Pt.1: Cancer, MCS and ME (There is a pdf version of this blog post below.)
The first reason why I am listing these three together is that, as we all know, there is an increased risk of the first two among ME/CFS patients.[1] However, I will just discuss cancer in this blog post.
The other reason why I am grouping these together is because these are three diseases I know well. That’s because my wife @ PWR (Peace without Rest) had them all at the same time. As I explained in my previous blog,[2] I became my wife’s (and my) “doctor” by default when our MD abandoned us due to his skepticism about her severe MCS, which followed about 3 years after her ME onset. Consequently, I began studying (self-directed) herbal medicine in a search to cope with my wife’s significant pathogen problem, among others.
By 1995, however, my medical “training” took a quantum leap forward when PWR was diagnosed with ovarian cancer. Due to PWR’s severe MCS, we had to fly by private plane outside the U.S. to seek the only medical treatment for cancer that wouldn’t itself endanger her life: antiparasitic therapy. As a result, we were effectively stranded there until she either died or recovered. Pretty pathetic, huh?
Since we had to live abroad indefinitely, I began to study the doctor’s books and soon became her research assistant. Fortunately for us, the doctor turned out to be right, and my wife not only recovered from the cancer quickly, but her MCS made an unexpected and dramatic improvement. Her ME also improved, though it happened more gradually. And all this occurred within 5 months.
So I thought I would share with my fellow patients the latest research on the subject. This is actually to prepare the way for my discussion of ME in the third blog I’ve planned, not just as an end in itself. So if you don’t mind waiting for this and wading through the first two blogs, I think you’ll understand how they all fit together by the time I get there.
The best place to start is to point out that parasites have been investigated as a cause of cancer for over 100 years.[3] The 1963 Bailey article just cited mentions one of the most likely candidates in humans (not fully confirmed at that time, however), a parasite from the trematode class, Schistosoma haematobium (S.h., for brevity). Since then, the role of S.h. has been further studied and positively confirmed as a carcinogen.[4] S.h. infection can lead to squamous cell carcinoma (SCC) of the urinary bladder. Here are selected quotes from Brindley & Loukas[5] (bolding mine, next 3 paragraphs):
The bladder is lined by a specialized epithelium termed the urothelium, which is exposed routinely to potential carcinogens and hence is at particular risk of cancer. The urothelium is a stratified epithelium composed of keratin 5 (K5)-expressing basal cells, intermediate cells, and umbrella cells. K5-positive basal cells likely give rise to SCC.p.3
Schistosome eggs entrapped in the bladder wall release metabolites, presumably to facilitate egress of the egg to the lumen and to the external environment.The process leads to hematuria and to chronic inflammation,in turn increasing the risk of urothelial hyperplasia, dysplasia, and SCC(Fig1).Urogenital schistosomiasis(UGS) is a chronic infection,often interrupted by drug treatment and often followed in turn by reinfection.Fibrosis induced by entrapped schistosome eggs may promote cellular proliferation,hyperplasia, and metaplasia that eventually induce carcinogenesis[10].Mass spectrometric analysis of urine during UGS reveals estrogen-like metabolites including catechol estrogen quinones(CEQ),likely of schistosome origin, CEQ-DNA adducts,and novel metabolites derived from 8-oxo-7,8-dihydro-20-deoxyguanosine(8-oxodG)[18].Nitrosamines and increased levels of beta-glucuronidase and cyclooxygenase-2 derived from schistosomes also represent potential bladder carcinogens.These helminth infection–derived carcinogens may damageDNA,leading to somatic mutations in oncogenes such as p53,retinoblastoma protein,epidermal growth factor receptor,and erbB2 receptor tyrosine kinase.p.3
Other helminth proteins induce changes that reflect the hallmarks of cancer, including EMT phenotypes, pro-inflammatory cytokines, and repression of apoptosis [32, 35]. Type 2 T helper cell (Th2) responses induced by schistosome proteins including interleukin 4-inducing principle of schistosome eggs (IPSE) not only facilitate egress of the schistosome egg to the bladder lumen by modulating the granuloma but also appear to modulate vasculogenic and cellular responses conducive to neoplasia [10, 36]. p.5
So, to quickly summarize, then, S.h. 1) releases its growth-enabling metabolites, 2) inflaming the tissue, 3) leading to cell proliferation and 4) the release of more carcinogenic growth-sustaining metabolites. All of these damage DNA and lead to genetic mutations.
