According to a 2006 estimate, 18% of the global cancer burden is attributable to infectious agents, but almost every indication is that this figure is far too conservative.1 Researchers confined by the logic of Koch's postulates have looked for a single microbe causing a single disease. Evidence is accumulating, however, that it is communities of microbes that are responsible for cancer. According to the Marshall Pathogenesis, chronic microbes persist, in large part, by dysregulating the Vitamin D Receptor (VDR), a key nuclear receptor with a well-characterized role in both the innate immune response and metastasis suppression. Indeed one of the hallmarks of cancer is a disruption in the vitamin D endocrine system including high 1,25-D and slowed activity of the receptor. As they progressively multiply through a process known as successive infection, microbes elicit an inflammatory response, a response which has been shown to increase over time the risk of metastasis.
Several patients have worked with their doctors to treat their cancer with the Marshall Protocol. However, the MP appears to be most effective as a preventative measure.
According to D.L. Mager, “An overwhelming body of evidence has determined that relationships among certain bacteria and cancers exist.”2 The growing number of examples of microbes associated with cancers include:
With the recent advent of high throughput sequencing studies, we can expect additional insights into how diseases like cancer are associated with shifts in microbial communities.
We conclude that there is a deregulation of the Vitamin D signalling and metabolic pathways in breast cancer, favouring tumour progression. Thus, during mammary malignant transformation, tumour cells lose their ability to synthesize the active form of Vitamin D and respond to VDR-mediated Vitamin D effects, while increasing their ability to degrade this hormone.
N. Lopes, VDR Signalling Disrupted in Breast Cancer11
According to the Marshall Pathogenesis, communities of microbes gain a survival advantage by reducing expression of the nuclear receptors that play important roles in the innate immune response, particularly the Vitamin D Receptor (VDR). Wang et al.'s analysis12 found that the VDR transcribes at least 913 genes including TLR2 and the antimicrobial peptides cathelicidin and the beta-defensins. When this metagenome reduces expression of the host VDR, in order to protect the microbiota against the endogenous antimicrobials, it also knocks out transcription of a key gene involved in cancer – MTSS1.
Wang's expression map found that the number one gene transcribed by an active VDR is CYP24A1 (also known as CYP24) and the number two is MTSS1, also known as tumor metastasis suppressor protein, which ends up as the “missing in metastasis” (MIM) protein. Several 2011 studies stated that the VDR acts to suppress tumors in skin.13 14
The slowed activity of the VDR in cancer patients has been widely noted. Several researchers have observed that the Vitamin D Receptor (VDR) becomes inactive in cancer patients at just the time when it should be most active.15
Lower than normal levels of 25-D have been generally associated with chronic disease but the field of oncology offers a number of counterexamples:
Alicia H. Chang and Julie Parsonnet of Stanford University writes that a transmissible cause of cancer was suspected as early as the 16th century. It was not until the late 20th century definitively identified a bacterial cause of at least some types of cancer to most researchers' satisfaction.24 Identifying the full range of microbes which cause cancer, however, has been more challenging. To date, there have been a handful of cases that fulfill Koch's postulates (e.g., H. pylori and gastric cancer) where a single microbe is known to cause a single type of cancer. Consistent with Koch, researchers have tended to work in this vein, for example, looking at the 500+ species that inhabit the colon in the hopes of pinpointing the one and only bacterial species responsible for colorectal cancer.25
A number of types of chronic infection have been observed to be associated with cancers in some studies, but without an identified specific bacterial pathogen. Examples are chronic ulcers and osteomyelitis sinus tracts (squamous cell carcinoma), chronic urinary tract infections (UTIs) (bladder cancer), and chronic prostatitis (prostate cancer).26
The Marshall Pathogenesis is at complete odds with Koch's postulates, suggesting that it is not one species but entire communities of microbes that are responsible for many cancers. The process by which a person accumulates microbes responsible for disease is known as “successive infection.” In successive infection, an infectious cascade of pathogens progressively slow the immune response and allow for subsequent infections to proliferate, resulting in dysbiosis (microbial imbalances). According to this model, a single microbe may not need to be present in all cases of disease in order to be implicated in it.
