A NEW PARADIGM FOR CANCER THERAPY AND CURE
The rationale for the proposals herein are based upon the concept that present day human molecules that have evolved in some cases over billions of years will be effective cancer therapeutic agents. These researched, identified molecules have been shown to be involved in cellular differentiation, growth, regeneration, remodeling, rejuvenation, intercellular communication, and as phenotype instructional entities. They have also demonstrated by direct observation, and in a myriad of in vivo and in vitro studies, to induce cancer cells and tissues to become more normal and to inhibit cancer recurrence. Their evolutionary histories suggest that they were instrumental in guiding complex metazoan organisms into their specific present day morphologies, which includes the human specie. Specifically named in the paper are Cellular Fibronectins, and the myriad of biological interacting molecules that are loosely categorized as The Extracellular Matrix.
The United States Congress Office of Technology Assessment commissioned Drs. Doll and Peto, British cancer epidemiologists, to research the causes of cancer in the USA. The work finished in 1981, was published as a 115 page paper with statistics of every known type of cancer worldwide, and numerous references documenting the data. There was ample evidence therein that many common types of cancer are avoidable with evidential suggestions to enhance cancer avoidance. Among the vast amount information presented in this study were the lists of established human carcinogenic agents and their respective circumstances of exposures. Although there have been recent great emphasis in the genetic causes of human cancers, these researchers after reviewing thousands of statistics worldwide stated that “the relevance of genetic susceptibility to the common types of cancer remains obscure”.(1)
Cancer therapy has not appreciably changed for many decades. Chemotherapy, radiation and surgery are still the mainstay of the clinical treatment for malignancies. It is ironic that most chemotherapeutic agents and many sources of cancer radiation treatments are carcinogenic. Surgical treatment of tumors where possible, in many instances has proven the most desirable therapeutic choice. However, there is a propensity for cancer recurrence at the surgical site. (2)
Herein is a proposal for a new type of cancer therapy based on observations of the natural biological activities of normal human cells. The biological molecules that the cells produce maintain their differentiated state, regenerate, remodel, and rejuvenate these cells and tissues are of primary importance in the considerations in this concept’s proposal. However, before we embark upon the rationale of this concept, an examination of their evolutionary significance is in order.
Within the past decade the physical and astrological sciences have revealed a plethora of information regarding our universe. Extrapolation backwards from our expanding universe has determined that our universe is about 13.7 billion years old. The first “ stable” element in the universe, hydrogen, formed about 200,000 years after the initial expansion ( Big Bang). Before the period hydrogen formed, there was apparently a period wherein free electrons, photons, and the material that became quarks,(deemed the primary manifestation of matter) were in chaotic swirling expanding masses. Therefore, from our prospective, hydrogen can be considered the first evolutionary construct of our universe. In simple terms all other evolutionary manifested matter are the additions of quarks, which are deemed the materials that compose the nuclear protons and neutrons and additional electrons to orbit around the nucleus. Most stars in general make and burn mainly hydrogen and a little helium, but little else. We on planet Earth are lucky, our star, The Sun has many more heavier elements. Our solar system was probably formed from an exploding star over 5 billion years ago. Heavier elements form from exploding stars. Therefore, the swirling masses that formed our solar system presented our planet with all of the diverse wide spread elements that are represented by the Periodic Table. Our planet had all the perfect ingredients for biological evolution. The main ingredients being water and elements that would form stable molecules. Further, the Earth’s orbiting distance from the Sun was ideal for the perfect evolution of diverse biological entities. (3) p. 346
Our 4.5 billion year old planet, already had, from archeological evidence, bacterial type organisms 3.5 billions years ago. These organisms somehow adapted to an extremely hostile environment that had little or no oxygen, however they resided in a water-world that apparently came into existence 4.4 billion years ago. These thermaphils type bacteria evolved as the planet gradually cooled. Due to close contact of these bacterial types of organisms, they freely exchanged genetic material in a process named “Horizontal Gene Transfer”. It was thought that this behavior gave these early organisms greater evolutionary potential. Finally, when the planetary niches of these organisms became at a distance wherein they could not interact, a new evolutionary stage began. There are three distinct classifications of biological categories existing on the planet presently. Recently named Domains, they are: 1) Archaea. 2) Bacteria 3) Eucarya. (4)
Archaea are single cell organism that occupy very diverse and what can be considered hostile niches. Bacteria are the most prevalent types of organism on the planet. The Eucarya are the organism that eventually evolved into multicellular organisms. The eucaryotic division of plants and animals are believed to have occurred about 2 billion years ago. The human specie is the objective subject that this paper will eventually focus upon after a review of its evolution. (5)
A DIFFERENT VIEW OF SCIENCE
In the past, and for the sake gaining insight into the nature of “everything”, science has arbitrarily compartmentalized itself into theoretical physics, astro-physics, astronomy, biology, biochemistry, chemistry, botany, genetics, etc.,etc. This linear compartmentalization may notallow a realistic lateral insight into what our limitations may be especially in the so called biological sciences. Reduction science has been an important tool in biology, however, limitation as to its total value must be recognized. What follows will eventually question the finite conclusions that can be drawn from reduction of biological tissues.
