This is a pretty cool study with some interesting findings! Cancer immunotherapy has a long history but has become very prominent in recent years. (Fun fact: the senior author on this paper, Ed Engleman, co-founded of one of the first cancer cell therapy companies, Dendreon, in the early 90s). However, the success of immunotherapies has been limited by the immune-exclusionary nature of the tumor microenvironment (TME). Why some tumors are immune-hot and others are immune-cold is still a very open research question.
In this study, the authors demonstrate pretty convincingly that erythropoietin (EPO, a hormone that stimulates red blood cell production in the bone marrow) reduces the recruitment of tumor-cell-killing T cells to the TME. It does this by acting on tumor macrophages, another type of immune cell, and changes the state of these cells to facilitate accumulation of immunosuppressive cells.
They work out the mechanism largely through mouse models and associative analysis in human tissue samples, but I thought it was interesting that this finding aligns with the clinical observation that cancer patients who receive recombinant EPO for treatment of anemia frequently experience tumor progression.
After reading this, I am going back to check out EPO expression in old datasets that I worked with haha.
This identifies one way solid tumors avoid immune attack and identifies corresponding therapeutic targets that could span solid tumor types.
EPO (erythropoietin) (aside from stimulating red-blood-cell production) also converts tumor-local macrophages from attacking to suppressing immune attacks. Tumors are shown to produce EPO themselves.
Tumors spontaneously regressed due to revived immune response when blocking either EPO or the EPO receptor on the macrophages.
The model was murine liver cancer, but high blood EPO levels are known to be poor prognosticators in many solid tumor cancers.
This summary points to NRF2 (nuclear factor erythroid 2-related factor 2) as a regulatory target, but without any detail.
AFAICT there are no approved drugs blocking EPO receptors and no drugs to reduce EPO; there are some anti-anemia drugs that increase production.
Tumors excreting chemicals to prevent destruction doesn’t sound like DNA damage, that sounds like evolution.
We know some cancers can be caused by viruses. And we know a few cancers that act like viruses in dogs and Tasmanian devils, and some rare cases in humans.
We only figured out that ulcers are bacterial in origin within the lifetimes of many HN readers, and there are signs that other GI issues may be bacterial or viral (or bacteria-targeting viral) as well.
Maybe we need to start culturing and DNA testing cancers.
We already culture and DNA test cancers. Sometimes we can point at a secondary tumor and say "it came from this primary tumor". And we already know viral and bacterial infections can increase the likelihood of people getting malignant tumorws.
Most scientists wouldn't call the hallmarks of cancer "evolution". I think instead most would say that cancer is an almost certainly unavoidable outcome of the complexity of eukaryotic organism's control of cellular replication.
There's a series of papers organized around the "Hallmarks of Cancer" which help explain why nearly all tumors show the same properties- and how they are effectively due to dysregulation of evolutionary checkpoints and signalling. generally, an organism with a malignant tumor is less likely to reproduce. However, it's really far more complex than that ,
Do we understand the early dynamics of cancer? Do the hallmarks need to appear more or less at the same time by chance, or can the cancer cells acquire them sequentially, which would then induce a local microevolution process?
You're right, DNA damage is just one of the types of genetic variation in cancer. There are many other structural variations that act like remixes.
"Maybe we need to start culturing and DNA testing cancers."
I assure you this is being done at a massive scale.
Due to cellular stress, cancer cells disobey multi-cellular governance. They behave more like independent organisms fighting for survival, reverting to primal programming.
Oh I know we are trying to genomically test them for oncology research and potential treatment plans, but do they do paternity tests on them?
I was trying to remember which mammal in Australia gets tumors from fighting, and I found a reference to a mother getting melanoma from her daughter. It’s unclear to me whether the cancer transmission was rare or the identification is rare.
There’s very often a comparison to the somatic (i.e. non-cancer) genome of the same patient. It’s a great way to quality control that there wasn’t some sample mixup in the lab.
Transmission of cancer is rare in humans—if it were not, it would make someone’s career to find many cases of it. While we can’t say that all sheep are white, we’ve looked at enough of them to say that black sheep are not common. Furthermore, it’s very clear how the Tasmanian devil cancer is spread—it’s around the mouth while they are biting each others faces; it’s not as obvious how one would spread most human cancers.
A cancer is necessarily a line of cells that survived despite the mechanisms that should prevent it from surviving. It's evolution in a way - genotype a sequence of random mutations and environmental factors away from the original that allows the cell line to sidestep the immune system. Coincidentally the immune system based off of the same original genotype. The ones that don't survive are not causing cancer.