In almost all examples of bacterial inflammation and human cancer, the implicated bacteria reside in the host for many years and create an environment of persistent inflammation. Specific bacteria that have been shown to cause chronic inflammation and an increased risk of cancer include Helicobacter pylori (gastric adenocarcinoma) and Salmonella enterica serovar Typhimurium or Paratyphi (biliary cancer).
Alicia H. Chang 27
Chang offers several examples of why chronic microbes are key to cancer:
According to Chang,37 Virchow first described the irritation hypothesis of carcinogenesis in the 19th century concluding that chronic irritation stimulated the cancer cells to grow. The inflammatory process is characterized by damage caused by the host's immune response to the infection rather than by the infecting organism itself. Over 100 years since Virchow's discoveries, the “chronic irritation hypothesis” remains a widely supported mechanism for carcinogenesis by infectious agents. Today the relationship between inflammation, innate immunity and cancer is widely accepted.38
During a normal response to infection, inflammation is created as a means for the host to combat invading pathogens. Inflammation is first initiated by the recruitment of phagocytes to the site of infection. The phagocytes recruited to the site of infection also secrete proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), and chemokines that attract more phagocytes and other cells of the immune system to the site of infection to amplify the inflammatory response. These cells respond through physiological processes mediated by the cellular enzymes NADPH oxidase, superoxide dismutase (SOD), myeloperoxidase, and nitric oxide synthase (NOS).
The result is the release of reactive oxygen and nitrogen oxide species (ROS and RNOS) to kill potential pathogens. The free radicals and secondary products derived from them, such as secondary amines, HNO2, N2O3, and peroxynitrite, may damage DNA, proteins, and cell membranes and indirectly induce cell repair. Areas of tissue injury and inflammation trigger regenerative cell division from tissue and marrow-derived stem cells. Increased cell division may lead to point mutations, deletions, or translocations as damaged DNA escapes the repair system; the aberrant DNA is then propagated by subsequent cell division. This can result in disordered cell differentiation and, ultimately, oncogenesis. Hence, chronic inflammation, caused by microbes, instigates a cycle of cell damage, repair, and compensatory proliferation that promotes the development of cancer cells.39
According to some sporadic reports, cancer regresses following spontaneous bacterial infection.40 Competition between an ever-changing mix of microbes, and the variable attention the immune system pays to any one component of that mix, may explain the waxing and waning of different cancerous states.
For example, H. pylori can cause gastric cancer or MALT lymphoma in some individuals. In contrast, exposure to H. pylori appears to reduce the risk of esophageal cancer in others. Salmonella typhi infection has been associated with the development of gallbladder cancer; however S. typhi has been associated with positive outcomes for melanoma, colon and bladder cancers.41
Further, the live bacterium, Bacillus Calmette-Guérin (BCG) (see below), touted by some as a cancer vaccine, may also “work” by changing the path of successive infection, thus leading to immune disease (and cancers). After such an insult, the immune system focuses on Mycobacterium bovis (main component of BCG) and away from the chronic pathogens fueling the inflammation or cancer.
Some have suggested provocatively that communities of metastatic cancerous cells closely resemble communities of microbes known as biofilm.
We suggest that the quorum-sensing-controlled bacterial biofilm formation process closely parallels the steps in metastatic colonization. Cells migrate toward/on target surfaces (organ-specific homing), show cell-cell and cell-matrix interactions (tumor cell-stromal cell crosstalk), remain subclinical until they can mount an effective attack (dormancy), form complex structures with channels for nutrient flow (vascularized lesions), and contain resistant cells which can cause disease recurrence (persistors). Using ovarian cancer as an example, we present data supporting the connection between metastatic colonization and quorum sensing and discuss the implications for understanding and controlling metastasis formation.
Jonathan Hickson et al. 43
Even researchers studying a high-priority, frequently studied disease such as cancer have failed to produce a telltale genetic association.
