CAN REGENERATIVE MEDICINE’S THERAPEUTICS CURE CANCERS?
The answer posed by the title should be an unequivocal YES. The rational for this view is based upon an expansive approach, reviewing a myriad of diverse research papers. Starting with the evolution of cells, we further identify the continuum that lead to the dynamic complexities of the modern day cells and tissues that are present in our human organism. A new concept of carcinogenisis is presented. The reversal of the cancerous state utilizing Regenerative Molecules is herein proposed.
Due to the complexities of biological organisms, research tends to specialize in linear compartmentalization in order to ascertain relevant scientific discoveries. The breakthroughs of numerous discoveries have resulted in countless well-documented scientific papers published in hundreds of well-respected scientific journals. However, these well-funded scientific endeavors rarely have clinical application especially in the field of cancer therapeutics. The attempt herein will endeavor to utilize a broad spectrum of diverse research papers in order to attain reasonable protocols for future cancer therapeutics utilizing the technology of regenerative medicine’s therapeutic agents.
Our 4.5 billion-year-old planet had single cell organisms at least 3.5 billion years ago. Cellularly preserved filamentous fossil microorganisms discovered in northwestern Western Australia, whose anatomical cell types are suggestive of cyanobacteria. Therefore, these oxygen-producing photosynthesis organisms may have been extant as early as 3.3 billion to 3.5 billion years ago according to the geological evidence. (1) 3.4 billion-year-old rocks showing microorganism fossils have also been discovered in the Barberton region of South Africa that are similar to the finds in Western Australia. Morphological, geochemical, and isotopic data imply that life was relatively widespread during that early Archean Period. (2) Cyanobacteria, deemed as one of the earliest prokayotes, used as their food source in primitive oceans, sodium bicarbonate, carbon dioxide, and salt water, to produce their own fossilized remains, called stromolites, and molecular oxygen. It is widely recognized that the molecular oxygen released by these prevalent planetary species eventually changed the total worldwide atmosphere. It is further conjectured that the significant amounts of oxygen in the evolving earth’s environment led to the evolutionary explosion of all types of diverse species. (3)
The cells now present in Human beings have had 3.5 billion-years of evolutionary history. Understanding the complexities of all of our biological, chemical, physical, structures, and their various physiological activities has been the daunting task of scientific research for centuries. There have been many breakthroughs in how normal cells and tissues work on gross observational levels. However, at the cellular, sub- cellular, and subatomic levels, the essence of these realms is not this at time knowable. Nonetheless, there have been various therapeutic agents that have helped humans that have become ill with a myriad of clinical conditions. These therapeutic agents help restore their healing functions and allow them to recover full health. However, in the field of cancer, therapeutic breakthroughs do not seem to be forthcoming.
The endeavor herein is to show that our 3.5 billion normal human differentiated cells can produce normal human molecules that some day can be used as therapeutic agents for cancer therapy. These molecules will be identified and the technology to obtain them will be discussed.
THE MATERIAL THAT FOLLOWS WILL NOT BE AN INDEPT RESEARCH STUDY OF THE DYNAMIC COMPLEXITY OF THE BIOLOGICAL AND PHYSIOLOGICAL ACTIVITIES OF HUMAN CELLS AND TISSUES. IT WILL BE A SIMPLIFIED OVERVEIW OF THE EVOLUTIONARY PROCESS THAT BROUGHT THE HUMAN ORGANISM TO THIS TIME IN OUR HISTORY.
ANATOMY OF NORMAL HUMAN CELLS: EVOLVED 3.5 BILLION YEARS
The breakthrough in imaging the actual anatomical structures of cells came in 1976. Before that period cell’s cytoplasm was thought to be all liquid, as staining techniques only showed indistinguishable granular space. In a classic paper, Drs. John Wolosewick and Keith Porter, changed the whole concept of the anatomy of cells. Their new technology was used on a human diploid line WI-38, derived from fetal lungs. Briefly, the cells were grown on plastic coated, carbon-shadowed gold grids. They were fixed with glutaraldehyde, post-fixed with osmium tetroxide, stained with uranyl salts and critical -point dried. Viewed with a high-voltage electron microscope, the dawn of a new era of recognizing the immense complexity of the anatomy of all cells had begun.
