Microbiologia do câncer e implicações na intervenção precoce CWD , L-formas

Hypothesis: The Microbiology of and its Potential Implications for Early Intervention Ron Falcone website

Introduction The century's old debate as to whether are simply opportunistic infections "after the fact" or whether they can initiate cancer has been a contentious one. As early as the 1920's,

Thomas Glover isolated a bacterium which he named "Glover's organism". Two decades later,

Virginia Livingston believed that a single, ubiquitous pathogen she identified as a

Mycobacterium (and which she named Progenitor cryptocides) was the primary cause of most human cancer. A handful of others also claimed discovery of a cancer-causing organism which appeared cameleon like, and seemed to defy one, universal taxonomy. From a mainstream standpoint, scientists disagreed with Glover and his later contemporaries, instead arguing that cancer-related pathogens were simply opportunists, contaminating diseased tissues after the fact.

But in the 1990's, Shy Chung Lo of the Armed Services Institute of Pathology cultured

Mycoplasma fermentans from cancer, injected the organism into animals, and was then able to induce cancer; in effect, Lo had established Koch's Postulates, proving that bacteria were indeed able to directly cause cancer [1].

Other investigators corroborated Lo's Mycoplasma research. For example, Chan reported the prevalence of mycoplasmal DNA in ovarian cancer[2]; Schmidhauser demonstrated that the p37 gene associated with mouse sarcoma originates from Mycoplasma and that a proportionate increase in malignant invasiveness was related to such exposure[3]; Ushio found that Mycoplasma-infected cells have a higher ability to metastasize in vivo than non-infected cells[4]; and Bogoch demonstrated that Mycoplasma secrete a similar polysaccharide used by cancer antigens to avoid immune-system recognition.

Although mainstream scientists generally disregarded the notion of a "cancer germ"---even as late as the 1990's---conclusive evidence now linking H.pylori with has rendered this position obsolete. In addition, science now appears to be moving toward a greater acceptance of multiple species of cancer bacteria implicated in different forms of cancer. For example, Salmonella typhi, Streptococcus bovis and Chlamydia penumoniae[5] are being associated with gallbladder, colorectal, and lung cancer, respectively. And a percursory review of the scientific literature clearly has shown an exponential increase in cancer bacteria-based findings, beginning in the early 1990's and continuing through to the present.

As the evidence continues to accumulate, the long held paradigm of microbiology that consigns a specific bacterium to a specific infectious disease may not correlate with the multiple species of bacteria now being associated with cancer.

Cancer Bacteria and HCG

Beside their potential role in oncogenesis, different genera and species of bacteria have consistently tested positive for the human growth hormone choriogonadotropin (hCG).

While bacterial hCG is a finding that's not been actively pursued in mainstream laboratories, we feel it represents a major milestone in the cancer process.

The first investigator to discover a bacteria-hCG link was Virginia Livingston in 1974[6]. Her findings were corroborated by Cohen and Strampp two years later[7]. In1987, Acevedo also found HCG but in a majority of different bacterial species isolated from cancer patients, including Streptococcus faecalis, haemolyticus and Staphylococcus epidermidis as well as gram-negative diptherioids[8].

Acevedo's findings contradicted Livingston's claim of an "ubiquitous" or universal cancer bacterium---and this, in turn, was presented as proof against Livingston's bacterial theory in a report issued by the American Cancer Society (ACS) in 1990[9]. It will be noted, the ACS based its negative conclusions on the fact that different bacterial species could secrete hCG, and also on an inability to isolate Livingston' s specific bacterium, Progenitor cryptocides. However it should also be noted that the ACS did not disprove whether or not Livingston's cultures were actually oncogenic. Fundamentally, Acevedo did agree with Livingston's premise that cancer- associated bacteria have "revertant" forms, lack true cell walls, are filter passing (able to simulate viruses) and also intermittently acid fast---characteristics considered by some to implicate the controversial phenomenon known as "pleomorphism".

In additional studies, Acevedo also found evidence of hCG in all cancer cell lines he examined, regardless of their origin[10]. These studies offer compelling proof that hCG is a common cancer marker found in many, or possibly most types of cancer, and its presence is significantly higher in disease tissues than in normal ones[11].

Bacteria, Cancer and HCG: An Unholy Trinity

We hypothesize that the relationship between bacteria, cancer and hCG has vast implications both in our understanding of the century's old riddle of how cancer tissues evade host immunity, and equally important, in the potential realm of therapeutic intervention. The discovery of hCG as a viable tumor marker may now solve a riddle which has baffled scientists for more than a century---i.e., how cancer cells grow unchecked with little, or no resistance.