To provide more color on cancers caused by viruses, the World Health Organization (WHO) estimates that 9.9% of all cancers are attributable to viruses [1].
Cancers with established viral etiology or strong association with viruses include:
The guy who won the Nobel prize for giving himself an ulcer estimated it as 90%, which is very comfortably “most”. If that has been drastically estimated down I hadn’t heard.
Also don’t abuse advil, kids. OTC painkillers can burn a hole in your digestive tract. I in fact know someone missing a few feet of intestine because of chronic back pain and overuse of non narcotic painkillers.
I did the oops too much Advil on myself naively over years. Gastritis and resolves once the cause is figured out but scared me to respect otc meds more.
Yeah the real outcome of all this was "stress is not a cause of ulcers and other GI issues, but it can increase the negative impact" and "some uclers and other GI issues can be treated by antibiotics".
Stress of course makes pretty much all multicellular organisms more susceptible to pathogens and environmental toxins. But it’s the trigger not the bullet.
Huh. I assumed this was going to be a collision of acronyms but erythropoietin is the same EPO used medicinally to treat anemia and abused by several generations of endurance athletes (complications include strokes and heart attacks from blood clot).
It’s a stress-signaling hormone produced by the kidneys when they detect hypoxia and triggers more red blood cell production in bone marrow.
What makes this mildly funny, though I admit in quite poor taste, is the fact that Armstrong did indeed suffer of cancer to which he lost a testicle before his comeback to win multiple Tour de France back to back. So theoretically his EPO positive results could be attributed to those tumors producing it, if this research is to be believed. Maybe not all of the times though.
Or, consider that the causation could have been the other way around. The EPO could have made him more susceptible to cancer.
There is a mountain of evidence that the drug cheating was systematic. You can read The Secret Race, or draw your own conclusions from the $5 million false claims act settlement.
He was on steroids post treatment as well. Chemotherapy likes to cause anemia. In fact I think that’s where I first heard of EPO. Some survivor crowing about the efficacy at making them feel human again.
And they’ve discovered in more recent studies that steroid use has effects that last about twice as long as it’s detectable in your body (2 vs 1 year?). If sports weren’t such a young person’s game, I’d worry about people taking off for “surgery” and coming back built like a linebacker but testing clean.
Lance Armstrong never failed a drug test. The CEO of the insurance company responsible for underwriting bonus payments for Tour de France wins had read a book full of circumstantial evidence of the US Postal Service team doping and contested paying out the bonus. He knew they'd lose, but wanted to force the hands of some investigative body with real power to actually look into it. Federal prosecutors took up the case for a couple years, but then dropped it. Then USADA finally got a bunch of his former teammates and medical staffers to testify against him. Lance didn't even contest the finding because the evidence was so overwhelming, he figured his best course of action at that point was trying to keep the report confidential and winning in the court of public opinion instead, convincing all of his adoring fans that he was the victim of a witch hunt.
Obviously, that didn't work, but I guess he was just ahead of his time. These days, he could have run for president.
Fair enough. I should specify he never failed a drug test from the period in which all of his UCI and Olympic wins were rescinded, which I believe was 1998 to 2005. I'm also reasonably sure he never got popped specifically for EPO. There has been a test to find recombinant EPO since 2000, but it can only detect its presence for something like 18 hours after injection and you only need to inject weekly. Out of other ways to blood dope, only tranfusion from another person is detectable by any means whatsoever. It's why they use the athlete biological passport instead and look for increases in red blood cell count or hematocrit that are not physiologically possible without doping.
He was working with doctors who were knowledgeable of techniques the UCI was not testing for yet, and in masking. That’s why he got popped on the stored samples. They have rules against doping that are set up to cover substances they don’t have tests for yet and that is part of why they store samples.
But they were also using “blood doping” which is essentially giving blood transfusions to yourself. One of his lieutenants, Tyler Hamilton, got busted for it a few years before Lance got caught. He claimed he was innocent and maybe it was chimerism or an absorbed twin. But this dumb fucker had already been caught doping several times before, one of which stuck and the other failed on a technicality (frozen backup sample could not be tested) My guess is they switched bags and he’s lucky he got a compatible bloodtype and didn’t stroke out. He got caught doping again in 2009 and received an 8 year ban, and retired. And later was stripped of his gold medal as well.
The only legal form of blood doping is altitude training and that effect doesn’t last long enough for the Tour or the Gira. But could allow someone to get an early lead.
