If you read the science, you’ll see that bacterial endotoxin (LPS) has been shown to promote the growth and spread of cancer. But only when it comes to leukemia, melanoma, lymph node metastasis, oral squamous cell carcinoma, lung, breast, pancreatic, colorectal, liver, gastric, gallbladder, esophageal, cervical, bone and prostate cancer.
Truth is, all cancers likely get a boost, one way or another, from endotoxin, and though you might not know it, this is good news. Maybe not the be all end all solution to every disease problem, but it means more than most realize. Endotoxin exposure is an important part of the puzzle regarding the progression of metabolic illness, and an awareness of it can open the way to better understanding of what leads to cancer, and what helps prevent or treat it.
I’m not a doctor, and this article is not intended as advice for the treatment of cancer, or disease of any kind. I’m also not suggesting that all you need to do is deal with endotoxin, and just like that, cancer is solved. But when you look at the vast amounts of high quality biological evidence relating to the subject of bacterial endotoxin (lipopolysaccharide/LPS) and cancer, it makes you wonder why people don’t know about it, and that includes many health professionals.
If I were to say to you that stress causes cancer, or that chronic low level inflammation is a powerful driver of cancer spread, you probably wouldn’t blink an eyelid. But mention lipopolysaccharides in conversation, and people start to look at you like you’re speaking Greek or Latin, or a combination of both. (Ok, you are, but you know what I mean.)
You see, there’s a powerful relationship between bacterial endotoxin issues, stress, and the stimulation of chronic inflammation and metabolic dysfunction, and all these things have been shown to be directly involved in the development and metastasis of cancer, as well as inflammatory disease in general. And this makes a lot of sense when you examine it more closely. And making sense of cancer seems like a worthwhile objective.
“…low levels of circulating Gram-negative bacterial endotoxin lipopolysaccharide (LPS) appear to be one of the key culprits in provoking a non-resolving low-grade inflammation…low-grade endotoxemia may skew host immune environment into a mild non-resolving pro-inflammatory state, which eventually leads to the pathogenesis and progression of inflammatory diseases…”
“Inflammation is a potent promoter of tumor metastasis…Lipopolysaccharide (LPS) is a major structural component of the outer membrane of Gram-negative bacteria and is a potent inducer of inflammation through the production of various cytokines, growth factors and inflammatory mediators…LPS promoted lung metastasis of breast cancer…”
The mediators of inflammation, toll-like receptor (TLR) proteins, nuclear factor-kappa B (NF-κB) transcription factor proteins, tumor necrosis factor-α (TNF-α), interleukins and other cytokines and inflammatory things, play a role in the metabolic response to bacteria and bacterial toxins (such as endotoxin), and have been shown to be involved in cancer development and progression.
“TLRs, a family of pattern recognition receptors, have been shown to be closely related to cancer progression…In our study, it seems that treatment of LPS, a ligand of TLR4, increased TLR4 expression, thereby promoting MCF7 breast cancer cell migration or invasion.
“…NF-kappaB is one of the key factors connecting inflammation with cancer progression….lipopolysaccharide (LPS) promotes NF-kappaB activation in colon cancer cells and pancreatic cancer cells…Blockade of TLR4…decreased the LPS-dependent increased invasive ability…results suggest…TLR/NF-kappaB signaling pathway plays a significant role in connecting inflammation and cancer invasion and progression.”
“Chronic inflammation is a well-documented risk for carcinogenesis, particularly in the pancreas and gastrointestinal tract…LPS…induces…cells to produce proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukins, inducible nitric oxide synthase, and cyclooxygenase-2…”
Although there’s probably an endless number of ways that the inflammatory substances can interact with and promote each other (and knowing all of these ways would probably be useful), what I am most interested in is the overall picture.
The inflammatory process can have a protective role, but nobody is suggesting (I don’t think) that chronic inflammation is something to strive for, and much can be gained from a general understanding of things (like endotoxin) that can connect stress, metabolic energy system suppression and inflammation, with cancer development.
The thing is, you can’t really talk about stress, inflammation and metabolic disease, without talking about bacterial endotoxin issues, and you can’t talk about excessive endotoxin exposure, without also talking about the inflammatory stress substances like serotonin, estrogen, nitric oxide (NO), histamine and lactate.
