Mary is a 46-year-old mother of two daughters, ages 17 and 19. Eight years ago she was diagnosed with breast cancer, and after a conventional course of chemotherapy followed by radiation, the cancer was driven into remission. Lately she is having increasingly severe back pains. At a routine check-up, she mentions the pains to her surgeon, who performs a bone scan. The scan reveals several "hot spots," regions of increased metabolic activity in her spinal column. The diagnosis made on a biopsy of one of these hot spots catches her completely off guard: metastasis of her breast cancer.

[Karl:  Note that the original cancer was never "cured," but "driven into remission."  The word "cure" is hardly ever used in relation to cancer because it is so common for what happened to Mary to happen to anyone.  You get cancer, there is some treatment, there is then no further trace of the cancer, but it is still there, spreading, even if only slowly, until it shows up in some different place.   The PET scan referenced in my note above can "see" something only as big as about five millimeters.  A few cancer carrying cells would be much, much smaller than five millimeters.  Cancer grows quite slowly when it starts, so there can be this spreading from a tiny beginning, not discovered for years, even.

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Patients like Mary inevitably ask the question: Why me? But for those of us who study what cancer is, its development and spread, the question is rather: Why at all?

[Karl:  Here is where these authors show their "true colors." I consider "free radicals" to be the sole cause of cancer, yet these authors do not even mention the words.  It is common for scientists to use the grammatical "passive voice" of a verb to hide the causative agent.

So, below, the authors say that the "cells become disorganized."  The verb in green here is in the passive voice and hides from the reader what exactly is CAUSING this "disorganization."  Thus, typical of most science, paid for by drug companies, or where the authors are looking for drug company jobs or grants, they have learned to NEVER touch on that which the drug companies cannot touch!  No drug can remove or neutralize "free radicals," so the drug companies don't want to hear about them.

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The simple answer is that in cancer the genes and chromosomes of cells become disorganized, leading them to enact genetic programs far different from the intended normal program. It has often been noted that cancer cells are unusual because they are undifferentiated; that is, they lose functions and, as a result, fail to fully develop the characteristics and proper activities of mature cells of their type. Quite remarkably, metastatic cancer cells gain new functions, taking on characteristics unrelated to the normal, often sedentary cell type.

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Most cells are designed to remain fixed in their organs in order to perform the specialized activities for which they are particularly adapted. They are held tightly in place by molecular tethers that link them with the other cells and the proteinaceous matrix in that tissue. Clearly, these cells are not meant to roam around the body and take up residence in other organs. Metastatic cancer cells are altered in such a way that they can break those bonds. Further cellular remodeling allows metastatic cells to chew through the proteinaceous walls that line tissues and blood vessels and quite literally walk away from their parent organ to invade other tissues and organs.

[Karl:   This is rather far-out stuff.  Here is yet another "Greek language" explanation of this word "tether" and how it applies to metastasis:

The major barrier for invading tumour cells, migrating leukocytes, and growing blood vessels (endothelial cells) is the basement membrane (BM) that surrounds the vessels, and the extracellular matrix (ECM) which forms a scaffold in tissues to hold cells together.

The BM and ECM are composed of an interlocking network of proteins and complex carbohydrates, and for cells to breach this barrier, they deploy a battery of enzymes that break down these proteins and carbohydrate components.

The major carbohydrate is heparan sulphate (HS), which acts as the glue to maintain the integrity of the BM and ECM. The enzyme responsible for cleaving HS, heparanase, has been shown to play a key role in the degradation of the BM and ECM, and its activity strongly correlates with the metastatic capacity of tumour cells and the migratory capacity of leukocytes and endothelial cells.

HS in the ECM also binds a number of angiogenic growth factors, and the release of these by heparanase promotes angiogenesis and tumour growth. Following our recent cloning of mammalian heparanase, we have been able to develop the tools to investigate how heparanase functions at the molecular level and to directly determine the role of heparanase in cell invasion, angiogenesis and inflammation. (source)

You can take from the above, in simple terms, that cancer normally starts in normal cells, and most cells are fixed in place by something called "tethers" or "bindings."  When a cancer cell starts growing beyond the size and supply of nourishment (mostly sugar) it demonstrates a very strong urge to "survive" and so it works to "break loose" from its restrictive area and "move" to a new location.  This may not be scientific, but it is probably helpful in understanding the process.

The so-called scientists who wrote this article MUST have known about the generally secret research being done (in the open, but not publicized) which has "exactly" spotted the cause of the "breaking loose" and the "eating through" the shell that surrounds the cancer.  If you want the full story, and have the time to study, you'll be spending many hours on these pages!