As for Lance not getting caught between 1998 and 2005, that’s only barely technically true. He was caught using corticosteroids in a test in 1999, but explained it away with a topical steroid allegedly for saddle sores. He confessed later that it was a cover up for his doping. He also tested positive for EPO six times during this period but as the tests were still experimental, there was some clever lawyering that kept it from sticking.
Laurent Fignon and Eddie Merckx have both been accused of stimulant use which cost them only one or two races instead of years.
Richard Virenque was a popular French rider who won the King of the Mountain many many times, when he went down it was for an entire cocktail of drugs including HGH.
And I had forgotten that Christian Vande Velde was caught in the postal service bust. He’s a commentator for NBC now. I wonder what Liggett thinks of that.
This is a pretty cool study with some interesting findings! Cancer immunotherapy has a long history but has become very prominent in recent years. (Fun fact: the senior author on this paper, Ed Engleman, co-founded of one of the first cancer cell therapy companies, Dendreon, in the early 90s). However, the success of immunotherapies has been limited by the immune-exclusionary nature of the tumor microenvironment (TME). Why some tumors are immune-hot and others are immune-cold is still a very open research question.
In this study, the authors demonstrate pretty convincingly that erythropoietin (EPO, a hormone that stimulates red blood cell production in the bone marrow) reduces the recruitment of tumor-cell-killing T cells to the TME. It does this by acting on tumor macrophages, another type of immune cell, and changes the state of these cells to facilitate accumulation of immunosuppressive cells.
They work out the mechanism largely through mouse models and associative analysis in human tissue samples, but I thought it was interesting that this finding aligns with the clinical observation that cancer patients who receive recombinant EPO for treatment of anemia frequently experience tumor progression.
After reading this, I am going back to check out EPO expression in old datasets that I worked with haha.
It would be nice to see the original article.
But at face value this looks very promising.
This identifies one way solid tumors avoid immune attack and identifies corresponding therapeutic targets that could span solid tumor types.
EPO (erythropoietin) (aside from stimulating red-blood-cell production) also converts tumor-local macrophages from attacking to suppressing immune attacks. Tumors are shown to produce EPO themselves.
Tumors spontaneously regressed due to revived immune response when blocking either EPO or the EPO receptor on the macrophages.
The model was murine liver cancer, but high blood EPO levels are known to be poor prognosticators in many solid tumor cancers.
This summary points to NRF2 (nuclear factor erythroid 2-related factor 2) as a regulatory target, but without any detail.
AFAICT there are no approved drugs blocking EPO receptors and no drugs to reduce EPO; there are some anti-anemia drugs that increase production.
> AFAICT there are no approved drugs blocking EPO receptors and no drugs to reduce EPO
Such receptors have a protein structure definitive for them, so a bespoke RNA (mRNA) therapy might be a means of generating receptor blockers?
Edit: looks like this applicable. two interesting articles...
https://pubmed.ncbi.nlm.nih.gov/28629523/
https://www.genengnews.com/topics/cancer/blocking-erythropoi...
yeah i cannot read the full article
Tumors excreting chemicals to prevent destruction doesn’t sound like DNA damage, that sounds like evolution.
We know some cancers can be caused by viruses. And we know a few cancers that act like viruses in dogs and Tasmanian devils, and some rare cases in humans.
We only figured out that ulcers are bacterial in origin within the lifetimes of many HN readers, and there are signs that other GI issues may be bacterial or viral (or bacteria-targeting viral) as well.
Maybe we need to start culturing and DNA testing cancers.
We already culture and DNA test cancers. Sometimes we can point at a secondary tumor and say "it came from this primary tumor". And we already know viral and bacterial infections can increase the likelihood of people getting malignant tumorws.
Most scientists wouldn't call the hallmarks of cancer "evolution". I think instead most would say that cancer is an almost certainly unavoidable outcome of the complexity of eukaryotic organism's control of cellular replication.
There's a series of papers organized around the "Hallmarks of Cancer" which help explain why nearly all tumors show the same properties- and how they are effectively due to dysregulation of evolutionary checkpoints and signalling. generally, an organism with a malignant tumor is less likely to reproduce. However, it's really far more complex than that ,
Do we understand the early dynamics of cancer? Do the hallmarks need to appear more or less at the same time by chance, or can the cancer cells acquire them sequentially, which would then induce a local microevolution process?
>>> generally, an organism with a malignant tumor is less likely to reproduce.
Huh?