Rising levels of these and other related things are involved in the promotion of what has been referred to as the cancer metabolism, and they have a tendency to rise in response to ongoing stress, thyroid suppression and inflammation, as well as being able to promote inflammation and biochemical stress. It can be a bit of a circular problem.
When stress is high and blood sugar supplies run low, metabolic energy system function is interfered with in a manner which can promote bacterial excess, and which can eventually lead to rising systemic circulation of endotoxin. Endotoxin is itself directly inflammatory, as well as being able to interfere with cellular energy metabolism, increasing many of the inflammatory stress substances which have been shown to encourage cancer.
“Gram-negative bacteria significantly promoted lung cancer development including growth and metastasis in dose dependent manner. Mechanistically, Gram-negative bacteria activate TLR4 and TLR9 signaling and enhance lipid synthesis in human lung cancer cells.”
“TLR4 and the intestinal microbiota were…required for…HCC promotion, mediating increased proliferation…and prevention of apoptosis…the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.”
“TLR4 protein was increased in ESCC [esophageal squamous cell carcinoma] tumor tissues compared with the adjacent normal tissues. TLR4 over-expression was significantly correlated with tumor differentiation grade, lymph node metastasis, and UICC stage. LPS-induced activation of TLR4 signaling promoted cancer cell proliferation, increased production of proinflammatory or immunosuppressive cytokines TNF-α, TGF-β and inhibited the anti-inflammatory cytokine IL-10.”
A suppressed thyroid metabolism is likely to promote cortisol and adrenaline release, as well as increased levels of estrogen, serotonin, NO, lactate, histamine, and greater circulation of polyunsaturated free fatty acids, encouraging the potential for systemic inflammatory issues. Subclinical hypothyroidism can activate TLR4 and can increase levels of NF-κB, TNF-α, IL-6 and IL-1β. All of these things promote inflammation and can further interfere with metabolism, creating even more opportunity for bacteria to feed and multiply, and for endotoxin to circulate through to the main system. All have been shown to be connected to cancer development.
As silly as it would be to argue that energy system suppression and unresolved low level inflammation is something to aim for, many of the substances of stress still get interpreted in a positive light. But don’t ignore science showing how rising levels of things like NO, serotonin, estrogen, lactate and the polyunsaturated fats (PUFAs) are involved with the progression of cancer and disease. And don’t ignore how all of this ties in with bacterial issues, and other things like the various cytokines that also promote inflammatory conditions like cancer.
“Chronic inflammation is a key contributor to carcinogenesis in various organs including the stomach, colon, lung and liver. Given the relationship between inflammation and carcinogenesis, recent studies have addressed the role of TLRs in inflammation-associated carcinogenesis in various cancers including GC [gastric cancer]…Our results described the involvement of TLR4 signaling in promoting tumor development by showing that LPS can significantly induce human GC cells to proliferate.”
“The link between systemic inflammation and promotion of tumor metastasis is well established…IL-6 contributes to lung and breast cancer cell malignancy and effusion…LPS promotes…up-regulation…of IL-6…in a dose-dependent manner…human breast cancer cells showed significant biological changes after LPS stimulation…and a tendency that TLR4 overexpression in tumor tissue was related with lymph node metastasis…TLR4 played a significant role in breast cancer metastasis…”
LPS (endotoxin) itself, through activation of toll-like receptor 4 (TLR4), activates multiple cells to release proinflammatory cytokines (cell signaling proteins), including TNF-alpha, interleukin (IL)-1β, and IL-6 (mostly from monocytes and macrophages). Endotoxin promotes NO (nitric oxide), which also encourages TNF-alpha, a powerful regulator of immune response. TNF production dysregulation has been implicated in inflammatory disease including cancer.
“Proinflammatory cytokines and growth factors such as IL-6…have been established as important NO-induced biomarkers that are up-regulated in breast cancer…and correlate with poor prognosis…NO also induced TNFα…reports have shown elevated levels of TNFα in cancer patients… The ability of NO…to regulate different cytokines…elucidates their crosstalk in the promotion of tumor growth and metastasis…the participation of inflammatory factors such as TNFα and other cytokines…can have a major effect on survival.”
