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Recently there was a nice confirmation of a long held hypothesis that source of cells in cancer (at least one type) are due to stem cells. Thus, the long held idea that a positive feedback loop of worsening genome degradation (after an environmental insult) which leads to rapid cell division, metastasis
etc seems not to be the whole story. Rather, cancer stem cells within the tumor seem to fuel the tumor growth.
Now I am not sure if people know exactly what a cancer stem cell is, where it comes from etc? I asked a cancer researcher at an adult league sporting event but he just pointed with his beer and told me it was my turn to go.
But it got me to thinking, what if the stem cells in cancer are just normal stem cells that very much enjoy being inside a small mass of tissue. Thus, there is an initial environmental insult which leans toward a clump of cells being formed. And then because of the local inflammation, stem cells home to the inside of the tumor start proliferating, and then your totally fucked. Thus the initial environmental insult to DNA is really just creating a stem cell niche.
The thing that makes me think that the inital tissue mass could make a nice stem cell niche is that it would likely be hypoxic (low O2). Tumors are well known to be hypoxic in the center and weirdly so are stem cells niches (bone marrow in vivo has very low O2 and many cultured stem cells are grown in low O2 which helps prevent differentiation). In fact the homeostatic downstream signalling of this hypoxia (through a protein called VEGF) is what induces blood vessels to grow towards tumors.
So, in summary, instead of:
1) a positive feedback loop of worsening genome degradation (after an environmental insult).
maybe
2)A) initial DNA insult B) small clump of cells creates hypoxic niche C) stem cells arrive to fix injury but are all like "Whoa, it's nice in here, let's just hang out and create more cancer."
Anyway, I found a journal abstract from 2011(just found the popular write up) that supports this hypothesis, where they found a bunch of "normal" stem cells in high percentage of human ovarian cancers, but not much else in terms of lit, so it may be another case of seeing what you want in the noise.
However, if true, I think it leaves open a whole new strategy to beating cancer. Instead of targeting cell division like in chemotherapy, to kill the tumor, just try and change it. In other words, "differentiate" the source stem cells, turn them into hair cells, fat cells whatever. Make the niche uninhabitable for them. One way maybe to do this would be just to hyperoxygenate the inside of a tumor. I predict that initally it would grow, but than it would stop and plateau. Another maybe to inject known differentiaion inducing factors into a tumor which would drive the stem cells down a particular differentiation pathway. Maybe try this on terminally ill patients with tumors to close to valuable organs to start.
Normal Stem Cells in cancer
http://www.scienced...07/110718132128.htm
[leinypoo13, Aug 28 2012]
Cancer as cure
http://www.ted.com/...re_of_medicine.html
[2 fries shy of a happy meal, Aug 28 2012]
Differentiation treatment
http://en.wikipedia..._leukemia#Treatment
reinventing the wheel is still inventing the wheel. [bungston, Aug 28 2012]
MMPs and cancer
http://clincancerre...ontent/9/2/551.full
[leinypoo13, Aug 28 2012]
Oxygen helps fight cancer
https://www.science...ghting-immune-cells
Self promotion [leinypoo13, Mar 14 2015]
[link]
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Make it think it's in skeletal muscle tisue. [link] |
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Hyperbaric oxygen therapy? |
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It's a known technology to take patients to
the verge of oxygen narcosis - the
phenomenon has been thoroughly
investigated for divers.