Brindley & Loukas also the other two acknowledged parasitic carcinogens (also trematodes), the liver flukes Opisthorchis viverrini (O.v.) and Clonorchis sinensis (C.s.)—I will not discuss this one here. Here is a clear description of how these parasites initiate cancer (next 3 paragraphs):
Communication between helminths and host cells likely evolved to facilitate parasitism. Communicating metabolites may, however, contribute to carcinogenesis [8, 29]. For example. O. viverrini secretes a growth factor termed Ov-GRN-1 that shares homology with human granulin [30]. Secreted Ov-GRN-1 may promote angiogenesis and also wound repair of the bile ducts damaged by the liver fluke [11, 30] (Fig 2). Moreover, Ov-GRN-1 may mimic the action of interleukin-33 (IL-33), an epithelial mitogen for cholangiocytes, in the development of CCA [31]. IL-33 primes type 2 innate lymphoid cells to induce proliferation of neighboring cholangiocytes by the release of Interleukin-13 (IL-13). Antibodies to Ov-GRN-1 blocked its ability to drive proliferation of host cells [30, 32].
Liver flukes also secrete extracellular vesicles (EVs) [33] (Fig 1). The membranes surrounding EVs are enriched in tetraspanins, proteins that interact with transmembrane and cytosolic signaling proteins [34]. Cholangiocytes internalize both O. viverrini EVs and Ov-GRN-1 [32]. Antibodies to a tetraspanin located on the surface of O. viverrini EVs block the internalization by cholangiocytes of liver fluke EVs and suppress the proliferation and secretion of IL-6 by cholangiocytes [33].
Where opisthorchiasis is endemic, people can remain infected for decades. Opisthorchiasis provokes inflammation of the biliary tree, with hyperplasia and metaplasia of the cholangiocytes that line the biliary tract adjacent to the flukes. Opisthorchiasis-induced fibrosis engulfs the proliferating cells, manifesting as biliary periductal fibrosis [4, 11]. Chronic inflammation in response to parasite metabolites and growth factors is implicated in the inflammatory response linked with infection [11]. Additional factors including carriage of Helicobacter* and other microbiome changes within the biliary tract might participate [8, 12]. Elevated plasma interleukin-6 (IL-6) is associated with marked increase in risk of periductal fibrosis during opisthorchiasis and compounds pathogenesis by promoting a fibrogenic inflammatory milieu. The cell of origin of CCA is the cholangiocyte, a specialized epithelial cell that lines the bile duct. Following initiation, for example by oxidation of cholangiocyte chromosomal DNA by oxysterols generated by reactive oxygen species (ROS) and reactive nitrogen species (RNS) arising during opisthorchiasis-induced oxidative stress [13] and/or oxysterols released by the liver fluke [8, 14], oncogenesis appears to be promoted by cholestasis and chronic inflammation. The release and downstream consequences of IL-6, platelet-derived growth factor, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) are pivotal to the proliferation of cholangiocytes. Autonomous proliferation, evasion of apoptosis, and angiogenesis sustain the incipient neoplasm [11].
Thus, just as we saw with S.h., O.v. 1) releases its growth-enabling metabolites [this time, notice the underlined words above indicating growth factors], 2) inflaming the tissue, 3) leading to angiogenesis [new] and cell proliferation and 4) the release of more carcinogenic growth-sustaining metabolites [again, notice growth factors]. All of these damage DNA and lead to genetic mutations.