QUANTUM MECHANICS AND BIOLOGICAL TISSUES
During the past 80 years, physicists have determined that at the microscopic, atomic subatomic realms, of our universe, the mystical “ principle of uncertainty” is a valid concept. This also true here on planet Earth. (3) To restate, the principle in the relationship to biological reduction science, one can never be assured that the reduced biological products are what can be expected from the intact original cells or tissues. These reduced products, although research and named, there is a strong possibility that they are not realistic entities that evolutionary processes intended. To date, they have not proven valid therapeutic agents. Further, at these very tiny submicrosopic levels a relatively new science has added to the enigmatic nature our actual reality.
There has been recent research that equates quantum mechanics in biology, medicine, and neuro-psychology. The premise Hermansen, et al papers on this subject is that biological organization is guided by energetic changes on the level of quantum mechanics.(6)
According to string theory, the universe is made up of tiny strings whose resonant patterns of vibration are the microscopic origin of particle masses and force charges. String theory also requires extra space dimensions that must be curled up to a small size to be consistent with our never having seen them. Nonetheless, a tiny string can probe a tiny space. As a string moves about, oscillating as it travels, the geometrical form of the extra dimension plays a critical role in determining resonant form of the vibration. Because the patterns of the string vibrations appear to us as the masses and charges of elementary particles, we conclude that these fundamental properties of the universe are determined, in large measure by the geometrical size and shape of the extra dimensions. (3) p. 206 This far-reaching insight of string theory predicts that besides the 3 dimensional world plus space-time that will are familiar with, there are 7 other curled up dimensions. This theory for the first time solves the problem of the long sought after “Unified Field Theory”, also known as T.O.E., the Theory Of Everything .
Let us reexamine our simplest element, hydrogen in terms of string theory. Hydrogen is described as having a single proton nucleus, which is manifested by 3 quarks, and a single orbiting electron, which is manifested by a single vibrating string. The quarks are also deemed to be manifested by vibrating strings. Therefore, the “ESSENCE” of our simplest element is manifested at a non-observable level. The rest of the heavier progressing element that make up the Periodic Table have additions of neutrons protons, and electrons that are all manifested by vibrating strings. The combinations of any molecules that are composed of these elements at the level of their essence are unknowable. The combination of molecules that compose vital dynamic biological tissues at the level of their essence are unknowable. “We live in an “ UNKNOWABLE MULTIDIMENSIONAL METAPHORIC UNIVERSE”. As part of our universe we humans are obliged to recognize this actuality. Applying this reality to biological reduction endeavors portends great limitations to reducing biological tissues. The countless number of biological molecules that have been discovered, reduced to their elemental parts, named, observed by careful scientific technologies, cannot give the ultimate finite essence of their respective biological interactions.
String theory principles were expressed in a recent research paper equating multidementional aspects of human brain tissue. The authors calculations suggests that brain space could contain inordinately large amounts of information reflecting the nature of extraordinary large increments of space and time.(7)
THE PROBLEM WITH THERAPEUTIC DISCOVERIES
Living biological cells and tissue are millions of times more complex than the molecules that are used to treat their individual pathologies. Seeking new drugs for the main subject herein, cancer, has not progressed for many decades. “Cancer Kill” therapeutics has proven toxic for normal cells and tissues and well as cancer tissues. The survivability of malignant cells, to date, has mystified researcher trying to find therapeutic agents that can treat and/or cure this world wide scourge. A new approach must be initiated.
EVOLUTION OF MULTICELLULAR ORGANISMS
Multicellular animal eukaryotes departed from multicellular plant eukaryotes approximately 2 billion years ago.(8) Early evolving multicellular animals are believed to be, with archeological evidence, primitive type sponges.(9) Fossilized sponges found at about 800,000 years ago, are seen as much like live sponges found today. (10) Fossilized sponges already show sophisticated extracellular matrices, as present day sponges.(11) It is deemed that the ability of primitive singular eukaryotic cells to generate the structural molecules of the extracellular matrix (ECM) initiated the ability for singular celled animals to adhere and communicate with each other. The molecules of the ECM seem to be the key to metazoan multicellular evolution.
