Cancer.. where to look for clues

I’ve been interested in cancer for quite a while. Even before I got affected, the complexity and the link with metabolism caught my attention. Despite digging up all the details of how cancer develops and works, I somehow never could find a distinct feature of a cancer cell. I could not find a single feature that I could not find back in other normal cells.

They do what is normal for growing cells, they do what is normal for cells under hypoxic conditions. They behave similar to embryonic cell proliferation, to immune cell proliferation. Except… they don’t differentiate. Why don’t they differentiate?

“But isn’t it clear” you may ask? “It is a genetic disease right? So mutated genes of course!” Really? Thomas Seyfried already showed that by taking the nucleus (where the cell genes are located) and putting them in another cell doesn’t create a tumor cell. However, putting the mitochondria from a cancer cell into a normal cell does cause the cell to become cancerous.

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source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

Mutated nuclear DNA doesn’t seem to cause a cell to be cancerous. The mitochondria however contain mitochondrial DNA. Perhaps mutations there cause cancer? That doesn’t stride well with the way mitochondria work.

They are highly susceptible to damage indeed but through evolution they developed a build-in mechanism to eliminate malfunction parts. Through fission and fusion they continuously break up and digest malfunctioning mitochondria via a process called mitophagy to then build up again towards bigger properly functioning mitochondria.

Then along comes my investigation on the root cause of atherosclerosis and it drives my attention to the role macrophages play in the pathology. There I get to learn about how monocytes get stuck at locations of inflammation via signaling molecules (cytokines). Locally they start to perform their job where they stimulate satellite cells to become active and start proliferating. Again this is happening through signaling via cytokines. The macrophages also change profile in this process. This causes their metabolism to switch from glycolysis towards fat oxidation. And once more this is triggered by external signaling.

After all this comes along a video on my feed in youtube. PhD Mina Bissell from UC Berkeley explains about her life work. She shows how the extracellular matrix (ECM) is driving behavior.

Her work supports Thomas Seyfried. When implanting tumor cells into a chicken wing, it develops like a cancer. Those cells in a petri dish develop like a cancer. Inserted into the wing of an embryo, they behave like normal cells despite having mutated nuclear genes! The context, the surrounding is different, not the cells!

Proliferate or differentiate under influence of the ECM. This is very important. It shows why cell cultures fail to provide similar results in vivo. They are missing the context.

ECM

What are the components of the ECM? Here’s a good introductory video.

Notice here lamina which has been central in the work of Bissell.

  • Collagen
  • Proteoglycans
  • Lamina
  • Fibronectin

If you watch the video then notice at some point he says how the structure gives cells some resistance to migrate, they ‘feel’ there is no room to proliferate! The cells ‘feel’ this through interaction with the ECM.

When he discusses proteoglycans, he explains about hyaluronic acid (HA or also known as hyaluronan) and how it attracts water so that together it forms a gel-like structure.

I found the following article a true eye-opener. They did research towards the effect of a breakdown of the HA. When this structure is lost around cells, they change metabolism towards glycolysis and take up an accelerated migration pattern.

When HA is lost, the inhibitory effect on GLUT1 translocation to the membrane is lost. This allows the cells to increase glucose uptake in support of glycolysis. This switch in metabolism is what cells do to proliferate. This is what enables them to turn on the right genes for building copies of themselves and construct the raw material for building these copies. This is not a special feature of cancer and you certainly don’t need a mutated gene.

As you can see in the next picture, every single cell line they tested this with responds in a similar way, starting to increase glucose uptake and increase lactic acid production. They used primary, immortalized, murine, human cells, as well as cancer cells. A very diverse array of nuclear genetic material yet they are all responding.

Loss of HA also allows cells to migrate more which reminds us of metastasis in cancer.

“Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization” https://www.sciencedirect.com/science/article/pii/S009286741831033X

When we look at how muscle repair works then we note a similar behavior for satellite cells (which get activated and proliferate thanks to macrophage signaling). What we note is that amongst others, the ECM factors (collagen, fibronectin) are listed as regulators of their proliferating state. Including beta1 integrin which was used by Bissell.

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How much research is done on cells without providing an ECM? Wouldn’t it invalidate their applicability? By not providing an ECM during testing, we know what cells do without it. They proliferate. You don’t need a cancer cell, you don’t need genetic mutations. Trying to develop drugs that interfere with the growth will likely interfere with the growth of all cells. It is not specific enough.

Unless loss of ECM is part of cancer but that is not the case.