However, there is one additional factor* here with O.v. not mentioned by the authors in their discussion of S.h. It is the mention of the parasite carrying its own carcinogenic bacteria, Helicobacter. This key point will factor greatly into our discussion of MCS and ME in the next two blogs. Here are two additional articles discussing this phenomenon regarding O.v. and a parasitic nematode, Brugi malayi.[6], [7]
On a related note, researchers in another study were astonished that they were able to implant the HIV-1 virus inside a different Schistosoma (mansoni).[8]
Summary
We have seen how two specific trematodes (S.h. & O.v.) initiate cancer, using their growth factors, causing inflammation, angiogenesis, cell proliferation, and continued growth factors. We have also seen evidence of several trematode parasites carrying their own bacteria, and that viruses can easily live within them.
Regarding the certainty of a link between parasites and cancer, I only have time to ask this question: What if our vantage point today is analogous to that of Bailey in 1963 regarding S.h.? Bailey considered the evidence significant but not yet conclusive. Thirty years after this article, PWR’s doctor published her findings confirming the carcinogenicity of S.h. (3-12-18 clarification: The doctor also published the same about Cloronchis sinensis, a close relative of O.v. Even though she was not the first researcher to find the roles of these parasites in cancer, she was the first to popularize and publish the information for the general public (including even more significant information about their roles in carcinogenesis that has not yet been discovered by others). But it took the scientific establishment (government and institutional) at least 10-20 additional years to come along.
My question to you, the patient, is “How long do you plan to wait before finding out for yourself?" All articles cited are free except the Bailey one (just a free page of the Introduction). If anyone is interested, I can cite more portions of that, or perhaps someone knows how to access a free version. Please check in for my next blog on MCS.
The first reason why I am listing these three together is that, as we all know, there is an increased risk of the first two among ME/CFS patients.[1] However, I will just discuss cancer in this blog post.
The other reason why I am grouping these together is because these are three diseases I know well. That’s because my wife @ PWR (Peace without Rest) had them all at the same time. As I explained in my previous blog,[2] I became my wife’s (and my) “doctor” by default when our MD abandoned us due to his skepticism about her severe MCS, which followed about 3 years after her ME onset. Consequently, I began studying (self-directed) herbal medicine in a search to cope with my wife’s significant pathogen problem, among others.
By 1995, however, my medical “training” took a quantum leap forward when PWR was diagnosed with ovarian cancer. Due to PWR’s severe MCS, we had to fly by private plane outside the U.S. to seek the only medical treatment for cancer that wouldn’t itself endanger her life: antiparasitic therapy. As a result, we were effectively stranded there until she either died or recovered. Pretty pathetic, huh?
Since we had to live abroad indefinitely, I began to study the doctor’s books and soon became her research assistant. Fortunately for us, the doctor turned out to be right, and my wife not only recovered from the cancer quickly, but her MCS made an unexpected and dramatic improvement. Her ME also improved, though it happened more gradually. And all this occurred within 5 months.
So I thought I would share with my fellow patients the latest research on the subject. This is actually to prepare the way for my discussion of ME in the third blog I’ve planned, not just as an end in itself. So if you don’t mind waiting for this and wading through the first two blogs, I think you’ll understand how they all fit together by the time I get there.
