitamins supplementation paradoxes, which is a separate point. I also disagree with with you there (these supplement studies also control for various health factors as well), and feel it's much more the problem of absolutely no regulation and there really is nobody making sure the supplement contains the thing it says it is in the quantities it says it does, with nothing else. Also people tend to over do things, and over supplement with the "if some is good more is better". Taking to much vitamin C for instance, spikes your iron absorption, and iron is the most powerful oxidant in your body, or just taking too much iron outright. I could go on and on about supplements, but I'll spare you.
The people that do these studies aren't as dumb as you seem to think they are nor are the type of confounding variables you are expressing foreign to them. Not even study can get exactly the quality or quantity of date it wants, that's why its a good idea to look at multiple studies and examine large-scale trends and repeatably, which is the type of studies I linked.
I wouldn't feel comfortable reading too much into this one's conclusion. "Low-carb w/o any additional specificity looks like bad news" seems technically fair to me, but actual diets are going to tend to distinguish fat and protein as well as their sources so that isn't a a very logical stopping point for an actual decision. Including core concerns like fat vs protein and plant vs animal sources can yield different conclusions, as the meta linked in the sub-thread above did.
Folic acid is required for stable DNA, something that cancer doesn't need at all (it needs mutations for plasticity).
Its also needed for DNA production, but many more cells need it, those that have short lifespan - cells lining the stomach for example, sperm cells, some immune cells etc.
What you're saying about stable DNA makes sense. I'm curious, though, if the supplementation helps the body generate more NAD+ (relative to someone with a deficiency), and if that could help cancer proliferate in its earliest stages (hence why the correlation is most pronounced in people already likely to develop cancer--smokers).
NAD is essential for many functions, especially longevity as sirtuins require it for proper function.
As far as I know only massive Vitamin C doses uniquely influence cancer in negative manner and get pretty much no effect on non cancer cells. Massive vitamin C infusions (which work via mechanism similar to chemotherapy) while can't cure cancer per se, have potential to make life span and quality of life much longer (toward chronic disease).
At this point there is literrary nothing you can recommend to your friend.
Is this why some people think fasting can help? It gives the body a chance to clean up cancer cells, since you have more time in a catabolic state?
- No sugar input => low insulin (insulin promotes cancer)
- No nutrition for cancer cells => no folate etc.
- Metabolic slowdown due to starvation => means everything works slower including cancer
- Promotion of autophagy which consumes damaged organelles. This one is dubious as cancer cells can do autophagy themselves to stay alive, but I suppose that due to extensive mutations in cancer there is still a chance that normal cells do it more efficiently. In healthy parts of the body this can also lead to better immune system as damaged parts of it could be replaced in the process. On the other hand, good immunity needs various vitamins and minerals most of which can't be produced or stored.
When we look at apparent inefficiencies of life systems (singletons and complete systems) we have to take into account setting and environmental factors as well as the various layers of abstraction.
Looking down at cancer (similar to a defect in software) and questioning why it behaves in seemingly counter intuitive ways makes it all the more appearent that we are still at the tip of our scientific and spiritual understanding for models of healthy systems, both cellularly and holistically as life on our planet.
As above so below.
Based on this research cancer switches to a process which accepts the inputs at hand and processes outputs for growth (often rapid growth).
Regardless of how it looks as a spectator, the cells inside you make billions of individual decisions each second and those decisions may have eventual degrgations over time with enough entropy.
The cell has blueprints and is on a mission, sometimes it's mission is corrupted or the order of operations is abnormal.
I like how they make mention yeast fermentation as a similar process and I didnt know our cells could run both processes. I wonder why? Do we use fermentation at various parts of our human development?
(Some animals and some other eukaryotic organisms use other fermentation variants, e.g. alcoholic fermentation by yeasts or fermentation of glucose + water into acetic acid + carbon dioxide + dihydrogen in cells with hydrogenosomes.)
The energy produced thus is many times lower than the energy that could be produced by oxidizing the same quantity of glucose into water and carbon dioxide.
While the energy is low, the power is very high, because the fermentation is done by a simpler sequence of reactions and a much larger quantity of glucose can be fermented in a given time than the quantity that could be fully oxidized.
So the difference between using glucose fermentation and using the oxidation of either glucose or fat is like the difference between using supercapacitors and using batteries.
Some devices are optimized for high power but lower energy storage capacity, while others are optimized for low power but much higher energy capacity.
In most cells there is a more complex hierarchy of energy-producing mechanisms, which are ordered from the highest power and lowest energy capacity to the lowest power and the highest energy capacity. For example, in the muscles of vertebrates, you have, in the order from above, ATP hydrolysis, phosphocreatine hydrolysis, glucose fermentation and finally glucose & fat oxidation.
The vertebrates are actually much better than most other animals at glucose fermentation, which gives them a significant advantage.
Because of that, the vertebrates are able of short bursts of activity that use a very high power, e.g. running short distances or jumping or catching a prey, before having to reduce the power to the lower level that can be sustained for a long time by the aerobic oxidation.