If it were not so potentially damaging, metastasis might be just an interesting cellular oddity. But the fact is that the metastatic tumor is often more dangerous than the original, or primary, tumor. Metastatic cancer cells crowd out normal cells in the tissue and deprive them of nutrients. In effect, the metastatic cells starve and displace functional cells. This can be lethal when the organ—or organs, since cancer cells can go almost anywhere and often end up in several new organs—can no longer perform its vital functions.

Over the past few decades, biologists have become ever more precise in determining the genetic, biochemical and cellular changes that drive a cell

first to become cancerous and

then to become metastatic.

And new discoveries are being reported daily. So, although not all of the details are entirely known, a comprehensive picture of these alterations is emerging. Each new piece of information not only contributes to this overall picture; it also provides a site of potential therapeutic intervention to inhibit the progression of cancer—if not, someday, to eliminate it entirely.

Carcinogenesis

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A diagnosis of cancer marks an abrupt change in the life of the patient. A line of demarcation has been drawn. Life seems to be separated into before and after. Yet the events that lead a cell to become cancerous take place gradually, sometimes over periods that can exceed 10 years. During this lengthy evolution, cells undergoing cancerous transformation accumulate genetic abnormalities, one important consequence of which is that cellular growth becomes deregulated.

[Karl Note:  This is important, even vital, data.  More people need to realize that they should be living a life style that PREVENTS cancer, not wait until 10 years of slow growth springs upon them! Amazingly "chelation therapy," particularly "oral chelation therapy" has a tremendous success record on this line.

The number of cells in normal tissue is strictly controlled by a system of checks and balances. Cells that are too old, that fail to function properly or that are otherwise no longer needed are programmed to die, a process known as apoptosis. These cells are replaced by new cells, derived from primitive precursors, also called stem cells, that divide and then differentiate into the mature cell type that performs a specific function. In time, these too undergo apoptosis, only to be replaced by younger cells.

Cell death does not take place because a cell just falls apart. Rather it is the result of a carefully controlled genetic program. Given the proper signals, particular genes are activated that encode proteins that carry out the cellular suicide.

[Karl Note: This author has said it, but it is worth repeating -- what a fascinating thing it is for a free radical to CHANGE a cell so that it "lives longer" than it should!  This could be a clear philosophical signal that "death" has a vital role to play in "life!"

Not all cells undergo apoptosis. There is, in fact, a striking variation in the longevity of different cell types. Nerve and muscle cells, for example, are extremely long-lived—if all goes well, they endure for the entire life of the individual. Once these cells reach their fully mature state they can no longer divide, and it is unlikely that there are populations of stem cells that can generate replacements when they die.

Other cells are actually designed to die shortly after reaching maturity. Often these are the cells that turn over frequently, such as skin cells, or the epithelial lining of the digestive system. The epithelial cells lining the digestive tract mucosa live for a maximum of four days after reaching maturity. High-turnover tissues are endowed with a population of stem cells ready to replenish their respective tissues with mature cells, as older cells are sloughed off, used up or eliminated. For example, stem cells in the bone marrow divide continuously to provide sufficient numbers of blood cells. Similarly, the stem cells in the digestive tract are constantly dividing to replace worn-out mucosal epithelial cells.

Some tissues maintain cell-growth rates intermediate between these two extreme scenarios. For example, under normal circumstances, cell division in the liver takes place at a very low rate: At any given time, only one in 10,000 liver cells is dividing. But cell-division rates can be driven up when needed, for instance, to replace cells damaged by viral infection or removed by surgery.

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Clearly, then, maintaining the proper number of cells in any tissue requires a delicate balance between cellular production and elimination. Essential to this balance is apoptotic cell loss on one hand and cell division on the other. When an excess of cells is produced by unrestrained cell division, or when too few cells are eliminated by apoptosis, an overabundance of cells accumulates in the tissue. This basically describes the situation in cancer.

Regulating Proliferation

As with all cellular functions, a cell's life and death are under strict genetic control. These genes encode proteins that sense growth signals from the environment, or drive the cell through its replicative cycle and check for cellular and genetic abnormalities. Some of these regulatory proteins make the necessary corrections to damaged genes. Other proteins direct the cell to exit the cell cycle in order to differentiate. Still other proteins remove old or defective cells from the replicative cycle and send them en route to apoptosis.

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It stands to reason that if any of these genes or the proteins they encode become faulty, the cell-division cycle will become abnormal.