When cells become malignant, their surfaces change and become charged with carbohydrate residues. One of these residues---a simple sugar known as an oligosaccharide---combines with another sugar, sialic acid, a key molecule of hCG. Sialic acid, in turn, appears to protect the cancer cell from host immunity because it is a negatively charged molecule; immune system cells are also negatively charged[12]. In effect, HCG creates an "electric shield" (i.e., like poles repel) which appears to have evolved as an ingenious survival mechanism, not only for tumors, but for human life itself. In the latter case, HCG plays a significant role in protecting the developing human embryo from host immunity, just as it does with cancer. Without this effect, the mother's immunity would seek and destroy the fetus[13],[14]---a partly foreign protein in the uterus comprised of both friendly (host) and foreign (DNA) from the mother and father.

Other insidious roles of HCG in cancer are tumor angiogenesis (formation of blood networks for malignant tissues), promotion of tumor invasiveness, and nourishment of tumors.

Are human quasi-manifestations of fetal life gone berserk, but expressing the same intention to live and grow? The parallels are indeed striking. For example, the primary manufacturers of fetal hCG are specialized placental cells called trophoblasts, whereas in cancer, the exact source of hCG is not clearly understood. Several possibilities include genes coded to produce hCG, or bacteria interfacing with cancer cells through DNA transfer, or via what has been described as a "plasmid vector". It may be that cancer bacteria serve as the biologic equivalents of trophoblasts in some capacity, but the latter arising via the evolution of human life and the former, as an adaptative mechanism of evolution.

In the final analysis, cancer shares many similarities with fetal life and it is here that the ultimate solution to this disease may lie. Indeed, this idea has gained support among leading scientists working in the fields of genetics and immunobiology.

Dr. Robert Weinberg, the first discoverer of a cancer gene and now an MIT professor of biology stated:

It's now increasingly apparent that one mechanism, quite possibly the dominant mechanism, involves the ability by the cancer cell to resurrect early embryonic behavioral programs...This movement in the embryo is superficially similar to metastasis. The way cancer cells acquire this embryonic trait of being able to move throughout the organism depends on their ability to resurrect these early embryonic behavioral programs, which they do through their ability to induce the expression of early embryonic transcription factors [proteins that control the expression of a large number of genes]. In this case, these transcription factors control groups of genes that, when turned on, allow the cancer cells to move, to become invasive, to resist programmed cell death (which otherwise threatens their existence once they leave the primary tumor), and even to release degradative enzymes that break down the [surrounding tissue that] represents an impediment to the forward march of the cancer cells[15].

In a similar vein, Italian researchers wrote in the journal Immunobiology:

The model that most resembles the behavior of tumor cells in terms of growth, infiltration and suppression of the immune system of the environment in which they live is undoubtedly that of the embryonic cell. The fetus behaves like an allogenic transplant within the mother's body, using every means it has to escape from and defend itself against the mother's immune system. The majority of these mechanisms are the same as those found in tumor cells (including)...antigenic loss and induction of apoptosis in infiltrating lymphocytes...A careful and comparative study of key mechanisms capable of triggering tolerance or cytotoxicity in both embryonic and tumor cells could prove immensely valuable in designing new strategies for anti-tumor [16].

Deadly Symbiosis: An Additional Role for Cancer Bacteria

Bacteria may play another critical role in neoplasia beyond their possible involvement in disease causation and hCG synthesis. In 2004, Dr. D.H. Robinson reported that cancer bacteria were capable of acquiring eukaryote-like qualities in what he has termed "prokaryote to eukaryote transformation". Through a process involving "vertical DNA transfer," transformed bacteria are able to "self-organize" into structured tissues and to form vascular networks. (Such self- organizing structures are not, insists Robinson, "biofilms")[17]. The symbiotic coupling of eukaryotically transformed bacterial tissues with cancer might help provide the latter with tumoral blood supply and assist in such factors as immunosupression and metastasis .

POTENTIAL ADJUVANT

If cancer, co-existing bacteria, and the common denominator hCG form a three-tiered foundation in tumor formation, would addressing this "cancer trinity" via adjuvant strategies that neutralize their effects be a logical starting point for ? Might a to fight bacterial infection and another to counteract hCG antigen on the tumor cell make therapeutic sense and synergistically augment each others' effectiveness?

Over the past century, anti-bacterial have been used and various degrees of success have been claimed, though serious clinical trials are lacking.

In what might possibly be considered the first trial of its kind, an active vaccine manufactured by exposing horse blood to bacteria cultured from cancer patients was given to one-hundred pathologically confirmed cases of cancer. Reports of remissions were made, but the trial was not blinded or randomized, and quality control is impossible to determine[18].