To date, the most primitive metazoan ever found, microscopic Kantharella antarctica, is an animal that is considered the missing link for the evolution of the single cell protists (protozoa) that became multicellular metazoans. This 24 celled water borne animal has the very primitive ECM, containing only 3 structural molecules, laminin, collage IV, and most prominently, a cellular fibronectin.(11) These same molecules are always found in simple, but less primitive metazoans such as hydra and sponges. However, these more advanced animals have many more structural molecules that are considered as part of their evolving EMC. As metazoans evolved so did the sophistication of their specie specific ECM. In fact, metazoan evolution at the least was helped by ECM evolution or even may have led that evolution. (13 )
CELLULAR FIBRONECTIN: AN EXTRAORDINARY EVOLUTIONARY MOLECULE
Cellular Fibronectin, a very large modular protein, was discovered in 1974 as a structural molecule present on the surface of normal cells, but not on cancer cells. The discovery of cellular fibronectin prompted a reevaluation of the structural glycoproteins and extracellular matrix (ECM). Until then, most biologists had written off the extracellular matrix as a boring conglomeration of inert, uninformative molecules. But, fibronectin suggested a different story, in which structural glycoproteins linked cells to the ECM but also participated in orchestrating various aspects of cell behavior.(14 ) Subsequent research have shown that the cellular type of fibronectin and its modular parts have an extraordinary history in evolution. A type of cellular fibronectin is found in the structure of many plants(15). The well researched Type III domains of fibronectin are also found in bacteria, (16 ) fungus, (17 ) protozoa,(18 ) and in Archaea.(19 ) From an evolutionary prospective, the evolving modular parts of this highly conserved protein may go back well over 2.5 billion years.
Cellular fibronectin, as a single protein can regulate such functions such as cell adhesion, cell shape, cell migration, cell surface architecture. Its research led to the discovery of the “Integrins”, the major family of protein receptors on cell surfaces that form the transmembrane link between glycoproteins and the internal structure of cells. The integrins are structures that inform the cells and their genetic machinery as to their environment, and subsequently how to behave in that particular environment. Of the 21 known integrins, cellular fibronectin lingands (binds to) with 10, far more than any other protein.
Cellular fibronectin’s highly conserved genome has given rise to a array of molecules that play important roles in modern day metazoans. The blood clotting molecules such as fibrin, plasma fibronectin, and Factor VIII, are progenies of cellular fibronectin. Other well known molecules such as vitronectin and tenascin, contain modular sequences from the more ancient cellular fibronectin.
The family of Collagens compose over 30% of human structural proteins. Two of the most prominent, collagens I and III come into fruition only if a cellular fibronectin’s preformed matrix is present. (20 ) Further, Fibronectin’s polymerization acts a switch that controls the organization and composition of the extracellular matrix and cell-matrix adhesion sites. This ability provides cells with a means of precisely controlling cell-extracellular matrix signaling events that regulate many aspects of cell behavior including cell proliferation, migration and differentiation. (21) Cellular fibronectin, THE ORCHESTRA LEADER OF THE EXTRACELLULAR MATRIX.
The term extracellular matrix (ECM) is used in the context herein is that all of the cell specific molecules that are made by normal human cells are considered ECM. These include all of the structural proteins, growth factors, growth-binding proteins, also other locally acting molecules within the ECM as well as those in adjacent cells such as cadherins, ephrines, notch family members and so on. This composite matrix, is not only a support/barrier, but also contain dynamic action zone that functions to instruct cellular phenotype, and control its individual cell type differentiation potential.(22)
CELLULAR FIBRONECTIN: THE RATIONALE FOR ITS USE AS A THERAPEUTIC
AGENT IN CANCER THERAPY
Cellular fibronectin has already been used in a FDA approved pilot clinical trial for periodontal disease. It was proven safe and effect for that therapeutic application. (23) In an in vivo mouse study, cellular fibronectin has been shown to inhibit cancer recurrence at the surgical site. Cancer recurrence at surgical sites is a continuing problem for all types cancer surgeries such as breast, colon, and oral cancers. (24) A continuation of this study has demonstrated that the inhibition not only occurred in the liver, but also the brain and the flanks of the test mice.(See Appendix).