Their approach combined with stereo-microscopy (viewing in 3-D) radically extended our knowledge of cellular ultrastructure. For the first time, revealed in 3-dimentions, were nuclei, mitochondria, microfilaments, the endoplasmic reticulum and ribosomes. Further complexities were seen at different magnifications. This epic work initiated expansive research in this field and further showed that in all normal cells, a totally organized anatomy that is unique for each and every differentiated cell type. (4).
The inventor of this technology, Professor Keith R. Porter, is considered by many as the father of biological electron microscopy. He was prominent in the founding of The Journal of Cell Biology, and The American Society of Cell Biology. (5) (6)
BIOLOGICAL ACTIVITIES OF NORMAL CELLS: EVOLVED 3.5 BILLION YEARS.
In 1982, The Cold Spring Harbor Laboratory was the host for The Cold Spring Harbor Symposia on Quantitative Biology; volume XLVI titled “Organization of the Cytoplasm”. Symposium participants from all over the world contributed over 90 papers, compiling over one thousand pages. Herein are some highlights from that ground- breaking conference. Though the papers quoted below are over a quarter of a century old, their insightful research has, to date, not been appreciably exceeded. The work therein confirms the unknowable dynamic complexity of living cells.
A single normal eukaryotic cell contains millions of protein molecules which are continually being synthesized and degraded. How all of these cell specific numbers of molecules are kept constant within a narrow range in unknown. Each differentiated cell type has their specific anatomical complex features. They all display cellular polarity, wherein the nucleus that contains its valuable genetic machinery is almost always located in the most secure anatomical position. Cells are also compartmentalized. It is surmised that each and every compartment is highly specialized. Further, the viscosity of the fluid portion of the cells are different within the membranous compartments and in-between the compartments.
Many diverse proteins spend their entire life in the same compartment in which they were synthesized. Others have to be transported across the hydrophobic barrier of one, or in some cases, two distinct cellular membranes in order to reach their intracellular compartment or to the extracellular site where can exert their particular functions. (7), (8).
Actins are intracellular microfilament proteins that have been shown responsibility for the cell’s shape, stiffness and overall integrity. It is in close communication with the cell’s nucleus. It also has a physical connection with the prominent extracellular protein Fibronectin. Fibronectin is a major cellular attachment molecule of the extracellular matrix that is an important constituent of the cell’s microevironment. (9) Another intercellular protein, Vinculin, is also associated with Actin. These internal complexes have been shown to be associated with extracellular molecules, which in turn renders cells to be adhesive to other cells and to attach to most all substrates; the phenomenon is known as anchorage dependent. Anchorage dependence supports activities such as control of cell growth, differentiation, formation of intercellular junctions, and the activation of metabolic pathways, (10) Cancer cells most often do not display anchorage dependence.
Endocytosis is the process whereby cells obtain their various forms of nutrition and other types of stimuli; Exocytosis is the process whereby cells release highly specialized microenvironmental molecules to their periphery and unwanted materials out of the cells. Coated pits are structures that are contained in the surfaces (plasma membranes) of all animal cells. They are the instruments by which cells selectively internalize macromolecules. The coated pits form buds by the membranes invaginating into cytoplasm forming a coated vessel, with which they carry and release their contents to specific organelles such as lysosomes. Amazingly, 2% of the surface of primary skin fibroblasts is constantly forming coated vesicle. That uptake rate is equivalent to that of the entire cell’s surface within 50 minutes. (10) There is strong evidence that some of these transporting vesicles are recycled many times. In some cases these vesicle may be used as many as 150 time during a 30-hour life span. (11)
The dynamic complexities of the total cell’s activities must include its nucleus.
EUKARYOTIC CELL’S NUCLEUS; EVOLVED 3.5 BILLION YEARS.
Animal cell’s nucleus occupies about 10% of the total volume and appears as a dense, roughly spherical organelle. Enclosed in a double membrane, which separates the cell’s genetic material from the surrounding cytoplasm. Mammalian nuclei have between 3000 to 4000 nuclear pores through which all of the biological activities are initiated.(12) (13)
The genetic material in the form of multiple DNA molecules are organized into structures called chromosomes. During most of the cell cycle these are further organized in a DNA- protein complex known as chromatin. During cell division the chromatin can be seen to form the defined double chromosome alignments that will divide equally when the cells split into two sister cells, assuring that each cell will contain identical genetic structures. There are two types of chromatin. Euchromatin is a less compact DNA form that contains genes that are frequently expressed by the cell. Heterochromatin are more compact complexes with the DNA that are infrequently transcribed.