Genetic mutations are rampant in cancerous tissue: compared to tissue from a healthy age-matched control, a lung cancer patient may have as many as 50,000 genetic mutations.44 However, among the inherited cancer syndromes with no readily discernible environmental influence, it is thought that only 1-2% are caused by high penetrance (high-risk) human genes.45
When diseases are not inherited in Mendelian ratios - somewhere between 0.01% and 0.001% of live births suffer from Mendelian diseases - geneticists have argued that those diseases are driven by effects reflecting a complicated interplay of human genes. But if a disease is a “genetic disease,” it should show very distinct patterns among twins, especially monozygotic (identical) twins. Because monozygotic twins are virtually identical in genetic makeup, the monozygotic twin concordance for such genetic diseases should be virtually 100 percent. For most diseases, this is not the case.46
Monozygotic twins share the same genotype because they are derived from the same zygote. However, monozygotic twin siblings frequently present many phenotypic differences, such as their susceptibility to disease [italics added] … Recent studies suggest that phenotypic discordance between monozygotic twins is at least to some extent due to epigenetic [changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence] factors that change over the lifetime of a multicellular organism.
P. Poulsen, et al. 47
One study found that genetic concordance rates for identical twin pairs by age 75 years were only 11% for colorectal cancer, 13% for breast cancer and 18% for prostate cancer, and these were lower in dizygotic twins (5%, 9% and 3%, respectively).48 These low concordance rates agree with other data on cancer incidence and provide little support for strong heritable effects in cancer.49
Infection with a bacteria called Helicobacter pylori has been widely recognized as the cause of stomach ulcers, but it is now thought to also cause stomach cancer.50 It's worth noting that the causative role H. pylori in stomach ulcers was not identified even though researchers were able to cultivate this bacterium in the laboratory and to see it under the microscope in gastric biopsies.
Persistent human papillomavirus infections have been recognized as the major cause of cervical cancer and may play a role in some cancers of the anus, vulva, vagina, and penis.51 Evolutionary biologist Paul Ewald has argued that infectious causation has often been accepted belatedly throughout the history of medicine and, if decades long trends are anything to go by, mainstream medicine will ultimately agree that the majority of cancers are caused by pathogens:
Back in 1975, mainstream medicine agreed that about 0.1% of human cancer cases were caused by pathogens. When it came to the rest of cases, their view was that they were probably caused by a combination of inherited predispositions and mutagens. Then in 1985, the percentage of cancer cases they tied to pathogens was 3%, and they continued to make the same argument about the remaining cases. In 1995 the percent of pathogen-induced cancer cases was accepted to be around 10%. Now, we’re at 20%. Still, mainstream medicine contends that the other 80% of cases do not have an infectious cause, but the question is – do you believe them anymore? In this sense, the clarity of hindsight can help a lot. Between evolutionary instinct and plain common sense we can view the issues of pathogens and cancer much more effectively.
Paul Ewald, PhD, Bacteriality.com
In a 2000 paper co-written with Ewald, Cochran and Cochran trace the long and seemingly inevitable acceptance of chronic diseases as being caused by infectious agents rather than genetic predisposition.52
Smoking has been called “the single most preventable risk of disease” but the underlying disease process by which smoking is said to cause death and disease is not well-defined. However, there are several areas of study which point to the role of pathogens and modulation of the immune response in the diseases caused by smoking:
The MP uses olmesartan to activate the VDR, a nuclear receptor which is downregulated in cancer. While the MP appears to be a sensible preventive, it is not suitable for treating active metastasis.
While it is pretty certain that olmesartan reactivation of the VDR (and MTSS1) will likely reduce metastasis, that has little application once the cancerous cells have already started to spread. While the MP can probably stop metastasis from developing, once a tumor is in place, and growing, it is almost certainly too late to contemplate non-invasive therapies like the MP.
Trevor Marshall, PhD
A 2010 meta-analysis of randomized controlled trials administering ARBs, the class of drugs (which olmesartan belongs to), concluded the the drugs were associated with a small increase in the incidence of cancer.58 This publication was widely rebuked, as one can see from the number of comments in PubMed referring to this article.
In the wake of the study, physicians contended that it is extremely unlikely that ARBs are associated with an increased risk of cancer, with one physician saying he has data that, if added to the analysis, would wipe out any cancer signal. (See also statement by Dr. Henry Black attesting to the safety of Benicar. Registration required.) Overall, they say, the media splash this paper has made could cause irreparable damage to the reputation of ARBs, which they consider vital tools in their armamentarium, and may unfortunately prompt many patients to stop taking the medicines, putting themselves at increased risk of cardiovascular and renal events.