Just to reiterate one key part for your question, all of the energy systems (ATP hydrolysis, phosphocreatine hydrolysis, glucose fermentation and finally glucose & fat oxidation) can produce energy in tandem and/or independently in muscle and other cells. But, first listed higher power systems are depleted within minutes and require expense of other systems to "recharge" (supercapacitor analogy) vs. glucose & fat oxidation can pretty much carry on constantly but are much lower power due to slower speed/higher complexity of their pathways (rather than just a battery I'd say an analogy of renewable energy [glucose] + battery storage [lipids in adipose] is more suitable i.e. steady input of energy source = steady utilization/output of work that can carry on pretty much constantly).
So, many systems can produce energy together/in tandem in the cells, but the higher power systems once exhausted can force your body to temporarily cease high intensity activity to rest and recover. Glucose and fat oxidation don't ever stop in that process, but in recovering those higher power systems your body prevents you from engaging in more high energy "burst" activities until those systems "recharge".
Training can allow you to modify these higher power systems to last longer, and recover quicker, but there will always be a top end constraint where every person "runs out of gas" when performing continuous high intensity/exertion activity.
That changes dynamically depending on environmental changes. Basically infinite plasticity. Not something we have in our human engineering.
That's not true if you're talking about software engineering and you include the developpers and product people in the system ;)
Its in good part inherited complexity (as humans didn't engineer humans). The other part is in Mytical Man Month :-)
Also, it's not exactly accurate to view something as "developed in public lab" or "developed in private lab", as often (also in this case) the research is done by the same people but they do the early stage in a public lab and then move on to (or create) a private lab for the later stage of technological readiness.
I.e. could you do a blood test to detect elevated levels of fermentation-based metabolism, indicating that it might be time to do a deeper cancer screen?
https://en.wikipedia.org/wiki/Lactate_dehydrogenase#Testing_...
From what I understand most experts seem to think it's probably safe and will extend health & life span, but the cancer risk is something that concerned me when I started. Surely if healthspan was as easy as just raising NAD+ levels the body would have already evolved this trait?
The best way of doing this, based on years of science, would be, well, to eat nothing for 24+ hours at a time, but make sure you stay hydrated; as in, actually fast. The second best would be to seriously curb your carbs, under 30g a day; also tied for second best is to eat just once a day, none of this unscientific three square meals hogwash.
Three of these together could halt the progress of some cancers, and before the shitstorm that was 2020, scientists were publishing papers involving animal models on this.
Steve Jobs did none of these, and was, sadly, off in la-la land when someone with his money and connections could have had access to next generation scientifically-based treatments. Fruitarianism is, frankly, dangerous.
So water and coffee or tea (without milk, of course) would be fine. You're trying to avoid an insulin response and firing up the entire machinery of digestion.
I think it's non-controversial to say that this starves the cancer cells.
Perhaps less certainly we can also say that digestion demands a lot of resources and is an interrupt for a lot of other processes. When your body has nothing to do for 24-36 hours eventually lower priority tasks get attended to ... like garbage collection.
Jobs had GEP-NET cancer, which have 5 years OSR of 70% at stage IV. It's a slow growing cancer, very survivable and even surgically curable in early stage.
The fast, almost always fatal is the pancreatic adenocarcinoma.
Also, the mortality rate of a cancer is a function of many variables (stage at the time of diagnosis, tumor differentiation, tumor location, etc.). A number like 95% doesn't make any sense without a lot of context.
This is why some chemo will result in for example hairloss; Because the cancer you're being treated for, has the same growth rate as the cells in your hair - and thus the chemo will also kill those cells.
If you are 350 pounds, can't you just not eat until you are 150 and be fine? (I am not suggesting that this is true or that anyone should try it; I don't know and I am asking the question.)
However, metabolism has non-energy needs which are supplied through food: vitamins, minerals, protein, and some fats that cannot be synthesized iirc. Though these needs are greatly reduced when fasting, they do not go to zero.
Google “angus barbieri” for the most famous, though not unique, example for medically documented long term fasting.
But at least with the poor countries I'm not sure if it's because people die of other reasons before they even could get cancer.
[0] https://qph.fs.quoracdn.net/main-qimg-a0728f7c2418f32922558b...
And then you can try to find other correlations.
It can't cure tho, because liver and kidney will create most important resources for body to be able to work.
This interview with Rhonda Patrick is a good introduction to his research, but it’s quite extensive and the papers are worth checking out if you’re interested in this topic.
It only proves that supplements work as indented in prolonging eycariotic cell life.
Its just that you don't want everything in your body to be boosted, just some - cancer is just one of those, you don't want various constituents of your body flora influenced as well, like parasites, harmful microbiota etc.
In either way, I'm pretty excited by all the recent findings and breakthroughs in both fields - longevity and figuring out cancer.
(not because of article which describes mechanism, but because of people who will jump to conclusion)