The best place to start is to point out that parasites have been investigated as a cause of cancer for over 100 years.[3] The 1963 Bailey article just cited mentions one of the most likely candidates in humans (not fully confirmed at that time, however), a parasite from the trematode class, Schistosoma haematobium (S.h., for brevity). Since then, the role of S.h. has been further studied and positively confirmed as a carcinogen.[4] S.h. infection can lead to squamous cell carcinoma (SCC) of the urinary bladder. Here are selected quotes from Brindley & Loukas[5] (bolding mine, next 3 paragraphs):
The bladder is lined by a specialized epithelium termed the urothelium, which is exposed routinely to potential carcinogens and hence is at particular risk of cancer. The urothelium is a stratified epithelium composed of keratin 5 (K5)-expressing basal cells, intermediate cells, and umbrella cells. K5-positive basal cells likely give rise to SCC.p.3
Schistosome eggs entrapped in the bladder wall release metabolites, presumably to facilitate egress of the egg to the lumen and to the external environment.The process leads to hematuria and to chronic inflammation,in turn increasing the risk of urothelial hyperplasia, dysplasia, and SCC(Fig1).Urogenital schistosomiasis(UGS) is a chronic infection,often interrupted by drug treatment and often followed in turn by reinfection.Fibrosis induced by entrapped schistosome eggs may promote cellular proliferation,hyperplasia, and metaplasia that eventually induce carcinogenesis[10].Mass spectrometric analysis of urine during UGS reveals estrogen-like metabolites including catechol estrogen quinones(CEQ),likely of schistosome origin, CEQ-DNA adducts,and novel metabolites derived from 8-oxo-7,8-dihydro-20-deoxyguanosine(8-oxodG)[18].Nitrosamines and increased levels of beta-glucuronidase and cyclooxygenase-2 derived from schistosomes also represent potential bladder carcinogens.These helminth infection–derived carcinogens may damageDNA,leading to somatic mutations in oncogenes such as p53,retinoblastoma protein,epidermal growth factor receptor,and erbB2 receptor tyrosine kinase.p.3
Other helminth proteins induce changes that reflect the hallmarks of cancer, including EMT phenotypes, pro-inflammatory cytokines, and repression of apoptosis [32, 35]. Type 2 T helper cell (Th2) responses induced by schistosome proteins including interleukin 4-inducing principle of schistosome eggs (IPSE) not only facilitate egress of the schistosome egg to the bladder lumen by modulating the granuloma but also appear to modulate vasculogenic and cellular responses conducive to neoplasia [10, 36]. p.5
So, to quickly summarize, then, S.h. 1) releases its growth-enabling metabolites, 2) inflaming the tissue, 3) leading to cell proliferation and 4) the release of more carcinogenic growth-sustaining metabolites. All of these damage DNA and lead to genetic mutations.
Brindley & Loukas also the other two acknowledged parasitic carcinogens (also trematodes), the liver flukes Opisthorchis viverrini (O.v.) and Clonorchis sinensis (C.s.)—I will not discuss this one here. Here is a clear description of how these parasites initiate cancer (next 3 paragraphs):
Communication between helminths and host cells likely evolved to facilitate parasitism. Communicating metabolites may, however, contribute to carcinogenesis [8, 29]. For example. O. viverrini secretes a growth factor termed Ov-GRN-1 that shares homology with human granulin [30]. Secreted Ov-GRN-1 may promote angiogenesis and also wound repair of the bile ducts damaged by the liver fluke [11, 30] (Fig 2). Moreover, Ov-GRN-1 may mimic the action of interleukin-33 (IL-33), an epithelial mitogen for cholangiocytes, in the development of CCA [31]. IL-33 primes type 2 innate lymphoid cells to induce proliferation of neighboring cholangiocytes by the release of Interleukin-13 (IL-13). Antibodies to Ov-GRN-1 blocked its ability to drive proliferation of host cells [30, 32].
Liver flukes also secrete extracellular vesicles (EVs) [33] (Fig 1). The membranes surrounding EVs are enriched in tetraspanins, proteins that interact with transmembrane and cytosolic signaling proteins [34]. Cholangiocytes internalize both O. viverrini EVs and Ov-GRN-1 [32]. Antibodies to a tetraspanin located on the surface of O. viverrini EVs block the internalization by cholangiocytes of liver fluke EVs and suppress the proliferation and secretion of IL-6 by cholangiocytes [33].