A suborganelle within the nucleus is the nucleolus. It produces the ribosomes that are the specialized dual proteins upon which all molecules are synthesized within the cell’s cytoplasm. The assembled ribosomal sub-units are the largest structures that are able to pass through the nuclear pores into the cytoplasm. Some ribosomes reside free in the semi-fluid portion of the cytoplasm, while the majority are bound to rough endoplasmic reticulum organelle. The bound ribosomes give this organelle its rough appearance. Proteins that are formed on the free ribosomes usually are used within the cell. The bound ribosomes produce polypeptide chains that are transported by vesicles to the cell’s plasma membrane or are expelled from the cell via exocytosis. These proteins may become part of the extracellular matrix that compose the microenvironment of that particular cell. Each differentiated cell type produces its own specific proteins. Some will be utilized internally; others will be transported extracellularly to become part of their specific microenvironments.(14)
Gene expression first involves transcription. DNA is used as a template to produce a single strand of RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. These transcribing RNA’s are called messenger RNA’s (mRNA), which then needs to be translated by ribosomes. The cytoplasm of normal cells are filled with thousands of diverse amino acids which will be used by the ribosomes to make peptides which are the major constituents of proteins. The ribosomes carry out the chemical reactions to add new amino acids to a growing peptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complimentary to the codon that it reads; the tRNA is also attached to the amino acid specified by the complimentary codon. When the tRNA binds to its complimentary codon in a mRNA strand the ribosome ligates (binds) its amino acid cargo to the new growing polypeptide chain. After its synthesis the new protein must fold into its active three-dimensional structure before it can carry out its cellular function. (15) However, it will need assistance from the Golgi Apparatus.
The Golgi apparatus’s primary function is to process and package macromolecules, such as proteins and lipids, after their original synthesis. It is a multi-layered processing factory wherein the molecules move into its entrance call the “cis”, and eventually exit through the “trans”. In most human cells the Golgi is a stacked four-layer organelle wherein the macromolecules are enzymatically modified into their exacting structures. It further acts like a post office whereby it packages and labels each particular macromolecule and sends them to their ultimate normal specified destination. (16) The molecules are transported to their destinations by a series of at least three different types of transport vehicles known as vesicles.(17)
To reiterate, the specific molecules that are transported through the normal cell’s membranes to form its microenvironmental tissues are supremely important to the cells. They form the informational highway that the internal genetic structures rely upon to instruct cell and tissue behavior. These specifically organized structures play vital roles in differentiation, proliferation, migration, polarity and survival.
MICROENVIRONMENT OF CELLS; EVOLVED 3.5 BILLION YEARS
The microenvironment of all normal human cells is as important as the cell’s internal anatomy. In fact a normal cell’s survival is completely dependent upon itsmicroenvironment. What is the composition of a normal cell’s microenvironment? In this paper the microenvironmet’s collective molecular structure will be heretofore called the Extracellular Matrix (ECM). The ECM has been considered the evolutionary structure that made multicellular life possible. Present day differentiated normal cells produce their own specific ECM molecules, after which they depend upon them for their differentiation, proliferation, migratory activities, polarity, survival, and as an information entity.(18)
There are hundreds of ECM proteins encoded in vertebrate genomes. Each cell type encodes its specific ECM for its own microenvironment. The cells thereafter depend upon this dynamic complex molecular entity for its very existence. Although the research of the ECM has been going on for decades, its complexity is still enigmatic, other than the realization of its great importance to normal cell and normal tissue survival.(19)
WHEN CELLS AND TISSUES BECOME MALIGNANT THE NORMAL ARRANGEMENT OF THE ECM IS COMPLETELY COMPROMIZED.
CARCINOGENESIS IN CELLS & TISSUES; EVOLVED 3.5 BILLION YEARS
There seems to be a general agreement amongst cancer researchers that about 10% of diagnosed cancers may have a genetic parameter. Without dwelling upon this conclusion, it is problematical when familial genes, that are deemed the culprits that render the propensities for tumor cell development, do not always prove that individuals with those particular genes get malignancies. There is constant speculation on the instigating factors that induce genetic related cancers. And, the complete dynamics concerning genetic cancers are still speculative. The major conceptual thinking in the genetic diagnostic community is that the genetic machinery has become in some manner flawed. The result of this genetic inadequacy results in tumor formation.