Two decades later, French researchers conducted a 3 year trial at the Saint Antoine

Hospital in Paris and reported "superior" results with a Mycobacteria-based vaccine given to surgically treated, primary lung cancer patients[19].

In 1990, a of Livingston's (made from patient-derived bacteria) didn't show benefit for patients suffering from advanced cancer. However, trial patients who also received conventional therapy also failed to respond and both sets of patients deteriorated at equal rates[20]. Barrie Cassileth, the trial coordinator, concluded that the ".....study...involved only patients with diagnoses and stages of disease for which there is no effective conventional treatment. Therefore, the results cannot be generalized to patients with less advanced stages of disease or to other treatment regimens." Cassileth also said that her study group "hypothesized that survival time would not differ between the two groups on the basis of the assumption that the unproved remedy would be no more effective with end-stage disease than conventional care, itself largely ineffective"[21]. Interestingly, BCG vaccine---which is currently in use as an approved cancer treatment and derived from the same genus of bacteria that figured so prominently in Livingston's therapy---was also used during the Cassileth study. BCG is now used to treat bladder cancer; it has also shown statistical benefit in the treatment of colon cancer[22].

Because a variety of bacterial species have now been associated with cancer,

Livingston's adherence to a Mycobacterium-only based theory was evidently incorrect.

However, her thesis of a microbiologic for cancer represented a starting point ahead of the science yet to be accumulated and now, scientists agree that bacteria do, in fact, cause some forms of the disease.

Beside antibacterials, there have been trials involving anti-hCG vaccines, and early results have been promising. We believe these results lend credence to our hypothesis of hCG as a critical component of the cancer trinity.

In a phase II trial of patients with extremely extremely poor prognosis , a combination of the anti-hCG vaccine Avicine (Avi Biopharma) with the cancer drug Gemzar (Eli Lilly) significantly extended life span beyond that usually attained from Gemzar alone (see anti-HCG trials). Unfortunately, plans to expand Avi

Biopharma's vaccine to Phase III never materialized, despite the positive reports.

Meanwhile, Lilly's drug continues being marketed and offered as a first line therapy.

Presently, two new biotech companies, CG Therapeutics, and CellDex Therapeutics are now acitvely developing newer and more potent anti-hCG vaccines, and clinical trial recruitment is underway. According to a press release issued by CG Therapeutics, they believe their vaccine to have major potential as a universal treatment for cancer. They go on to state that "Prior formulations of CG201(anti-HCG vaccine) showed safety and effectiveness in human Phase 1 and Phase 2 cancer treatment trials. The stimulated by CG201 blocked hCG's effects and extended survival in late-stage colorectal and pancreatic cancer patients" (see Anti-HCG Trials for further information, and additional links).

Conclusion

In conclusion, there are now very exciting developments regarding anti-hCG therapies for cancer, and the concurrent use of anti-bacterial vaccines is an area that may offer additional potential. We thus close our hypothesis with a brief summary of such adjuvant based on the concepts we've presented here and throughout this website:

AUTOGENOUS VACCINES are prepared from hCG-positive cultures, procured from individual cancer patients. Because a number of different bacterial species have been identified in human cancer, utilizing individual cultures for vaccine preparation has been suggested by several physicians; they see this as an ideal method of bypassing problems with bacterial classification as a prerequisite for treatment. Other factors cited as favoring autogenous vaccine treatments are their relative non-toxicity, and their compatibility with standard protocols.

ANTIBIOTIC THERAPIES have been used, or suggested, by health practitioners. If bacteria are an etiology in some cancers, reduction of bacterial infection may be accomplished via chemosensitivity testing of multiple antibiotics, with individual patient cultures. Bicillin, ampicillin and penicillin G have all been used in this regard. However with recent documentation of mycoplasma as possible factors in oncogenesis, non-bacteriostatic drugs including the tetracyclines might be more appropriate, considering the lack of cell walls and resistance to bacteriostatics by mycoplasma type organisms. The final determination would depend on the test results gathered for each patient.

ANTI-HCG SPECIFIC VACCINES would directly target cancer cell surface antigens, while antibacterial and antibiotic therapies address the underlying cancer 'infection'. Hypothetically, the 'electric shield' effect would be neutralized via anti-hCG treatment, exposing cancer cells to attack by the immune system.