Note also that the primary ARBs being evaluated, candesartan and telmisartan, have significant different actions than olmesartan. According to the in silico emulations of Dr. Marshall, they are VDR antagonists.
A variety of studies have suggested that vitamin D protects against cancer. This seemingly intuitive proposition is supported by neither epidemiological nor molecular evidence. In fact, the very opposite is true. This article reviews why this body of research is most likely incorrect – or at the very least, much more complicated than articles in the popular media would have a person believe.
According to the Marshall Pathogenesis, alteration of vitamin D metabolism by a pathogenic microbiota prevents any benefit from vitamin D supplementation.
Chemotherapy is aggressively immunosuppressive, and will allow a patient's bacterial load to return, by shutting down your immune system. For example, hepatitis infections59 as is pneumocystis pneumonia have been known to become reactivated during chemotherapy.60
Some physicians have recommended the Bacillus Calmette-Guérin (BCG) vaccine as a treatment for cancer. There is no evidence to support such an intervention. BCG is live bacterium, Mycobacterium bovis, and has been fingered as having directly caused sarcoidosis, for example.61 62
I understand your emotions regarding bladder cancer. I went through it but can now say I am convinced the MP has strengthened my immune system to prevent it again. My last two bladder scopes after surgery to remove tumors were negative (for the past year) and the FISH chromosomal test of the bladder wash was also negative for cancer. Take a look at my MP thread. I just posted an update earlier today. My doctor called Dr. Marshall and he explained to doc why BCG was not an option. I also declined chemo due to the disruption to the immune system. As Dr. Marshall said in a post the VDR transcribes an anti-metastasizing gene along with others to control/prevent cancer.
Researchers trialling gene therapies against cancer have been unsuccessful to date. Such initiatives have yet to take into account the types of intracellular microbes implicated by the Marshall Pathogenesis. One, a Duke University program, to tailor cancer treatments to certain cancers has ended in disaster and lawsuits.
Cancer kills when it is “invasive,” spreading from primary sites to other sites and proliferating there. The only sure way to know the disease is cancer is to allow it to progress to a point where there is no question one has a proliferative disease. Clearly, this is not a tenable option as at a certain point, it is impossible to intervene. However, the risk of a false positive is also great. Chemotherapy will destroy the immune system, allowing microbes to multiply and leading to greater chronic inflammation when chemotherapy is discontinued. These two considerations have to be balanced, and it is a matter of debate whether many oncologists fully appreciate this balance. It is worth noting that false positives increase the apparent “success rate” of oncology, and there is therefore limited incentive to minimize them.
If the public realized how high the false detection rate was, they would be more cautious, and not be hurried into surgery.
Trevor Marshall, PhD
In part because a missed diagnosis is so problematic, pathologists tend to err on the side of the false positives rather than false negatives. For example, it is not uncommon to receive a report that granuloma, which are found in sarcoidosis or Crohn's, are cancerous. Assuming that enlarged lymph nodes for illness (which naturally become enlarged during immunopathology) are cancer is also frequent:
Colonoscopes are not contraindicated by the MP, and may be warranted for high risk patients. It is okay to continue MP medications but one may want to adjust them to reduce immunopathology.
To date, animal models have had limited success to emulate cancers, particularly because the immune systems of even close relatives of humans are significantly different. For example, the infamous TeGenero study was initially trialled without a problem in apes. When it was introduced into the humans, it was a disaster.
Interviews of patients with other diseases are also available.
I was first diagnosed with Sarcoid in 1977, and like most of you have years of in and out of what seems like remission. To cut a long story short, I finally had a double mastectomy in 2006, and both my breasts came back from the lab, yes, with sarcoid throughout.
My PSA was through the roof during the first 18 months on the MP (3 - 4 times the safe level). I had a biopsy and a colonoscopy, all were good. As the inflammation in my glands settled so did the PSA. It has fallen well within the safe zone and remained there for nearly 2 years. Hope this gives you some comfort, although my Dr was insistent that I get it checked to be sure.
Sydney Chris, MarshallProtocol.com
My prostate and urine flow issues started 20 years ago. I am pretty pleased with all my improvements on MP in that department. Although I never had an elevated PSA my gland was large enough that my urologist wanted to microwave it. Now it is normal size and typical upon rectal exam.