This paper will endeavor to address carsinogenesis of the other 90% of cancers that are not deemed genetic. First, we must recognize that there are lists hundreds of environmental toxins that are known carcinogenic agents. A substantial number of these listed toxins have been shown by in vivo research to cause a myriad of malignancies in many species of experiment animals. In cancer patients, there are absolute infallible statistics that demonstrate that certain toxins cause specific cancers, such as lung cancers, (tobacco smoke), mesothelioma (asbestos), and the like. (20) The question now becomes, how do these toxic materials cause similar cancers in the organs that they affect? Why do malignancies in specific organs that may be caused by different toxins appear to be biologically similar? Why don’t these very toxic materials kill cells? How does their presence cause malignancies? Why does it usually take a relatively long period of contact with these toxic agents before cells become malignent. The answer to these questions may be explained by the protective anatomy of cells that have had 3.5 billion years of evolutionary history.
The first line of defense of human tissues and cells are their microenvironmental structures. All fluids whether toxic or beneficial to human tissues are obliged to negotiate the barriers of tissue and cell membranes. The evolutionary experience of these structures try to attenuate the “bad stuff” while allowing the proper recognized nutritional, biological, and chemical agents to cross into cells. The endocytotic abilities of cells to enclose the proper exogenous materials have been explained above. However, when the toxic agents eventually cross the cellular membranes, they further encounter other protective disciplines that normal cells are able to deploy. The cytoplasm’s fluids have various viscosities, and there is a myriad compartments that may be impenetrable to various toxin. However, the real damages to those cells that have had toxic materials that finally enter into cell are the “DISRUPTION OF THE NOMAL FLOW OF PROTEIN LADEN VESICLES THAT FAIL TO REACH THEIR PROGRAMMED DESTINATIONS.” (21)(22) THAT DISRUPTION INITIATES CARCINOGENESIS.
The microenvironmental feedback mechanism to the cell’s nucleus has been compromised. What action do cells that have had a 3.5 billion evolutionary history do given these compromising circumstances? It has programmed into its genetic machinery the ability to SURVIVE. The nucleus changes its production of proteins, hormones, and enzymes. It changes the cell’s shape. It changes its agenda. It is no longer subservient to its host human organism. It is transforming into a more primitive type of cell. It has the capacity to grow faster. It does not die as often as its former self. It can join with other transformed sister cells to grow faster and be bulkier than when they were normal cells. They produce active destructive enzymes that destroy their external normal structural tissues and grow into the destroyed areas. Their adhesive proteins are not any longer produced or if they are produced these specific molecules cannot reach their normal programmed destinations. The differentiation state of those cells and tissues has ended. (23) As a total defiant act to their original host organism, they detach themselves individually or in small groups and move throughout the host organism and take up their malignant residency elsewhere. This is the dreaded metatastic aspect of cancer.
The observer is obliged to recognize that CANCER IS A SURVIVAL MECHANISM OF NORMAN HUMAN CELLS. The toxic material does not reach the nuclei’s protected genetic machinery. It is apparent the genetic reaction to the toxic invasion results in a program of survival. Unfortunately, that survival program leads to human cancers.
There has been a tendency of cancer researcher to try to analyze malignant cells and tissues in order to ascertain their biological and chemical activities and their compositions. This line of research has not led to breakthroughs for treatment of malignant cells and tissues. Can there be another approach in designing protocols for non-toxic therapeutic agents that would be able to stop the spread of cancer, and to reverse the malignant state? Regenerative Medicine’s therapeutic agents may hold the answer.
REVERSING CANCER IN CELLS & TISSUES; EVOLVED 3.5 BILLION YEARS
Cancer therapy would be best served by the education of the public worldwide, as to the causes of most cancers. Preventing cancers is a viable approach for the medical professions. There are substantial cancer epidemiological studies that show irrefutably that most cancers are avoidable. However, when a diagnosis of cancer is declared by a medical professional, the next step should be is to separate that individual from possible toxic materials in their close environment. That must be an obligatory agenda before determining which therapeutic agents will be prescribed.