But it begs the question, is it possible that the root cause of cancer has to be found in a disturbance in the cell environment? In its ECM?

Hypoxia

I suspect a situation of chronic hypoxia in the case of atherosclerosis because the cause of hypoxia is outside of the region that is affected by hypoxia. As a result the region itself tries to recover from it but is unable to.

We have to start somewhere so why not start with the hypothesis that in a similar way there is a disturbance in blood supply to a region in the body. This triggers inflammation and leads to a response to heal. But what if the response is not sufficient to fix the hypoxia? We go from acute to chronic.

Hypoxia certainly affects the ECM. It activates breakdown of the basement membrane while at the same time building up collagen.

“Hypoxia and the extracellular matrix: drivers of tumour metastasis” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283800/

What I understand from the basement membrane is that it gives the group of cells their purpose. It helps cells to differentiate, provide structure for organ development and so on. The basement membrane is stabilized by type IV collagen but hypoxia also upregulates type IV collagen-breakdown enzymes (MMP2, MMP9).

“Basement Membranes: Cell Scaffoldings and Signaling Platforms” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039528/

Tumor blood vessels

One thing I keep reading is how the neovascularization fails. The whole idea is to improve blood supply so that oxygen can be delivered to resolve the hypoxia. But it fails to do this properly.

Although there are manifold VEGF signals sent out for vascularisation, it could be that the proliferation of cells had a chance to build up in volume to interfere with proper development, interfere with the proper structure formation.

“Tumor Endothelial Cells” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282494/

Such defect in proper vascularisation could signal the entry into a more chronic state of hypoxia and exposes the inability to resolve the hypoxic situation.

Hypothesis

Something goes wrong at the very end of the microvessels, a malfunction of some sort. Because of this, oxygen delivery by the blood fails to reach a very small area which causes that area to become hypoxic.

Similar to atherosclerosis, the cause for the hypoxia is nearby but not in the area itself. This starts to set the normal hypoxia reactions in motion: macrophage attraction, cell growth, ECM remodeling, neovascularisation etc. all the steps needed to resolve the situation and all hallmarks that we are familiar with looking at cancer.

What should stop the growth however is proper vascularisation. But this fails because the cause of the initial damage to the blood vessel is still there. That damaged area is closest to the hypoxic region and from that damaged area it would normally start to grow new blood vessels.

But because the point to start new blood vessels from is also the point that is damaged, the formation of new blood vessels is impaired and is unable to rescue the hypoxic region in time.

Support for the hypothesis

A first detailed look at the situation shows us that loss of fatty acid synthase (FAS) enzyme increases malonyl-coa which acts as an inhibitor for mTORC1. This impairs the ability to grow new vessels.

“Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation” https://pubmed.ncbi.nlm.nih.gov/30146486/

insulin resistance

I know diabetes and hypertension are risk factors for cancer. I’m also aware that diabetes patients risk amputation due to capillary damage.

In the following article they explain the mechanism. FAS binds to Nitric Oxide Synthase (NOS). What they did was knock out FAS in endothelial cells. This caused the blood vessels to become leaky and “unable to generate new blood vessel growth“. This aligns well with the impairment of mTORC1.

“Root cause of blood vessel damage in diabetes discovered” https://www.sciencedaily.com/releases/2011/01/110129081530.htm

Looking at hypertension we see that the insulin-triggered vasodilation is impaired in the capillaries.

“Capillary recruitment is impaired in essential hypertension and relates to insulin’s metabolic and vascular actions” https://academic.oup.com/cardiovascres/article/49/1/161/292764

Vasodilation is dependent on NOS so what this all seems to suggest is that the endothelial cells have become insulin-resistant. They don’t respond to insulin signaling anymore.

“Role of Insulin Resistance in Endothelial Dysfunction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594115

I’m not fully clear why but we see higher circulating levels of FAS in diabetes. One possibility that we see is that FAS is mainly produced in the liver and possibly insulin resistance in the liver may cause FAS to be secreted into circulation.

“Extracellular Fatty Acid Synthase: A Possible Surrogate Biomarker of Insulin Resistance” https://diabetes.diabetesjournals.org/content/59/6/1506

“Circulating serum fatty acid synthase is elevated in patients with diabetes and carotid artery stenosis and is LDL-associated” https://www.sciencedirect.com/science/article/pii/S0021915019304411

Smoking

We know smoking is a risk factor for both atherosclerosis and for cancer. Although the following article is about smoking and atherosclerosis, I bring it up because it shows how smoking causes damage to the endothelial cells. Smoke isn’t selective to your heart. It is also increases the risk factor for amputation.