Living in a compression chamber for a few
days would be painless and relatively easy
and inexpensive to test. |
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This is totally not my subject, but it sounds like an intereting theory. |
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If this were true, how does metastisis occur? |
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Maybe the tumor is releasing so many stem cells that eventually some find their way into other niches throughout the body. |
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Or maybe this applies to some types of cancer but not others: maybe benign rather than malignant tumors. I hope not since universal cancer treatment with hyperbaric chambers sounds like a nice alternative to chemo. |
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bungston link shows it has been thought of and works at least for that type of leukemia. However, in this case they are suggesting that it is terminally differentiating a malignant cell by regulating an aberrant oncogene. This would mean that that the RA is differentiating an "already damaged cell" and "rescuing it" from becoming a tumor. |
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I guess if normal stem cells are in cancer (as in link), it raises the question of what is malignancy? Is a normal stem cell arriving at new place and contributing to a tumor a malignant cell? Presumably these would not have any genetic damage but still largely contribute to the lethality of the illness. |
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In terms of metastasis, one could hypothesize that original tissue damaged cells indeed do become translocated into the blood stream, not becuase they acquire any special properties or signals, but rather because tumor density itself (massively increased by proliferating stem cells) precipitates upregulating matrix metalloproteinases (MMPS). Tumors are well known to be chock full of MMPS. They basically break down the local extra cellular environment, decreasing cell to cell contact and increasing plasticity. Then depending on the type of cell that is initially damaged and it's complement of cell surface proteins, it would be more/less likely to metastasize to other parts of the body. |
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Thus, metastasis would be a) initial environmental insult b) create niche c) recruit stem cells d) proliferation and hypoxia e) matrix erosion sloughs off one or more "initial cells" f) these create a new niche somewhere else in the body and cycle starts over. |
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About, hyperbaric 02, I am pretty sure this has been tried for a long time to cure cancer and does not work. Not sure this disproves the hypothesis, but it certainly doesn't help. |
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I mean to add a meaningful anno once I have one, but I wonder if the credential threshold is too great to post ideas such as this on the Figshare.com site you've also put up? Figshare incidentally is owned by the publishers of Nature in some way. |
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Statements that are not true: |
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1) "Now I am not sure if people know exactly what a cancer stem cell is, where it comes from etc?" |
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Researchers are now very well aware of exactly how the reproductive instincts of cancer cells become perturbed. The type and point of differentiation when a stem cell line becomes cancerous determines the type and character of the cancer. |
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2)"what if the stem cells in cancer are just normal stem cells that very much enjoy being inside a small mass of tissue" |
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They aren't, they are stem cells that have suffered and insult to the system that regulates the formation of tissues and thus they continuously form new tissue, without responding to signals that would stop their reproduction or induce normal cell death (apoptosis). |
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3) "Thus the initial environmental insult to DNA is really just creating a stem cell niche." |
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No, as clearly demonstrated by genetic testing, the tissues produced by cancerous cell lines all bear the same tell tale marker of the parent stem cell, no matter where they are in the body. Introduction of the errant DNA in cells from the same stem line will produce the same cancer. Cancer is a disease of stem cells, and is generally more profound the more undifferentiated those cells are. |
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4) a positive feedback loop of worsening genome degradation (after an environmental insult). |
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This isn't cancer. Nobody believed this. |
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5) small clump of cells creates hypoxic niche C) stem cells arrive to fix injury but are all like "Whoa, it's nice in here, let's just hang out and create more cancer." |
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This doesn't describe the character of a tumor at all. Nor does it explain cancers of the blood cells. Generally cancers are rapidly dividing. |
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6) In other words, "differentiate" the source stem cells, turn them into hair cells, fat cells whatever. |
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The exact system that is broken in the first place? The system that told them to divide X number of times until a new tissue was produced? Yes, if we could fix that bit of their DNA it would work, sadly we don't have any way to do that. Nothing that we can introduce into their locality, short of killing them, will cause this change. |
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It is very clear that you are not at all aware of the diversity in types of cancer. This theory of hypoxia induced cancer does not explain tumor formation or why it is possible to produce tumor tissue in vitro using only a few stem cells. You simply looked for anything that would support an idea that appealed to you, ignoring the massive body of evidence to the contrary and thus you should most certainly try to make millions of dollars selling this idea to similarly gullible saps who are also willing to ignore the scientific consensus. |
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Ha! Good, I am glad you challenged the idea. Of course,
claiming you have a brand new idea of how to treat cancer
should be treated with derision and most likely be thought
of before and dismissed for good reason. If this truly was
novel it would be pretty incredible. One in a million that an
outside the discipline guy has a valid idea within the
discipline. I am not a charlatan though, just curious, so
bear with me. It seems to me the sword of Damocles of this
idea is that whether or not there are normal local ir
circulating stem cells that migrate and enter the tumor. If
not true (as you state) boom, idea is retarded and done. If
true, then there may be some merit. I think there is
evidence for this (link) and others have found this too, this
is what I am basing my idea on. Is this true or have I read it
wrong? |
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clearly in all in-vivo cancers there is support and tissue formation by non-cancerous cell. This noncancerous tissue is dynamically produced when the cancerous cell line signals that cells and tissues from other lines are needed to support it's growth. These tissues try to accommodate those signals as best they can, though, given the disordered nature of cancerous growth, it is not always in an effective or logical way. In this way, the spread of cancer saps the resources of the body by forming highly demanding, illogical and inefficiently laid out, unneeded tissues. |
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But still the root cause of these tissues are stem cells with specific breaks in their genomic sequence. This understanding of cancer explains why it moves in the body, why there are so many types of cancer, and why some types of cancer are more malignant than others.