Numerous microbiologists have recognized that in many instances, long term-term cancer cells grown in vitro become normal. Conversely, it has been seen that normal cells grown in vitro can become malignant, and if these cells are injected into susceptible animals they tumors form. The formerly cancerous normalized cells do not cause cancers when injected into test animals. What insights can we ascertain from this extraordinary happenstance? ANSWER: THE CANCEROUS STATE IS REVERABLE! (24)
The growth and differentiation of an anaplastic glioma cell line, U-343 MA-A was induced to normalcy by the total ECM 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 tumors grown of plastic alone. (25)
CELLULAR FIBRONECTIN, WHOSE MODULAR PARTS HAVE AN EVOLUTIONARY HISTORY OF OVER 2 BILLION YEARS HAS SHOWN TO BE A PROBABLE VALUABLE CANCER THERAPEUTIC AGENT:
+ In an in vivo mouse study, cellular fibronectin has been shown to inhibit cancer recurrence at surgical sites. Cancer recurrence is a continuing problem for all types of cancer surgeries. Breast, colon, and oral cancers are prime examples. (26)
+ Cellular fibronectin was 50-fold more active in restoring a more normal morphology to transformed cell originally missing the cellular fibronectin molecule, than plasma fibronectin. (27)
+ 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, (28)
+ Exogenous fibronectin restores the missing fibronectin matrix and receptor organization of SV40-transformed human fibroblasts, thereby inducing these transformed cells to a more normal phenotype, (29)
+ Fibronectin when used as an adhesive substrate on a human monocytic leukemia cell line THP-1 resulted in changes in both call 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 correlated with the adhesion process. (30)
+ A study to test the effects of fibronectin on tumor cell proliferation, adherence, and invasiveness had the following results. The growth of the 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 cell’s fibronectin expression and its biological behavior. With increased fibronectin levels, malignant phenotype is changed and invasive ability is inhibited. (31)
+ In a human breast cancer migration and invasion study, it found that purified intact fibronectin was found to inhibit invasiveness. (32)
+ 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 the administration of the fibronectin. (33)
+ B16 Melanoma cells chemically linked to fibronectin altered their tumor producing potential. (34)
+ Cellular fibronectin produced by CHIFYX (Formerly Fibrogenex) restored a more normal morphology to a long-term ovarian cancer cell line, OVCAR7. Experiment done by Dr. Nelly Auersperg, The University of British Columbia, British Columbia’s Women’s Hospital and Health Care, Room 2H30, 4500 Oak Street, Vancouver, B.C. V6H 3N1.(35)
RESTORING THE MICROENVIRONMENT OF MALIGNANT CELLS
It is evident as stated in the previous section that the cancerous state has already been experimentally shown to be reversible. Which Regenerative Medicine’s therapeutic agents would best be utilized clinically for cancer therapy? A first choice would the singular macromolecule Cellular Fibronectin. It would be prudent to utilize the cellular fibronectin purified from the normal cell type to treat the same malignant cell type in the cancer patient. Cellular fibronectin may have slightly differing structural domains in different differentiated cells. Matching cell types would assure clinical expediency.
Cellular fibronectin, as a single protein can regulate such functions as cell adhesion, cell shape, cell migration, and cell surface architecture. Its research led to the discovery of the” Integrins”, the major family of protein receptors on the cell surfaces that form the transmembrane link between glycoproteins and the internal structures of cells. The integrins are structures that help to 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) with 10, far more than any other protein.
The vast family of collagens composes over 30% of human structural proteins. Two of the most prominent, Collagens I and III come into fruition “only” if its adjacent cellular fibronectin’s preformed fibril matrix is present. (36) Further, cellular fibronectin’s polymerization acts as a “switch” that controls the organization and composition of the ECM and the cell-matrix adhesion sites. This ability provides cells with a means of precisely controlling cell ECM signaling events that regulate many aspects of cell behavior including proliferation, migration, and differentiation. (37) Cellular fibronectin fulfills the role of “THE ORCHESTRA LEADER OF THE EXTRACELLULAR MATRIX” Clinically, cellular fibronectin could prove to be a valuable cancer therapeutic agent.