What is meant by this? Like if you have cancer, you are less likely to want to reproduce? Or, less likely to reproduce due to the illness?
You're right, DNA damage is just one of the types of genetic variation in cancer. There are many other structural variations that act like remixes.
"Maybe we need to start culturing and DNA testing cancers." I assure you this is being done at a massive scale.
Due to cellular stress, cancer cells disobey multi-cellular governance. They behave more like independent organisms fighting for survival, reverting to primal programming.
Oh I know we are trying to genomically test them for oncology research and potential treatment plans, but do they do paternity tests on them?
I was trying to remember which mammal in Australia gets tumors from fighting, and I found a reference to a mother getting melanoma from her daughter. It’s unclear to me whether the cancer transmission was rare or the identification is rare.
There’s very often a comparison to the somatic (i.e. non-cancer) genome of the same patient. It’s a great way to quality control that there wasn’t some sample mixup in the lab.
Transmission of cancer is rare in humans—if it were not, it would make someone’s career to find many cases of it. While we can’t say that all sheep are white, we’ve looked at enough of them to say that black sheep are not common. Furthermore, it’s very clear how the Tasmanian devil cancer is spread—it’s around the mouth while they are biting each others faces; it’s not as obvious how one would spread most human cancers.
somatic = cancer. germline = inherited.
Oh that makes sense. I forgot about differential analysis.
Is HPV an example?
Not really. It's a virus that can cause cancer and not the cancer itself.
tasmanian devils [edit: I guess you already said that] https://en.wikipedia.org/wiki/Devil_facial_tumour_disease
Yup. Link is handy though. Someone will post it to the front page in 14 hours :)
Tasmanian devils.
The cancer problem always struck me as more of a control theory challenge than a purely biological one.
A cancer is necessarily a line of cells that survived despite the mechanisms that should prevent it from surviving. It's evolution in a way - genotype a sequence of random mutations and environmental factors away from the original that allows the cell line to sidestep the immune system. Coincidentally the immune system based off of the same original genotype. The ones that don't survive are not causing cancer.
To provide more color on cancers caused by viruses, the World Health Organization (WHO) estimates that 9.9% of all cancers are attributable to viruses [1].
Cancers with established viral etiology or strong association with viruses include:
- Cervical cancer - Burkitt lymphoma - Hodgkin lymphoma - Gastric carcinoma - Kaposi’s sarcoma - Nasopharyngeal carcinoma (NPC) - NK/T-cell lymphomas - Head and neck squamous cell carcinoma (HNSCC) - Hepatocellular carcinoma (HCC)
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC8831861
>Tumors excreting chemicals to prevent destruction doesn’t sound like DNA damage, that sounds like evolution.
One cell's DNA damage is another cell's evolution.
> ulcers are bacter
To be clear, some peptic ulcers are caused by H. pylori, but not all ulcers.
The guy who won the Nobel prize for giving himself an ulcer estimated it as 90%, which is very comfortably “most”. If that has been drastically estimated down I hadn’t heard.
Also don’t abuse advil, kids. OTC painkillers can burn a hole in your digestive tract. I in fact know someone missing a few feet of intestine because of chronic back pain and overuse of non narcotic painkillers.
> The guy who won the Nobel prize for giving himself an ulcer estimated it as 90%
That's worldwide. In developed countries the proportion is closer to 10 to 15% [1, 2]
[1] https://www.jwatch.org/na50875/2020/02/24/prevalence-h-pylor...
[2] https://pubmed.ncbi.nlm.nih.gov/31972622/
I did the oops too much Advil on myself naively over years. Gastritis and resolves once the cause is figured out but scared me to respect otc meds more.
Yeah the real outcome of all this was "stress is not a cause of ulcers and other GI issues, but it can increase the negative impact" and "some uclers and other GI issues can be treated by antibiotics".
Stress of course makes pretty much all multicellular organisms more susceptible to pathogens and environmental toxins. But it’s the trigger not the bullet.
They do genetically sequence cancers today, at least looking for specific markers.
[flagged]
https://de.wikipedia.org/wiki/Alfons_Weber_(Mediziner,_1915)
Full paper link for the interested: https://ehdijrb3629whdb.tiiny.site
"404 Sorry, this content doesn't exist."
Let me guess, this research was sponsored by Lance Armstrong?
Huh. I assumed this was going to be a collision of acronyms but erythropoietin is the same EPO used medicinally to treat anemia and abused by several generations of endurance athletes (complications include strokes and heart attacks from blood clot).