Where opisthorchiasis is endemic, people can remain infected for decades. Opisthorchiasis provokes inflammation of the biliary tree, with hyperplasia and metaplasia of the cholangiocytes that line the biliary tract adjacent to the flukes. Opisthorchiasis-induced fibrosis engulfs the proliferating cells, manifesting as biliary periductal fibrosis [4, 11]. Chronic inflammation in response to parasite metabolites and growth factors is implicated in the inflammatory response linked with infection [11]. Additional factors including carriage of Helicobacter* and other microbiome changes within the biliary tract might participate [8, 12]. Elevated plasma interleukin-6 (IL-6) is associated with marked increase in risk of periductal fibrosis during opisthorchiasis and compounds pathogenesis by promoting a fibrogenic inflammatory milieu. The cell of origin of CCA is the cholangiocyte, a specialized epithelial cell that lines the bile duct. Following initiation, for example by oxidation of cholangiocyte chromosomal DNA by oxysterols generated by reactive oxygen species (ROS) and reactive nitrogen species (RNS) arising during opisthorchiasis-induced oxidative stress [13] and/or oxysterols released by the liver fluke [8, 14], oncogenesis appears to be promoted by cholestasis and chronic inflammation. The release and downstream consequences of IL-6, platelet-derived growth factor, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) are pivotal to the proliferation of cholangiocytes. Autonomous proliferation, evasion of apoptosis, and angiogenesis sustain the incipient neoplasm [11].
Thus, just as we saw with S.h., O.v. 1) releases its growth-enabling metabolites [this time, notice the underlined words above indicating growth factors], 2) inflaming the tissue, 3) leading to angiogenesis [new] and cell proliferation and 4) the release of more carcinogenic growth-sustaining metabolites [again, notice growth factors]. All of these damage DNA and lead to genetic mutations.
However, there is one additional factor* here with O.v. not mentioned by the authors in their discussion of S.h. It is the mention of the parasite carrying its own carcinogenic bacteria, Helicobacter. This key point will factor greatly into our discussion of MCS and ME in the next two blogs. Here are two additional articles discussing this phenomenon regarding O.v. and a parasitic nematode, Brugi malayi.[6], [7]
On a related note, researchers in another study were astonished that they were able to implant the HIV-1 virus inside a different Schistosoma (mansoni).[8]
Summary
We have seen how two specific trematodes (S.h. & O.v.) initiate cancer, using their growth factors, causing inflammation, angiogenesis, cell proliferation, and continued growth factors. We have also seen evidence of several trematode parasites carrying their own bacteria, and that viruses can easily live within them.
Regarding the certainty of a link between parasites and cancer, I only have time to ask this question: What if our vantage point today is analogous to that of Bailey in 1963 regarding S.h.? Bailey considered the evidence significant but not yet conclusive. Thirty years after this article, PWR’s doctor published her findings confirming the carcinogenicity of S.h. (3-12-18 clarification: The doctor also published the same about Cloronchis sinensis, a close relative of O.v. Even though she was not the first researcher to find the roles of these parasites in cancer, she was the first to popularize and publish the information for the general public (including even more significant information about their roles in carcinogenesis that has not yet been discovered by others). But it took the scientific establishment (government and institutional) at least 10-20 additional years to come along.
My question to you, the patient, is “How long do you plan to wait before finding out for yourself?" All articles cited are free except the Bailey one (just a free page of the Introduction). If anyone is interested, I can cite more portions of that, or perhaps someone knows how to access a free version. Please check in for my next blog on MCS.
- http://onlinelibrary.wiley.com/doi/10.1002/cncr.27612/full
- http://forums.phoenixrising.me/index.php?entries/how-i-became-a-doctor-by-default.2339/
- http://onlinelibrary.wiley.com/wol1/doi/10.1111/j.1749-6632.1963.tb13429.x/abstract This free page is not a true abstract, but the first page of the introduction.
- https://www.cancer.org/cancer/cance...ctions-that-can-lead-to-cancer/parasites.html
- http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006393
- http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0000538
- http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004962
- http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005931