Specific total Extracellular Matrix molecules should be considered as Regenerative Medicine’s therapeutic agents that could restore their missing counter parts in malignant tissues. These complete entities will be purified from the normal cell cultures that are the exact cells that are now malignant in the cancer patient. The rationale herein is to utilize these molecules to reestablish the microenvironment of the malignant cell and tissues. Molecules taken from human cultures and applied to human tissues have never given any untoward side effect. These molecules will also have relevance in stem cell therapy.
The exacting clinical applications of the molecules named herein will be part of the new protocol designs for their future clinical trials.
THE TECHNOLOGY FOR PURIFYING REGENERATIVE MEDICINES THERAPEUTIC AGENTS.
Large Scale Tissue Culture Technology has already successfully been able to purify the molecules referred to in this paper. CHIFYX, a Regenerative Medicine company has already purified several types of Cellular Fibronectins and some of their related total ECM. One of their cellular fibronectins was used in a FDA, IRB approved clinical trial at UCLA. Its fibronectin product proved safe and effective in that trial in inducing chronic diseased periodontal tissues back to normalcy. The molecules purified by CHIFYX’s proprietary technology all contain their normal carbohydrate moieties and are recognized by human tissues as self, BECAUSE THEY ARE SELF.
The contention herein is to point out that heretofore there has been a continuing failure within the cancer research community to provide treatments and cures for this devastating condition. Contributing to that failure is the total lack of recognition of a survival capacity of normal cell when confronted with carcinogenic agents. This ability is wrongly deemed as a pathological state. Wherein it is actually a survival state. The complex dynamics of a normal cell’s anatomy, biology, physiology, and structural integrity has been discounted in designs of therapeutic agents. Kill cancer cells has been the paradigm for many decades. It has been a total failure with horrendous side effects that hastened many painful deaths. Limiting a tumors blood supply by toxic anti vascular endothelial growth factors as therapeutic agents for the past two decades has failed. A substancial component of that failure is the recognition that our normal human cells and tissues have had a 3.5 billion-year survival history of evolution.
The proposals herein state that new non-toxic therapeutic agents could help in restoring the microenvironment of malignant tissues back to their normal state. The missing molecules that comprised the microenvironment of normal cells must be applied back to those tissue and cells that have become malignant. These complexes will induce those cells and tissue back to their normal state. THIS IS THE NEW REGENERATIVE MEDICINE. THIS IS THE NEW PARADIGM FOR CANCER THERAPY.
1. Schopf JW, and Packer BM. Early Archean (3.3-billion to 3.5-billion-year-old microfossils from Warrawoona Group, Australia. Science. 1987 Jul 3;237: 70-3
2. Altermann W, and Kasmierczak J. Archean microfossils: a reappraisal of early life on Earth. Res Microbiol. 2003 Nov; 154(9): 611-7
3. Ohno S. The reason for as well as the consequence of the Cambrian explosion of animal evolution. J Mol Evol. 1997; 44 Suppl 1: S23-7
4. Wolosewick JJ and Porter KR. Stereo high-voltage electron microscopy of whole cells of the human diploid linee, WI-38. Am J Anat. 1976; 147(3); 303-23
5. Powell K and Leslie M. Porterplasm and the microtrabecular lattice. Archive, The Journal of Cell Biology. 170 No. 6. 2005
6. Wolosewick JJ. Joining the trek with Keith up the Serpentine Road–the lattice from another perspective. Biology of the Cell 94 (2203) 557-559
7. Blobel G. Regulation of Intercellular Protein Traffic. Cold Spring Harbor Symposia on Quantitative Biology Vol. XLVI Organization of the Cytoplasm. 7-16
8. Wojcieszyn JW, et al. Measurements of the Diffusion of Macromolecules Ijected into the cytoplasm of Living Cells. Ibid 39-44
9. Hynes RO et al. Relationship between Microfilaments, Cell-substrtum Adhesion, and Fibronectin. Ibid 659-670