It’s a stress-signaling hormone produced by the kidneys when they detect hypoxia and triggers more red blood cell production in bone marrow.
What makes this mildly funny, though I admit in quite poor taste, is the fact that Armstrong did indeed suffer of cancer to which he lost a testicle before his comeback to win multiple Tour de France back to back. So theoretically his EPO positive results could be attributed to those tumors producing it, if this research is to be believed. Maybe not all of the times though.
Or, consider that the causation could have been the other way around. The EPO could have made him more susceptible to cancer.
There is a mountain of evidence that the drug cheating was systematic. You can read The Secret Race, or draw your own conclusions from the $5 million false claims act settlement.
You know that I was only joking right? The man admitted all his abuse on day time TV.
He was on steroids post treatment as well. Chemotherapy likes to cause anemia. In fact I think that’s where I first heard of EPO. Some survivor crowing about the efficacy at making them feel human again.
And they’ve discovered in more recent studies that steroid use has effects that last about twice as long as it’s detectable in your body (2 vs 1 year?). If sports weren’t such a young person’s game, I’d worry about people taking off for “surgery” and coming back built like a linebacker but testing clean.
Lance Armstrong never failed a drug test. The CEO of the insurance company responsible for underwriting bonus payments for Tour de France wins had read a book full of circumstantial evidence of the US Postal Service team doping and contested paying out the bonus. He knew they'd lose, but wanted to force the hands of some investigative body with real power to actually look into it. Federal prosecutors took up the case for a couple years, but then dropped it. Then USADA finally got a bunch of his former teammates and medical staffers to testify against him. Lance didn't even contest the finding because the evidence was so overwhelming, he figured his best course of action at that point was trying to keep the report confidential and winning in the court of public opinion instead, convincing all of his adoring fans that he was the victim of a witch hunt.
Obviously, that didn't work, but I guess he was just ahead of his time. These days, he could have run for president.
> Lance Armstrong never failed a drug test
That's not how I read this part of the Wikipedia article[1]:
> In June 2012, USADA accused Armstrong of doping and drug trafficking, based on blood samples from 2009 and 2010
[1] https://en.wikipedia.org/wiki/Lance_Armstrong_doping_case#20...
Fair enough. I should specify he never failed a drug test from the period in which all of his UCI and Olympic wins were rescinded, which I believe was 1998 to 2005. I'm also reasonably sure he never got popped specifically for EPO. There has been a test to find recombinant EPO since 2000, but it can only detect its presence for something like 18 hours after injection and you only need to inject weekly. Out of other ways to blood dope, only tranfusion from another person is detectable by any means whatsoever. It's why they use the athlete biological passport instead and look for increases in red blood cell count or hematocrit that are not physiologically possible without doping.
He was working with doctors who were knowledgeable of techniques the UCI was not testing for yet, and in masking. That’s why he got popped on the stored samples. They have rules against doping that are set up to cover substances they don’t have tests for yet and that is part of why they store samples.
But they were also using “blood doping” which is essentially giving blood transfusions to yourself. One of his lieutenants, Tyler Hamilton, got busted for it a few years before Lance got caught. He claimed he was innocent and maybe it was chimerism or an absorbed twin. But this dumb fucker had already been caught doping several times before, one of which stuck and the other failed on a technicality (frozen backup sample could not be tested) My guess is they switched bags and he’s lucky he got a compatible bloodtype and didn’t stroke out. He got caught doping again in 2009 and received an 8 year ban, and retired. And later was stripped of his gold medal as well.
The only legal form of blood doping is altitude training and that effect doesn’t last long enough for the Tour or the Gira. But could allow someone to get an early lead.
As for Lance not getting caught between 1998 and 2005, that’s only barely technically true. He was caught using corticosteroids in a test in 1999, but explained it away with a topical steroid allegedly for saddle sores. He confessed later that it was a cover up for his doping. He also tested positive for EPO six times during this period but as the tests were still experimental, there was some clever lawyering that kept it from sticking.
Laurent Fignon and Eddie Merckx have both been accused of stimulant use which cost them only one or two races instead of years.
Richard Virenque was a popular French rider who won the King of the Mountain many many times, when he went down it was for an entire cocktail of drugs including HGH.
And I had forgotten that Christian Vande Velde was caught in the postal service bust. He’s a commentator for NBC now. I wonder what Liggett thinks of that.
Sources: a bit of memory but mostly https://en.wikipedia.org/wiki/List_of_doping_cases_in_cyclin... which, by the way, has become ridiculously, alarmingly long. Jesus Christ.