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Stress (adrenaline, Noradrenaline) As The Main Driver Of Cancer Metastases

  1. I just posted a study in which it was shown that surgical removal of a tumor results in massive and uncontrolled formation of metastases across the entire organism.
    Universal Test For Cancer Progression/stage

    Here is the quote again, just to make the point of this thread clear.
    "...The antimetastatic effect of LO, injected in different concentrations (Table 1), was studied. Reduction of the volume and number of metastases of Lewis carcinoma in mice was observed after injection of the preparation in a dose of 10 IU/kg, whereas the maximal antimetastatic action was observed when the enzyme was used in a dose of 50 IU/kg. As Table 2 shows, surgical removal of the primary tumor (on the 15th day after transplantation) led to a sharp increase in the volume and number of metastases in the lungs compared with intact animals. The possible cause of this phenomenon, according to several investigators, may be stressor reactions arising in the host after resection of the tumor [1]. When the enzyme was injected into mice in a concentration of 50 IU/kg the number of metastases in the lungs was reduced by 3.6 times and their volume was reduced by 10 times compared with values obtained in animals not receiving the preparation."

    Well, apparently the effects of stress on cancer metastases are not completely unknown in Western studies. However, mainstream oncology still vehemently denies that cancer has any link to stress, be that for its genesis or progression. One of the main finding of the studies below was that that adrenaline is the main mediator of the stress signal that causes tumors to metastasize, and blocking adrenaline's effects was highly therapeutic. While I am not discounting the effects of adrenaline on remodeling of the lymphatic system, a much more likely growth promoting effect would probably be the increase in lipolysis and fatty acid oxidation (FAO) - a topic on which I posted quite a few times before.
    In light of the studies below and the role of FAO in cancer growth, what would a simple combination of clonidine and niacinamide do as cancer treatment...

    Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination
    "...Stress is implicated in increased tumor progression risk and poor survival in cancer patients. A number of recent studies have linked these effects to the promotion of tumor cell dissemination through the bloodstream via stress-induced pathways. Now, a mouse study led by researchers in Australia has revealed the mechanisms by which stress modulates cancer’s spread through another transport network open to tumor cells—the lymphatic system. The findings were published today (March 1) in Nature Communications."

    "...“We found that stress helps to build new lymphatic freeways out of the tumor [and] modulates how quickly lymph flows through lymph vessels,” said Sloan, adding that “stress increases the speed limit on these little lymphatic highways and helps cells transit more quickly out of the tumor.” Since tumor cell dissemination is a key step in cancer metastasis, the team wanted to test whether dissemination through the lymphatic system could be reduced by blocking stress signaling pathways. The researchers turned to beta-blockers—cheap, widely available drugs commonly used to treat hypertension—which inhibit signaling of norepinephrine (or noadrenaline), a stress hormone already implicated in cancer progression risk. Administering beta-blockers to tumor-bearing mice, the researchers were able to minimize changes in the density of lymph vessels at the primary tumor site, and subsequently reduce metastasis to the lymph nodes. By contrast, artificially stimulating norepinephrine receptors increased both lymph vessel density and metastasis. Through a series of further experiments, the team demonstrated important roles for macrophages involved in inflammatory signaling and a set of tumor-secreted vascular endothelial growth factors (VEGFs) in the regulation of lymph vasculature remodeling and tumor cell dissemination."

    "...The study also included an analysis of observational data from a cohort of nearly 1,000 breast cancer patients in Milan, which corroborate the team’s findings in mice: patients taking beta-blockers showed a significantly lower incidence of lymph node and distant metastases, even once potentially confounding factors such as age and treatment type had been taken into account."

    Does Stress Feed Cancer?
    "...A little stress can do us good—it pushes us to compete and innovate. But chronic stress can increase the risk of diseases such as depression, heart disease and even cancer. Studies have shown that stress might promote cancer indirectly by weakening the immune system's anti-tumor defense or by encouraging new tumor-feeding blood vessels to form. But a new study published April 12 in The Journal of Clinical Investigation shows that stress hormones, such as adrenaline, can directly support tumor growth and spread."

    "...But real tumors behave differently than cancer cells in vitro, so Sood and his team extended their exciting findings into a mouse model of cancer. After receiving a transplant of ovarian cancer cells, mice were restrained to cause stress. As such, their tumors grow more quickly. Isoproterenol (a drug similar to adrenaline) had the same accelerative effect. The tumor-feeding effects of behaviorally and pharmacologically induced stress, both of which were mediated by FAK, were inhibited by the adrenaline-blocking drug propranolol."