“Cigarette smoking, endothelial injury and cardiovascular disease” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517732/#__sec4title

“A comparison of diabetic smokers and non-smokers who undergo lower extremity amputation: a retrospective review of 112 patients” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474996/

We would expect this in the hypothesis if cancer originates from damaged blood vessels.

Fatty acid types

The following paper found that palmitic acid and linoleic acid cause a similar impairment. Both types of fatty acids are more prevalent in our diet (linoleic acid, palmitic acid) and from endogenous production (palmitic acid) due to a high carbohydrate diet combined with insulin resistance.

“Free Fatty Acids Inhibit Insulin Signaling–Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN or Inhibiting Akt Kinase” https://diabetes.diabetesjournals.org/content/55/8/2301

Thomas Seyfried

The experiment that Seyfried showed us is somewhat a result after the facts. Proliferation is driven by the state of metabolism (glycolysis or oxphos). But the state of metabolism is switched (not driven) by the signals from the environments. In response to this signal, the structure of the mitochondria change to support this mode.

Glioblastoma cells in different ECM mediums (added on 2021.04.07)

The following paper shows nicely how the environment of the cells influences their behavior and morphology. They compared a typical collagen versus a GBM-patient tissue derived ECM. With the picture you can already see how the same implantation of cells proceed differently whereby only the ECM is different.

figure3

“The mode and dynamics of glioblastoma cell invasion into a decellularized tissue-derived extracellular matrix-based three-dimensional tumor model” https://www.nature.com/articles/s41598-018-22681-3

————————————-

I do not think cancer nor atherosclerosis can be defined as a metabolic disease because I do not see any impairment in metabolism. It is a problem with oxygen delivery driven by endothelial dysfunction. The nearby affected region is then inflicted with hypoxia which starts to drive the remodeling of the ECM. The remodeling drives the cells to their dedifferentiated embryonic state. The lactate production is to implement attachment as is seen under true embryonic development. Unfortunately, with impaired endothelial cells from which the vascularization should take place, this step of the process fails to be done properly so that the hypoxic situation remains unresolved.

What needs to be cured is endothelial dysfunction.

Current cancer standards of care

If this hypothesis turns out true, the current treatment options for cancer may actually cause cancer through the same mechanism, damage to the blood vessels.

Radiation therapy causes endothelial dysfunction.

“Radiation therapy impairs endothelium-dependent vasodilation in humans” https://www.sciencedirect.com/science/article/pii/S0735109700011906

But also chemotherapy results in impaired endothelial function. They try to deliver anti-angiogenesis resulting in an increased cardiovascular risk, trombosis, hypertension etc.

“Vascular Complications of Cancer Chemotherapy” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989034/

Second cancers, following treatment of the first cancer are recognized to be related to the treatment. Do note this is correlation, not necessarily causation.

“Second Cancers Related to Treatment” https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/second-cancers-in-adults/treatment-risks.html

3 thoughts on “Cancer.. where to look for clues

  1. Mina Bissell was impressive. Thanks for putting it up there. A few years after this video she did a paper showing that sugar itself could cause the EXCM to degrade and begin breast cancer.

    I have a cancer precursor condition in the blood. More and more paperers are coming out linking the clonal cells to a poor micro environment in the bone marrow AND hypoxia. In that, it is well known that viruses can cause the problem or blood cancer in general… and they suspect that in a hyperactive immune response, there is hypoxia for some of the cells mobilizing and rapidly reproducing to fight the infection.

    Now the 64K question: Why the hypoxia and what can be done to fix the microenviornment?

    Liked by 2 people

    1. As you can read in the post, I have a suspicion that there is a more systemic detrimental effect on the endothelial cells. In general hypoxia is overcome by neovascularization. Perhaps I’m wrong but I’m shifting my attention more and more towards all elements that affect endothelial functioning as I hope to find a potential answer on how to resolve the situation of hypoxia.

      Liked by 1 person

      1. What about water?
        1. Dehydration is more likely to happen as you age, even if you drink the same. Your kidneys do not concentrate the urine as well and you lose more water each time you go.
        2. ECM is 60% water… it is the main component.
        3. Sufficient water assists in the volume of the blood. Improving blood supply.
        4. Water is “H2o” so oxygen. Would that not add more oxygen to the ECM and the blood supply?

        There are some — not a lot – of studies saying sufficient hydration reduces cancer incidence.

        Liked by 1 person

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