Polar Bear, MarshallProtocol.com
New Evidence Links Virus to Brain Cancer - http://www.med.wisc.edu/news-events/news/new-evidence-links-virus-to-brain-cancer/32922
Title:Microbiome and Malignancy
Authors: Plottel, CS; Blaser, MJ
Author Full Names: Plottel, Claudia S.; Blaser, Martin J.
Source: CELL HOST & MICROBE 10 (4): 324-335 OCT 20 2011
Document Type: Review
KeyWords Plus: EPSTEIN-BARR-VIRUS; HELICOBACTER-PYLORI INFECTION; BREAST-CANCER RISK; T-CELL RESPONSES; NF-KAPPA-B; URINARY ESTROGEN METABOLITES; LYMPHOID-TISSUE TYPE; POSTMENOPAUSAL WOMEN; GUT MICROBIOTA; LATENT MEMBRANE-PROTEIN-1
Abstract: Current knowledge is insufficient to explain why only a proportion of individuals exposed to environmental carcinogens or carrying a genetic predisposition to cancer develop disease. Clearly, other factors must be important, and one such element that has recently received attention is the human microbiome, the residential microbes including Bacteria, Archaea, Eukaryotes, and viruses that colonize humans. Here, we review principles and paradigms of microbiome-related malignancy, as illustrated by three specific microbial-host interactions. We review the effects of the microbiota on local and adjacent neoplasia, present the estrobolome model of distant effects, and discuss the complex interactions with a latent virus leading to malignancy. These are separate facets of a complex biology interfacing all the microbial species we harbor from birth onward toward early reproductive success and eventual senescence.
well-established tumor-promoting function of chronic inflammation (Karin and Greten, 2005)64
1000 types of cancer versus one
BRCA mutation genes
Question: I recently came across an article while doing a medline search entitled, “Association between low levels of 1,25 dihydroxyvitamin D and breast cancer risk.” The conclusions of the study were: “These data are consistent with a protective effect of 1,25-D for breast cancer in white women.” This concerns me because I carry the brca-1 mutation and so am already at a very high risk of getting breast cancer and according to the study lowering my 1,25-D will only further increase my risk.
The brca1 gene has only been shown to be a MARKER of breast cancer, not a cause. Second, Th1 inflammation is almost certainly a necessary precursor to breast cancer (i.e. a cause) Mutations in brca1 and brca2 are associated with increased incidence of cancers, not necessarily causal.
I have just come from a “Diseases of (DNA) Transcription” conference at the Salk Institute where there was not one scientist who knew exactly how genes mutate, or why, or what it means.
Sure, there are statistics linking shifts in haplotypes with certain diseases, but they are just as likely due to the mix of persistent pathogens your family has been passing down, as they are due to any Mendelian variation of the gene pool.
A person has to assess the relative likelihood of dying from Th1 disease and dying from cancer. 1,25-D is a measure of the Th1 reaction and is therefore intimately associated with breast cancer, in ways that this study investigators never dreamed of. If one doesn't understand the subtleties behind this kind of research, then one is going to have trouble assessing relative risks in medicine.
I have seen a number of Th1 patients erroneously diagnosed with cancer. The diagnosis of cancer is not precise. Flow cytometry senses the presence of both CD10 and bcl2, and these are elevated in Th1 disease. False positives are a fact of life, but patients rarely find out about them. False positives increase the apparent 'success rate' of oncology, and there is therefore little incentive to minimize them.
BRCA genes are turning out essentially useless to tell Breast Cancer predisposition, as now they are falling back on the old epidemiological factors before even screening
The relationship between cancer and inflammation is controversial. (IMO) A good review of the issues is available from JOIMR
Additionally, two of the markers used in Flow Cytometry (used as the 'gold standard' for breast cancer) bcl2 and CD10, are both elevated in the inflammatory diseases, leading to misdiagnosis in a lot of cases, probably in a majority of cases. These misdiagnoses also bias the epidemiological studies.