    "...But how closely does the stress caused by restraining a lab animal mimic that experienced by human patients? Sood and colleagues looked at samples from 80 cases of human ovarian cancer grouped according to patient stress using the National Institutes of Health's Center for Epidemiological Studies Depression scale as a surrogate marker. Patient stress (according to the scale), along with elevated stress hormone activity were associated with higher levels of activated FAK, which was in turn linked to faster disease progression."

    Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
    "...The studies, reported July 17 in PLoS Biology, demonstrate in mice that activation of the sympathetic nervous system -- the "fight-or-flight" response to stress -- primes the bone environment for breast cancer cell metastasis. The researchers were able to prevent breast cancer cell lesions in bone using propranolol, a cardiovascular medicine that inhibits sympathetic nervous system signals. Metastasis -- the spread of cancer cells to distant organs, including bone -- is more likely to kill patients than a primary breast tumor, said Florent Elefteriou, Ph.D., director of the Vanderbilt Center for Bone Biology."

    "...They found that treating the mice with a drug that mimics sympathetic nervous system activation caused more cancer lesions in bone. Using physical restraint to stress the mice and activate the sympathetic nervous system also caused more cancer lesions in bone. Treating the restrained mice with propranolol, one of a family of blood pressure medicines called "beta-blockers," reduced the number of bone lesions. The investigators demonstrated that sympathetic nervous system activation increases bone levels of a signaling molecule called RANKL, which is known to promote the formation of osteoclasts -- bone cells that break down bone tissue. RANKL has also been implicated in cell migration, and Elefteriou and colleagues were able to show that breast cancer cell migration to the bone depends on RANKL."
  2. Does that mean supplementing tyrosine and dopamine boosting agents may not be wise depending on the individual. What about anti-serotonin agents which have indirect dopamine raising effects?
    "Unlike many other hormones adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis.[75] Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious epinephrine administration, pheochromocytoma, and other tumors of the sympathetic ganglia.

    Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase."
  3. Related, can't remember if this has been posted here...

    Double-Edged Sword: Research shows killing cancer cells can also drive tumor growth

    Cancer therapies including radiation and chemotherapy seek to treat the disease by killing tumor cells.

    Now, a team including researchers at Harvard Medical School and Beth Israel Deaconess Medical Center have shown that the dead and dying cancer cells generated by chemotherapy and targeted cancer therapy paradoxically trigger inflammation that promotes aggressive tumor growth.

    In a study published in the Journal of Experimental Medicine, the team has illuminated the mechanism by which tumor cell death can drive primary tumor growth and metastasis.

    Moreover, the scientists also demonstrated that this unintended consequence of cancer treatment can be halted by resolvins, a family of molecules naturally produced by the human body. The findings represent a novel treatment approach to preventing tumor growth and recurrence.

    “In this study we demonstrate that chemotherapy-generated debris from dead and dying tumor cells can stimulate tumor growth, which has pivotal implications for the treatment of cancer patients,” said senior author Dipak Panigrahy, HMS assistant professor of pathology at Beth Israel Deaconess. “Conventional cancer therapy designed to kill tumor cells is inherently a double-edged sword.”

    The findings are consistent with clinical observations on radiation-generated debris dating back to the 1950s, but until now, few studies investigated the molecular mechanisms underlying the phenomenon.


    The researchers’ further analysis revealed that chemotherapy-killed cancer cells promote growth when a lipid molecule exposed on the surface of dead and dying cells triggers the release of cytokines, proteins that regulate the body’s immune and inflammatory response.

    The resulting “cytokine storm” in the tumor’s microenvironment in turn sets the stage to promote new tumor growth.