In vitro experiment have shown that fibronectin may be able to reverse cancer cells into a more normal phenotype. Cellular fibronectin was 50-fold more active in restoring a more normal morphology to transformed cells originally missing the protein than plasma fibronectin. (25)
Rous sarcoma virus (RSV) transformed cells, when treated with exogenous fibronectin reconstituted the cells. The study indicated that a morphological reversion occurred despite the continued presence of the RSV virus. (26)
Exogenous fibronectin restores the missing fibronectin matrix and receptor organization of SV40-transformed human fibroblasts, thereby rendering these transformed cells to a more normal phenotype. (27)
Fibronectin when used as an adhesion substrate on a human monocytic leukemia cell line THP-1 resulted in changes in both cell morphology and cell function. This experiment indicated that cell adhesion to fibronectin is a prerequisite to the differentiation of the leukemia cells. Modulation of integrins involving protein kinase reactions correlates with the adhesion process.(28)
A study to test the effects of fibronectin on tumor cell proliferation, adherence, and invasion had the following results. The growth of the fibronectin treated cancer cells decreased over the controls. The adhesiveness of the cells to the ECM was significantly increased. The conclusion of this experiment stated that a pronounced correlation exists between cells fibronectin expression and its biological behavior. With increased fibronectin levels, malignant phenotype is changed and invasive ability in inhibited. (29)
In a human breast cancer cell migration and invasion study, it found that purified intact fibronectin was found to inhibit invasiveness. (30)
Exogenous fibronectin was able to restore a more normal morphology and substrate adhesion patterns in transformed hamster fibroblasts. The restoration of the more normal morphology occurred only 2 hours after fibronectin’s administration. (31)
B16 Melanoma cells chemically crosslinked to fibronectin altered their tumor producing potential. (32)
Cellular fibronectin produced by CHIFYX, (Formerly Fibrogenex) restores a more normal morphology to a long term malignant ovarian cancer cell line, OVCAR7. Experiment done by Dr. Nellie Auersperg, The University of British Columbia, British Columbia’s Women’s Hospital and Health Centre, Room 2H30, 4500 Oak Street Vancouver, B.C. V6H 3N1 (see copy of photo in appendix)
Redifferentiation of cancer cells is a well known phenomenon when malignant cell are kept long term in in vitro conditions. In fact normal cells kept in vitro often dedifferentiate in vitro and become malignant. (33) A logical conclusion can be drawn from this dynamic reversing phenomenon. That is, that cancer cells can be induced to become normal with the specific factors. From the preceding studies above, the extraordinary evolutionary protein fibronectin is a probable agent that can non-toxically bring this redifferentiating phenomenon into fruition.
From the studies mention above, it can be concluded that cellular fibronectin would be most effective against malignant tissues when place in direct contact with those tissues. Nonetheless, there may be another mode of therapy and that would be by IV injection. It has been recently found that there is a measurable plasma level of Cellular Fibronectin. This cellular fibronectin rises during many pathological conditions. This may be an in place defensive mechanism. (34), (35), (36), ( 37) Therefore cellular fibronectin given IV may not give any immunological or toxic side effects. This type of therapy may have positive results for metastases, leukemias, and lymphomas
THE EXTRACELLULAR MATRIX MOLECULES AS THERAPEUTIC CANCER AGENTS
Cellular fibronectin can be used along with specie specific ECM molecules to restore normal phenotype. The growth and differentiation of an anaplastic glioma cell line, U-343 MG-A was induced to normalcy by the total ECM molecules of normal human leptomeningeal cells. The tumor cells grown on this ECM were profoundly growth inhibited, developed multiple slender cytoplastic processes similar to those of normal astrocytes, and expressed more GFAP per cell than did tumor grown on plastic alone. (38) This is only a small example of what other specific cancer therapies that total specific ECM molecules may be capable of treating.
CONCLUSIONS: RELEVANCE: CLINICAL TRIALS
The ultimate ESSENCE of all the manifested matter in our universe, our planet and all of the contents thereupon including the human specie, is unknowable. Reduction science, although a valuable tool in evaluating biological systems, has limitations. The essential quality of the interactions of all pharmaceutical products as well as biotech products on biological cells and tissues can only be grossly observed. The safety and effectiveness of these products has always been guesswork. The ESSENCE of Cellular fibronectin and the extracellular matrix molecules suggested as therapeutic agents herein are also unknowable. Nonetheless, these molecules have had an extensive evolutionary history that has progressed to present day relevant biological functional significance. The rationale to use them in clinical trials for cancer is self-evident. They are the genuine parts of cells and tissues that have been shown to reverse the cancer phenotype to a more normal phenotype and to inhibit cancer recurrence at the surgical sites. They instruct cellular behavior, are involved with growth, differentiation, tissue repair, do not cause immunological reactions and are non-toxic.
OBTAINING SPECIFIC CELLULAR FIBRONECTINS AND SPECIFIC TOTAL ECM
MOLECULES FOR CLINICAL TRIALS FOR A VARIETY OF CANCERS
Purified Cellular Fibronectin is available for many types of cancer clinical trials. CHIFYX (Formally Fibrogenex) through their proprietary technologies produce a variety of cellular fibronectins. CHIFYX also produces a variety of diverse total ECM molecules. All contain their carbohydrate moieties and are recognized by human tissues as self, because they are self.
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