Your theory that cancer is caused by cells that need more air, and that somehow forget what they are supposed to become isn't supported. Sure some cancers might be substantially injured if we injected them with oxygen. I'm not sure if there are many tissues that could survive this treatment. The observation that the areas where stem cells occur and the inside if tumors might have similar properties is plainly invalid. Many tumors occur in the lungs, liver, kidneys, and other tissues constantly rich in oxygenated blood and no association has yet been made between small clusters of mutant non-cancer hypoxic tissue acting as a seed site for cancer. Under your proposed mechanism, how would cancer metastasize? |
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//clearly in all in-vivo cancers there is support and tissue formation by non-cancerous cell. |
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Ok, I think there is some misunderstanding about what I am saying. I am not saying that normal stem cells become cancerous. Really the crux of what I am saying there is a dangerous cancer messenger pathway that is independent of |
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1) tissue or cellular origin
2) genomic insult to parent cell (which tumor suppressor you knock out) |
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And that this may be very crucial for the morbidity and progress of cancers in general. |
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It is that when non-cancerous tissues (such as stem cells that migrate to the middle of a tumor and proliferate) it increases the density of the tissue, which in turn increases the HIF-1a (hypoxia-inducible factor pathways) which cause a host of problems that keep cancer cells a) alive b) resistant to immune response c) maybe metastasis. |
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Well known down stream pathways of hypoxia are: |
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a) VEGF signaling-angiogenesis for increased blood vessel support to tumor (ironically researchers have been trying to stop this vessel growth for tumors for many years) |
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b) SDF signaling- this is a chemokine that attracts through CXC receptors among other things circulating stem cells (this is a well known mechanism of stem cell homing and why stem cells "know" to go to injury areas) |
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So if an initial insult of cancer, lets say "thymine dimer" in a tumor supressor gene of a skin cell, (keritanocyte) causes a small clump of cells to form (what I am calling a niche), the hypoxia induces stem cells to arrive at the tumor and perhaps add to the density of the tumor. This in turn induces angiogenisis, increasing growth near the surface but also creating more hypoxia near the center, more stem cells arrive and so on... |
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The idea is to stop this feedback loop by making the tumor inhospitable to the recruitment of more normal tissue that feeds the cancer. Thus, raise O2 or try and target the non cancerous stem cells for differentiation (through other means) to stop it's secondary effects on the cancerous cells themselves. Perhaps this will slow the growth allowing the immune system to have it's way with the cancerous cells. Your suggestion that tumors in lungs and other areas of the body are non-hypoxic, I am not sure is true. I believe that the cellular density would rapidly alter the O2 diffusion characterstics in a tumor more so than proximity to ambient O2 |
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In this scenario, the non-cancerous cell growth would allow metastisis of the cancerous cells by increasing overall MMP production of the tumor allowing the cancerous cells to escape into the bloodstream and implant somewhere else. Then the whole cycle would start again. |
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I think the perfect experiment to test my assumptions is to inject different (in terms of aggressiveness) in vitro cancer lines into mice and assay the extent to which normal stem cells are recruited into the tumors (if at all) and see if there is a correlation between morbiditiy, metasis, rate of tumor growth etc and recruitment rate. |
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If there is a correlation, than target these cells for differentiation treatment and see if you can change the curves. |
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But research clearly indicates that cancers are tissue specific. Possibly there are cancers that have this as a co-factor, but there are clearly many more that have other co-factors, such as hormonal stimulus, or blood sugar irregularity. Cancers of specific tissues are much more likely to be stimulated by the signals specific to those tissues than they are to localized affects like hypoxia. If growth factors for liver cells remain at a uniform level then a cancer of the liver will only grow at, say, 1.1x the local growth rate for healthy tissue, but if we briefly introduce a growth factor that accelerates the growth of liver tissue the local healthy cells will grow at a regulated 1.3x while the cancerous cells will begin to grow at an unregulated 2-3x. In tumors of the reproductive tissues hormonal factors are so influential that even very nasty mutations can sometimes be static for years so long as there is little regulatory stimulation. I don't think that your approach of looking at cancer as a structure rather than a line specific tissue is accurate and I don't think that there is any known cancer that would respond to the introduction of oxygen by becoming a less malignant type of cancer, genetically. |
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[link] and comment from 2.5 years ago // Perhaps this will slow the growth allowing the immune system to have it's way with the cancerous cells. |
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Sweet, sweet victory lap. |
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I think you earned that victory lap. [+] |
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