The BRCA1 and BRCA2 genes are probably not good differential markers of cancer vs inflammation. The pathology report from MD Anderson again states there is no sign of proliferation of the cancer into the surrounding tissues, so the sentinel node biopsy is probably the best way to determine whether the lump is an old cancer or is still active.
Less than 10% of Breast cancers are due to BRCA1, most are due to Estrogen up-regulation. Since the Estrogen receptor transcribes the protein which folds to form the Vitamin D Receptor, excessive estrogen is probably associated with a disabled VDR, IMO.
~Trevor Marshall, PhD
BRCA1 and BRCA2 genes are no longer regarded as definitive
CHICAGO, Jan. 8,2008: BRCA genes get help in causing breast cancer-study
The risk of breast cancer among women carrying the well-known BRCA mutations is also affected by other genes, researchers said on Tuesday.
The study of close relatives of breast cancer patients who had one of the BRCA mutations showed the risk of the disease varied greatly between families, indicating that other genes must be involved.
So a woman who knows she has a BRCA1 or BRCA2 mutation still cannot know precisely what her risk of breast cancer is, the researchers reported in the Journal of the American Medical Association. “The implications of that are that there must be other genetic factors involved here,” Dr. Colin Begg of Memorial Sloan-Kettering Cancer Center in New York, who led the study, said in a telephone interview.
“Because if some carrier families have higher risks than other carrier families presumably there are other genes being passed through these families that elevate or lower the risks,” Begg said.
Begg's team studied 2,000 women diagnosed with breast cancer, and the families of the 181 patients who had BRCA mutations. They found that 5 percent of those with cancer in one breast had a BRCA1 or BRCA2 mutation and 15 percent of those with cancer in both breasts did.
All had been diagnosed early, before the age of 55. But only 25 percent of all the patients had a close relative with breast cancer. And 58 percent of those with BRCA1 or BRCA2 mutations had a mother, sister or other close relative with the disease, the researchers said.
They said this means a close relative of a BRCA carrier with breast cancer has a 40 percent risk of developing the disease herself by age 70. But this is an average risk and they found a considerable amount of variation in risk from one family to another.
Search for more genes
Among carriers, their risk of developing breast cancer by age 70 has been estimated at anywhere between 50 percent and 85 percent, Begg said.
They looked to see if perhaps the type of BRCA mutation might affect risk, but it did not appear to. Many different types of mutations were found but they usually did not significantly affect whether a woman or her relatives had breast cancer, Begg's team said.
“There's a lot of research going on at the moment in general to find additional breast cancer genes. What we're saying here is that research is likely to be successful,” Begg said.
~Andrew Stern, Reuters
The BRCA1 and BRCA2 mutations are most common among Jews of Ashken— descent. At least 2 percent of these descendants of Eastern European Jews are carriers. The incidence is lower in the general population, but not enough testing has been done to put a firm estimate on it. About 465,000 women died of breast cancer last year, making it the leading cause of cancer death among women worldwide, according to the World Health Organization.
Almost half of all cancer survivers have ill health in later years.
Gut Microbes. 2012 May 1;3(3). [Epub ahead of print]Microbes-induced EMT at the crossroad of inflammation and cancer.
Hofman P, Vouret-Craviari V. Source
IRCAN; France; University of Nice-Sophia Antipolis; Nice, France; Centre Hospitalier Universitaire de Nice; Hôpital Pasteur; Laboratoire de Pathologie Clinique et Expérimentale; Nice, France.
It is noteworthy that bacterial or viral infections, and the resulting chronic inflammation, have been shown to predispose individuals to certain types of cancer. Remarkably, these microbes upregulated some transcription factors involved in the regulation of the epithelial to mesenchymal transition, referred herein as EMT. EMT is a cellular process that consists in the conversion of epithelial cell phenotype to a mesenchymal phenotype. Under physiological conditions EMT is clearly important for embryogenesis, organ development, wound repair and tissue remodeling. However, EMT may also be activated under pathologic conditions, more particularly in carcinogenesis and metastatic progression. In this review, we make a parallel between microbes- and growth factors- induced transcription factors. A unifying EMT model then emerges that may help in understanding the development of microbial pathogenesis and in defining new potential future therapeutic strategy in treating diseases linked to infections.
Somebody else found a little piece of the puzzle and is well…. puzzled.