NON-SPECIFIC IMMUNOTHERAPIES have also been used in the adjuvant setting to help accelerate the body's natural defenses against cancer. There have been variable reports in the literature concerning such immunotherapies including several total remissions. The physician

Burton Waisbren MD treated cancer patients with a four-vaccine regimen consisting of BCG

(now approved for use in bladder cancer), transfer factor, lymphoblastoid lymphocytes and mixed bacterial vaccine (based on the earlier pioneering work of William Coley). He has reported cases of cancer remissions in the peer reviewed literature[23].

Non-specific immunotherapies might theoretically confer several advantages. First, their effectiveness might be potentiated when administered to patients with hCG-neutralized antigens and bacterial control; second, they have a track record of safety, are considered mostly non- toxic, and have reportedly shown efficacy; and finally, they are compatible with standard treatments when, and if indicated.

REFERENCES

1. Tsai S, Wear DJ, Shih JW, Lo SC. "Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation." Proc Natl Acad Sci U S A; 92(22):10197-201 1995.

2. Chan PJ et al. "Prevalence of mycoplasma conserved DNA in malignant ovarian cancer detected using sensitive PCR-ELISA." Gynecol Oncol, 1996 Nov, vol. 63, pp.258-260.

3. Dudler R, Schmidhauser C. "A mycoplasmal protein influences tumour cell invasiveness and contact inhibition in vitro." J Cell Sci 1990 Mar;95 ( Pt 3):499-506.

4. Ushio S, Iwaki K, et al. "Metastasis-promoting activity of a novel molecule, Ag 243- 5, derived from mycoplasma, and the complete nucleotide sequence." Microbiol Immunol 1995;39(6):393-400.

5. Mager DL "Bacteria and cancer: cause, coincidence or cure? A review". (2006). J Transl Med 4: 14.

6. Livingston, V. "Some Cultural Properties, Immunological and Biochemical Properties of Progenitor Cryptocides." Tran NY Ac Sci, 6 June 1974;36(6):569-82.

7. H Cohen and A Strammp. "Bacterial Synthesis of Substance Similar to HCG." Proceedings of the Society for Experimental Biology and Medicine 152, no.3 (July 1976).

8. H. Acevedo, Matias Pardo, Elizabeth Campbell-Acevedo and Gerald J. Dominigue. "Human Choriogonadotropin-like Material in Bacteria of Different Species: Electron Microscopy and Immunocytochemical Studies with Monoclonal and Polyclonal Antibodies." Journal of General Microbiology (1987), 133, 783-791.

9. American Cancer Society, Cancer Journal for Clinicians 40, no.2(March/April 1990).

10. Acevedo HF et al. "Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins." Cancer, vol.76, pp.1476-1475, 1995 Oct 15.

11. ibid.

12. Suzuki Y, Tateishi N, Maeda N. "Electrostatic repulsion among erythrocytes in tube flow, demonstrated by the thickness of marginal cell-free layer. Biorheology. (1998) Mar-Apr;35(2):155-70. 13. Cameo P, Srisuparp S, Strakova Z, Fazleabas AT. "Chorionic gonadotropin and uterine dialogue in the primate." Reprod Biol Endocrinol. 2004; 2:50 (ISSN: 1477- 7827).

14. Kayisli UA, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A. "Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system." J Immunol. 2003; 171(5):2305-13.

15. Katherine Bourzac, "How a Tumor Is Like an Embryo," Technology Review, Tuesday, November 06, 2007.

16. Ridolfi L, Petrini M, Fiammenghi L, Riccobon A, Ridolfi R. "Human embryo immune escape mechanisms rediscovered by the tumor." Immunobiology 2009;214(1):61-76.

17. Douglas H. Robinson. "Pleomorphic mammalian tumor-derived bacteria self- organize as multicellular mammalian eukaryotic-like organisms: morphogenetic properties in vitro, possible origins, and possible roles in mammalian 'tumor ecologies.' Medical Hypothesis, 26, April, 2004.

18. Glover TJ (1930). "The bacteriology of cancer". Canada Lancet and Practitioner 74: 92�111.

19. V Djurovic and G Decroix. "Five years of active non-specific immunotherapy with a transformed mycobacterium in surgically treated primary lung cancers. One to three years of post-operative follow-up," French Society of Medical Radiology 59, no.11 (1978):651-54.

20. Cassileth, B., et al. "Survival and Quality of Life Among Patients Receiving Unproven as Compared with Conventional Cancer Therapy." New England Journal of Medicine 324 (April 25, 1991): 1180.

21. ibid.

22. van den Eertwegh AJ. "Active specific immunotherapy in colon cancer." Cancer Res 2005;165:260-7.

23. B.A. Waisbren, "Observations on the Combined Systemic Administration of MBV, BCG, TF,and LL to Patients with Cancer, 1974-1985," J of Biol Response Modifiers 6 (1987): 1-19.