“Activation of TLR triggers a cascade of intracellular events, including innate immune responses through NF-κB–dependent and interferon regulating factor (IRF)-dependent signaling pathways. This is known to recruit and activate leukocytes to sites…melanoma cells responding to TLR activation cause innate immune responses that may set the stage for an active inflammatory state favoring tumor promotion and suppression of host-specific immunity…TLR ligand activation in melanoma cells induced migration.”
LPS (endotoxin) and NO (nitric oxide) promote activation of NF-κB, and NF-κB has been suggested to act like an “on signal” for the catabolic proinflammatory cytokines and growth factors. Interaction between bacteria and immune cells (neutrophils), can also increase the release of inflammatory cytokines, promoting tumor growth. LPS instigated NF-κB activation can stimulate tumor progression by promoting increased resistance to apoptosis as well as contributing to angiogenesis in tumors.
“LPS or endotoxin…may have a direct effect on tumor progression by promoting tumor cell adhesion and invasion. This effect is mediated by LPS-induced…activation of NF-κB…neutralization of LPS and modulation of NF-κB may be considered therapeutic strategies for the prevention of tumor relapse and metastasis…”
“…exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kappaB…”
“The induction of angiogenesis by LPS has been…shown…LPS might have noticeable effect in leukemia progression through stimulation of pathologic angiogenesis…avoidance/treatment of bacterial infections especially their LPS could be essential in management of tumors such as leukemia in which pathologic angiogenesis has played considerable role.”
Stress and inflammation also increase estrogen levels, and estrogen is known to promote cancer. Estrogen increases NO and enhances TLR4 activation and the dangerous effects of endotoxin, as well as the production of inflammatory mediators and cytokines, including IL-1beta, IL-6, and TNF-alpha. Progesterone is likely to be protective.
“…chronic E2 administration…increased both cytokine (IL-1beta, IL-6, and TNF-alpha) and inducible NO synthase…The proinflammatory action of E2 was also evidenced at the level of released IL-1beta and IL-6 by ex vivo LPS-activated macrophages…estrogens…enhance…ability to produce inflammatory mediators and cytokines upon subsequent TLR activation.”
Endotoxin (and other TLR4 agonists) help to shift cellular metabolism in the direction of aerobic glycolysis seen in cancer (much like Warburg metabolism), increasing lactate production.
Lactate has been shown to play an important role in the promotion of inflammation and cancer development, as well as in the activation of TLR4 and stimulation of the effects of endotoxin on cytokine expression and other inflammatory mediators, including prostaglandins and polyunsaturated free fatty acids, as well as nitric oxide and hypoxia inducible factor.
PUFAs interfere with oxidative metabolism, promoting lactic acid production and exacerbating the negative impact of endotoxin circulation, further increasing cancer progression. Sugar helps to reduce exposure to PUFAs, endotoxin and lactate, and is generally protective against stress, inflammation and metabolic suppression, and hence cancer.
“…bacterial infection and LPS increase lactate production…and lactate boosted LPS signaling-mediated inflammatory gene expression as shown by the present study. These findings…reveal a molecular mechanism by which the actions of LPS and lactate lead to a vicious cycle that promotes TLR4-mediated inflammation and contributes to a number of diseases…”
“Lactate is not only consumed by tumor cells for their survival, but it also stimulates angiogenesis…lactate has an immunosuppressive role, affecting several immune cell functions such as T-cell proliferation, cytokine production, and cytotoxic activity…lactate is needed not only for survival but also for promoting tumor growth…”
“Uncontrolled growth of cervical cancer cells is closely related to the excessive activation of…transcription factor, hypoxia-inducible factor-1α (HIF-1α)…TLR4 signaling pathway is positively correlated with high expression of HIF-1α….TLR4/iNOS pathway is highly expressed in cervical cancer…NF-κB…downstream of TLR4 signaling…promoted the production of the immunosuppressive cytokines…which promoted the growth of…cells and enhanced their resistance to apoptosis…”
But all you probably need to know, for starters, is that the inflammatory things all tie in together, and one of the important changes that can significantly increase protection from the cancer promoting impact of stress and metabolic suppression, is a reduction in exposure to the harmful effects of endotoxin. Dealing with digestion issues to improve cancer prognosis, is far from being a new idea.
