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on Gopher (inofficial)
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COMMENT PAGE FOR:
URI Tumor-derived erythropoietin acts as immunosuppressive switch in cancer immunity
biotechbio wrote 18 hours 36 min ago:
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.
ramraj07 wrote 37 min ago:
I actually don't mind if it's true, but your comment was the first
time I got a tingle that this was AI generated but I still could tell
it likely wasn't. Maybe used it to rewrite parts of your comment?
Anyways i appreciate it and agree with you. I myself am gonna go
check in the cancer cell line encyclopedia, which IME is the single
cleanest large dataset curated in biology in decades.
For others who might be curious, this study is genuinely good
(evidenced somewhat by it being published in Science, as a study that
is not in humans but still showing actual cancer curing efficacy not
just some pathway finding) is that they use difficult but necessary
model systems that emulate real tumor environments - these are
spontaneous tumors that show up in mice that have full immune
systems. Literally 99.9% of cancer study papers don't use such
systems and in my opin9on get fully invalidated for most
interpretation.
Anyways I'm curious if the microenvironment will just evolve quickly
to be EPO independent, as it typically seems to do something like
that in real long term tumor environments you encounter in people
compared to mouse models.
SimplyUnknown wrote 1 day ago:
Full paper link for the interested:
URI [1]: https://ehdijrb3629whdb.tiiny.site
damnitbuilds wrote 23 hours 14 min ago:
"404
Sorry, this content doesn't exist."
hinkley wrote 1 day ago:
Tumors excreting chemicals to prevent destruction doesnât 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.
loa_in_ wrote 5 hours 17 min ago:
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.
panabee wrote 22 hours 57 min ago:
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
- Kaposiâs sarcoma
- Nasopharyngeal carcinoma (NPC)
- NK/T-cell lymphomas
- Head and neck squamous cell carcinoma (HNSCC)
- Hepatocellular carcinoma (HCC)
URI [1]: https://pmc.ncbi.nlm.nih.gov/articles/PMC8831861
atahanacar wrote 23 hours 45 min ago:
>Tumors excreting chemicals to prevent destruction doesnât sound
like DNA damage, that sounds like evolution.
One cell's DNA damage is another cell's evolution.
dekhn wrote 23 hours 49 min ago:
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 ,
jhrmnn wrote 14 hours 17 min ago:
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?
rubicon33 wrote 15 hours 38 min ago:
>>> 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?
atombender wrote 1 day ago:
> ulcers are bacter
To be clear, some peptic ulcers are caused by H. pylori, but not all
ulcers.
hinkley wrote 22 hours 59 min ago:
The guy who won the Nobel prize for giving himself an ulcer
estimated it as 90%, which is very comfortably âmostâ. If that
has been drastically estimated down I hadnât heard.
Also donât 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.
Calavar wrote 19 hours 8 min ago:
> 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]
URI [1]: https://www.jwatch.org/na50875/2020/02/24/prevalence-h-p...
URI [2]: https://pubmed.ncbi.nlm.nih.gov/31972622/
jjtheblunt wrote 22 hours 37 min ago:
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.
dekhn wrote 23 hours 47 min ago:
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".
hinkley wrote 19 hours 47 min ago:
Stress of course makes pretty much all multicellular organisms
more susceptible to pathogens and environmental toxins. But
itâs the trigger not the bullet.
giantg2 wrote 1 day ago:
They do genetically sequence cancers today, at least looking for
specific markers.
Kalanos wrote 1 day ago:
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.
superfist wrote 1 day ago:
The cancer problem always struck me as more of a control theory
challenge than a purely biological one.
hinkley wrote 1 day ago:
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. Itâs unclear to me whether the cancer transmission
was rare or the identification is rare.
tdullien wrote 7 hours 17 min ago:
Tasmanian devils.
dekhn wrote 23 hours 55 min ago:
tasmanian devils [edit: I guess you already said that]
URI [1]: https://en.wikipedia.org/wiki/Devil_facial_tumour_diseas...
hinkley wrote 23 hours 2 min ago:
Yup. Link is handy though. Someone will post it to the front
page in 14 hours :)
rflrob wrote 1 day ago:
Thereâs very often a comparison to the somatic (i.e.
non-cancer) genome of the same patient. Itâs a great way to
quality control that there wasnât some sample mixup in the lab.
Transmission of cancer is rare in humansâif it were not, it
would make someoneâs career to find many cases of it. While we
canât say that all sheep are white, weâve looked at enough of
them to say that black sheep are not common. Furthermore, itâs
very clear how the Tasmanian devil cancer is spreadâitâs
around the mouth while they are biting each others faces; itâs
not as obvious how one would spread most human cancers.
Kalanos wrote 3 hours 24 min ago:
somatic = cancer. germline = inherited.
jjtheblunt wrote 22 hours 39 min ago:
Is HPV an example?
cogman10 wrote 22 hours 31 min ago:
Not really. It's a virus that can cause cancer and not the
cancer itself.
hinkley wrote 23 hours 3 min ago:
Oh that makes sense. I forgot about differential analysis.
mariusor wrote 1 day ago:
Let me guess, this research was sponsored by Lance Armstrong?
hinkley wrote 1 day ago:
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).
Itâs a stress-signaling hormone produced by the kidneys when they
detect hypoxia and triggers more red blood cell production in bone
marrow.
mariusor wrote 1 day ago:
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.
jamesliudotcc wrote 16 hours 47 min ago:
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.
mariusor wrote 12 hours 33 min ago:
You know that I was only joking right? The man admitted all his
abuse on day time TV.
nonameiguess wrote 22 hours 45 min ago:
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.
mariusor wrote 8 hours 2 min ago:
> 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
URI [1]: https://en.wikipedia.org/wiki/Lance_Armstrong_doping_c...
nonameiguess wrote 4 hours 44 min ago:
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.
hinkley wrote 2 hours 26 min ago:
He was working with doctors who were knowledgeable of
techniques the UCI was not testing for yet, and in masking.
Thatâs why he got popped on the stored samples. They have
rules against doping that are set up to cover substances
they donât have tests for yet and that is part of why
they store samples.
But they were also using âblood dopingâ 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 heâs lucky he got a
compatible bloodtype and didnât 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 doesnât 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,
thatâs 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. Heâs a commentator for NBC
now. I wonder what Liggett thinks of that.
Sources: a bit of memory but mostly [1] which, by the way,
has become ridiculously, alarmingly long. Jesus Christ.
URI [1]: https://en.wikipedia.org/wiki/List_of_doping_cases...
hinkley wrote 23 hours 4 min ago:
He was on steroids post treatment as well. Chemotherapy likes to
cause anemia. In fact I think thatâs where I first heard of
EPO. Some survivor crowing about the efficacy at making them feel
human again.
And theyâve discovered in more recent studies that steroid use
has effects that last about twice as long as itâs detectable in
your body (2 vs 1 year?). If sports werenât such a young
personâs game, Iâd worry about people taking off for
âsurgeryâ and coming back built like a linebacker but testing
clean.
w10-1 wrote 1 day ago:
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.
jjtheblunt wrote 14 hours 53 min ago:
> 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... [1]
URI [1]: https://pubmed.ncbi.nlm.nih.gov/28629523/
URI [2]: https://www.genengnews.com/topics/cancer/blocking-erythropoi...
badmonster wrote 1 day ago:
yeah i cannot read the full article
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