    “This protumor activity could fuel a positive feedback loop that is difficult to overcome with more aggressive cytotoxic therapy like chemotherapy and radiation,” said Panigrahy. “This may explain the inherent therapeutic limit to cancer treatments available today.”
    Resolvins suppress tumor growth and enhance cancer therapy
  4. I think agents like mirtazapine, which is known to raise adrenaline/noradrenaline, may have a negative effect but it has to be weighed against the benefit of opposing serotonin as 5-HT2B is apparently required for cancer formation. Increased formation of adrenaline from dopamine occurs only in some very specific conditions and for most people dietary tyrosine is probably benign. Low metabollism is the main reason for elevated adrenaline (and cortisol) which underscores the role of metabolism in cancer once again.
    Btw, not so sure adrenaline does not have any negative feedback. The drug clonidine is an alpha adrenergic receptor agonist and lowers adrenaline precisely through such a negative feedback mechanism, UNLESS the person has a pheochromocytoma which does not respond to that feedback. So, clonidine is a used similarly to the so-called "dexamethasone suppression test" with cortisol in order to test for ectopic production of adrenaline by a tumor.
  5. Thanks, these are very interesting studies and I don't think they have been posted on the forum before. Btw, that tumor-promoting lipid molecule the study talks about is phosphatidylserine (PS). PS stimulated tumor growth while neither phosphatidylcholine (PC) not dead cells by themselves had that effect. The study also says that chemotherapy on its own was useless and only when combined with blockade of PS it had therapeutic effects. So, chemotherapy (the way it is most commonly administered) is at best useless on its own and quite harmful (if done consistently enough to trigger blood accumulation of PS).
    "...To determine the extent to which either apoptotic or necrotic cells contributed to debris-stimulated tumor growth, we used flow cytometry to cell sort debris into apoptotic (annexin V+ PI−), necrotic (annexin V− PI+), and living (annexin V− PI−) cell populations. Apoptotic cells from cisplatin-generated LLC or gemcitabine-generated PancOH7 debris potently stimulated tumor growth, whereas living cells isolated from debris exhibited minimal tumor-stimulatory activity (Fig. 2, A and B). Necrotic cells alone exhibited no apparent tumor-stimulatory activity (Fig. 2, A and B). Because apoptotic debris stimulated tumor growth, we asked whether PS, which is presented on the surface of apoptotic cells and is detected by annexin V, could be a molecular mediator of tumor stimulation by the debris. Coinjection of PS liposomes (Hosseini et al., 2015) in lieu of debris with a subthreshold inoculum of 104 living tumor cells, i.e., LLC, EL4, or PancOH7, stimulated tumor growth in a dose-dependent manner in comparison with phosphatidylcholine (PC) liposomes (Fig. 2, C–E). Additionally, blocking PS in the debris with an annexin V–recombinant protein or an anti-PS neutralizing antibody drastically, albeit not completely, suppressed debris-stimulated tumor growth in a dose-dependent manner (Fig. 2, F–H). Intriguingly, chemotherapy alone did not exhibit therapeutic activity in debris-stimulated EL4 tumors (Fig. 2 G). In contrast, debris-stimulated tumors in which debris was treated with annexin V or anti-PS neutralizing antibody before injection were responsive to chemotherapy (cisplatin or vincristine; Fig. 2, G and H)."
  6. Ray talked about catecholamine toxicity is The Bean Syndrome letter.
    "Two features of mitochondrial damage in severe stress (regardless of whether endotoxin is involved) are a depletion of the antioxidant reserves, and loss of the ability to convert cholesterol
    into the protective steroid hormones. Mitochondrial damage is more likely in hypothyroidism, as I have discussed previously; thyroxin inhibits lipid peroxidation, end it tends to be inversely
    related to adrenalin, preventing or minimizing "catecholamine toxicity," for example."
  7. Does niacinamide antagonise or reduce NE signalling/release?

    Nevermind, it does the opposite

    Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives. - PubMed - NCBI

    Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives
  8. The paper you posted about here (Serotonin Is The Likely Cause Of Septic And Anaphylactic Shock) states that phosphatidylserine (PS) is a marker of activated platelets

    "We found that platelets were not activated or apoptotic, as evidenced by the lack of phosphatidylserine (PS) and P-selectin on their surface"

    "The absence of PS at the surface suggests that they are not procoagulant platelets, known as balloon- or zombie-like platelets"
    ....so PS would likely be a marker both of increased coagulation and likely subsequent hypoxia/ischemia ...and of platelet serotonin release.

    They speculate as to serotonin's role in sepsis..

    "As serotonin also mediates organ regeneration (52), its liberation may be pivotal to regrowth following insults caused by pathogen invasion."​

    ...hinting at the proliferation driven by serotonin.

    Not hard to see how PS would be associated with cancer then.
  9. Thanks. So, based on the findings of the cancer studies neutralizing/opposing PS somehow seems to inhibit tumor growth. Maybe opposing PS affects serotonin as well??