These days, most people are probably aware of the fact that chronic inflammation helps drive cancer, but that’s often as far as it goes. The information that comes after that tends to not be very helpful, to say the least, and is rarely understood in a legitimately holistic manner.
“Recent evidence demonstrated an enhanced metastasis of non-small cell lung cancer (NSCLC) cells induced by lipopolysaccharide (LPS) stimulation, which reflected an important role of inflammation in tumor progression…We found that LPS stimulation of NSCLC cells facilitates their metastasis…”
“Monocytes are the major inflammatory cells that infiltrate most solid tumors in humans…infiltrating monocytes…play a significant role in altering the tumor to become more aggressive…exposure to lipopolysaccharide (LPS) was suggested to promote cancer cell adhesion to monocytes…LPS…is specifically recognized by TLR4. LPS-mediated signaling has been shown to play an important role in regulating cancer progression…”
Endotoxin is connected one way or another, to the inflammatory things that suppress proper metabolic function, and promote oxidative stress, aerobic glycolysis, hypoxia, and cancer risk. That includes NO, serotonin, estrogen, lactic acid, the inflammatory cytokines and growth factors, and PUFA breakdown products.
There are a number of simple things that have been shown to be be preventative and curative, and one way or another they involve improving metabolism, lowering stress, assisting with digestive function, intestinal barrier function, liver performance, and as such, reducing exposure to endotoxin and other inflammation promoting things such as the PUFAs. You don’t need to be a biologist to benefit from this kind of information, and you don’t need to know all of it to get results.
The beauty of approaches that effectively reduce bacterial endotoxin issues is that they have a natural tendency to also improve thyroid energy metabolism and inflammation issues, lowering overall stress and susceptibility to inflammatory disease, including cancer.
“Robust evidence supports a strong link between inflammation and cancer, including HCC [liver cancer]…TLR4 activation by LPS and other pathogen‐associated molecular patterns (PAMPs) induces NF‐κB signaling and subsequent secretion of several cytokines (e.g., interleukin‐1) and other inflammatory molecules (e.g., tumor necrosis factor α), which regulate multiple reactions in hepatocytes, Kupffer cells, and hepatic stellate cells.”
The same can be true in reverse. Things that improve thyroid energy system function, also then reduce exposure to stress substances, such as the polyunsaturated free fatty acids, nitric oxide, estrogen and lactate, eventually improving digestive function and reducing the potential for exposure to endotoxin as well as the inflammatory things stimulated by endotoxin. And before you jump to any conclusions, reducing exposure to other kinds of bacteria that do not produce endotoxin, can also be beneficial.
“Gram positive bacteria do not have endotoxin, but the presence of these bacteria in tissues provokes an inflammatory response that is similar to that triggered by Gram negative LPS…The same cytokines elicited by LPS are released and the same types of physiological effects are seen….largely via the initiation of an inflammatory response through the stimulation of monocytes and macrophages and the subsequent release of proinflammatory cytokines, especially tumour necrosis factor-alpha (TNF-α) and interleukin-1…”
A diet avoiding the PUFAs, and limiting intake of difficult to digest starchy and fibrous grains, seeds, nuts, beans, legumes and under cooked vegetables, with enough protein from milk, cheese and gelatin, and plenty of sugar from sweet ripe fruits and juices, white sugar and honey, is one possible way to reduce exposure to bacteria, endotoxin and many interrelated cancer promoting inflammatory substances.
Some things that have been used to deal with endotoxin, TLR4 activation, inflammation and cancer, include minocycline, doxycycline, penicillin and some other antibiotics, cyproheptadine and famotidine, glycine and gelatin, methylene blue, vitamin C, A and D, activated charcoal, coconut oil, aspirin, taurine, Cascara Sagrada and Emodin, magnesium, coffee and caffeine, thyroid hormone, progesterone, pregnenolone and niacinamide.
Whole body hyperthermia, iron restriction, methionine restriction, occasional calorie restriction, improved calcium to phosphorous ratio, raw carrots and well cooked mushrooms, have also been shown to be cancer protective for reasons that can be seen as directly or indirectly related to bacteria and endotoxin.
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