10. Bretscher MS. Surface Uptake by Fibroblasts and its Consequences. Ibib 707-712
11. Brown MS et al. Recycling of Cell-surface Receptors: Observations from the LDL Receptor System. Ibid 713-722
12. Alberts, B et al. ed(2002) Molecular Biology of the Cell, Chapter 4 pages 191-234. (4th ed.) Garland Science
13. Paine P, et al. Nuclear envelope permeability. 1975 Nature 254(5496): 109-114
14. Hernandez-Verdun D, Nucleolus from structure to dynamics. Histochem. Cell Biol. 2006 125 (125) 127-137
15. Nicolini CL. (1997) Genome Structure and Function: From Chromosomes Characterization to Gene Technology. Springer ISBN
16. Glick BS. Organization of the Golgi Apparatus. Current Opinion in Cell Biology, 2003. 12: p 450-456
17. Rothman JE The Golgi Apparatus, Coated Vesicles, and Sorting Problems, Cold Spring Harbor Symposia on Quantitative Biology Vol.XLVI Organization of the Cytoplasm. 797-805
18. Streuli C Extracellular matrix remodeling and cellular differentiation. Current Opinion in Cell Biology 1999, 11: 634-640
19. Hynes RO The extracellular matrix: not just pretty fibrils. Science 2009 Nov 27: 326 (5957): 1216-9
20. Doll R and Peto R. The Causes of Cancer. Oxford University , 1981
21. Uchida N, et al. Kinetic Studies of the Intracellular Transport of Procollagen and Fibronectin in Human Fibroblasts. The Journal of Biological Chemistry Vol. 255, No. 18 Sept. 25, p.8638-8644, 1980
22. Arumugham RG and Tanzer ML. Abnormal Glycosylation of Human Cellular Fibronectin in the Presence of Swainsonine. The Journal of Biological Chemistry Vol. 258, No. 19, Oct. 10 p.11883-11889, 1980
23. Witteisberger SC et al. Progressive Loss of Shape-Responsive Metabolic Controls in Cell with Increasingly Transformed Phenotype. Cell Vol.24, p. 859-866, June 1981
24. Auersperg N and Finger CV. The differentiation and organization of tumors in vitro. Neoplasm and Cell Differentiation, Charger, Basel 1974: p. 279-318
25. Rutka JT Effects of Extracellular Matrix Proteins on the Growth and Differentiation of an Anaplastic Glioma Cell Line The K.G. McKENZIE AWARD LECTURE Can. J Neurol. Sci.1986: 13: 301-306
26. Murthy CR et al. The role of fibronectin in tumor implantation at surgical sites. Cline Exp. Metastasis. 1993. 11. P.159-173
27. Yamada KM and Kennedy DWG. Fibroblast Cellular and Plasma Fibronectins are similar but not indentical. The journal of Cell Biology. Vol.80, 1979 pp. 492-498
28. Wen-Tien Hen et al. Reulation of fibronectin receptor distribution by transformation, exogenous fibronectin, and synthetic peptides. J Cell Biology 1986 Nov.; 105: p. 1649-61
29. Roman J. The fibronectin receptor is organized by extracellular matrix fibronectin: Implications for oncogenic transformation and for cell recognition of fibronectin matrices. The Journal of Cell Biology, Vol. 108 1989: p. 2529-43
30. Shiva T. et al. Adhesion of human monocyte leukemia cell line to extracellular matrix is associated with cell differentiation and internal modification Biomedical Research Vol. 16 (4) p. 263-271 199
31. Gang W, et al. Effects of different expression levels of fibronetin on biological behavior of tumor cells. Gong Cue Sea Hz 1998 Jun; 78 (6) p. 430-9
32. Beam LT. And Steed P. Reproduction state of rat mammary gland storm modulates human breast cancer cell migration and invasion. Cancer Res. 2000 Jul 1; 60 (13);p3414-8
33. Singer II, Fibronexus formation is an early event during fibronectin-induced restoration of normal morphology and substrate adhesion patterns in transformed hamster fibroblasts. J Cell Sci. 1982 Aug: 56: p. 1-20
34. Bowers JCL et al. Altered characteristics of B-16 melanoma cell induced by chemically crosslinking fibronectin to cell surfaces. J. surge Once 1985 May; 29 (1): 11-14
35. Dr. Nelly Auersperg, Personal communication. Photo upon request
36. Velling T et al. Polymerization of type I and III collagens is dependent on fibronectin enhanced by integrins alpha 11beta 1 and alpha 2beta 1, J Biol Chem. 2002 Oct 4; 277 (40); 37377-81. Epub 2002 Jul 26
37. Sottile J, and Hocking DC. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions. Mol Biol Cell. 2002 Oct; !3 (10) ; 3546-59
Picture of cellular fibronectin reversing a long standing ovarian cancer cell line.