[Karl Note:  Again, note the "careful" absence of any reference to a causative agent -- such as the free radical!

For example, alterations to the series of proteins that detects external growth cues can lead to an abnormally prolonged growth cue. Problems with the proteins that regulate the cell cycle can, likewise, maintain cells in a proliferative mode when they normally would exit the cycle and start to differentiate and mature.

In recent years, scientists have found that in the majority of cancer cells, one or several of these growth-regulatory genes is either missing or defective. It should be noted that all of these genes, when functioning properly, are crucial in maintaining the normal growth characteristics for each cell type. These genes only promote cancer when they become mutated or altered.

[Karl Note:  Again, how amazing that the simple fact that a cell can "be missing or defective" is written without a thought of causation.  Surely a true scientist would wonder, "Why!"  Can they not at least look at the possibility that a free radical could, and actually does, cause this damage?

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Cells on their way to becoming cancerous accumulate a number of genetic and chromosomal abnormalities, each of which in some way pushes the cell further in the direction of unrestricted growth. At first, clusters of genetically identical cells are formed, each cell dividing with less restraint than its normal neighbors. This cluster does not at this point constitute a tumor.

When the cell mass attains a diameter of about 2 millimeters, the cells emit signals that recruit surrounding connective tissue and vascular cells to the tumor and induce them to grow into blood vessels.

[Karl Note:  Realize that the PET scan can only see something as big as 5 mm, so these cancerous beginnings are NOT seen with the usual tests.  When a cell mass starts creating its own "blood vessel system" within it, that is the preparing for the time when the usual body supply of blood won't reach these cells.  At this point the mass of cells is still depending on the oxygen in the blood for life.  That soon changes!

The cell mass literally stimulates the growth of its own blood supply from existing blood vessels, a process called angiogenesis.

[Karl Note:  This term become popular when "shark cartilage" started to be the item to prevent cancer.  That was because it was "found" that sharks never got cancer, it was also realized that sharks did not have "bones," but had cartilage and that there was something about shark cartilage which prevented this action of "angiogenesis."

There is some evidence that angiogenesis is probably initiated because cells in the mass, especially those in the interior, become starved for oxygen. In any event, once the blood supply is in place, the cell mass can import oxygen and the nutrients it needs to keep growing. Furthermore, the cells now have a conduit through which they can escape and invade other tissues. Angiogenesis seems to have an additional consequence. Connective tissue surrounding blood vessels release factors (as do the vascular cells) that stimulate the growth and motility of cancer cells. Strange as this may sound, cancer can only develop if the cancer cells are adequately supported by host tissues.

Escape

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The escape of cancer cells is not a trivial matter. As mentioned above, most normal cells are tightly hooked in place by chemical bonds linking them to neighboring cells, to the surrounding connective tissue matrix—the mortar of tissues—or both. This is especially true of the epithelial cells that line many organs and from which the majority of cancers arise. The cells are held in place by large molecules on their surfaces that connect with similar proteins on neighboring cells or with proteins in the matrix. In addition to these molecular tethers, most normal cells simply lack the migratory machinery of mobile cells.

The word "matrix" used here assumes vital importance, much more than given by these authors.  If this "matrix" degrades, it loses its ability to hold things together.  So, the body can produce "matrix degradation inhibitors!"

These items "inhibit" the "degradation" of the "matrix."  That is astounding -- it is central to all cancer research and treatment, but not allowed into the public arena.

These are special forms of enzymes, made, of course, from protein, but the special thing about these enzymes is that they don't exist without an atom of METAL in the molecule!  This is well accepted, but little known!

That METAL allows these enzymes to function to INHIBIT the destruction or "degradation" of the matrix.  When that metal atom, which MUST be there for the enzyme to work, -- when that metal atom changes to a free radical, THEN the enzyme is no longer capable of protecting the matrix.  The matrix "degrades" and the cancer cells break free -- to spread.  This is the truth that is being deliberately kept from you by drug companies who haven't figured out yet how to do something about that "metal atom, free radical" with a drug!

Something CAN be done about it with oral chelation! But, you won't catch the drug companies admitting that!

There are, of course, some important exceptions, most notably the white blood cells that constitute the immune system. These are designed to migrate out of the blood stream and into tissues to fight infection. In order for sedentary cells to metastasize, they must lose their adhesive connections and take on the migratory properties usually restricted to white-blood cells.

[Karl Note:  Do not miss the important information and explanation of the image by clicking on the image of the white blood cell.

The text which follows is FULL of technical references which I have NOT tried to explain further.  You can read this type of stuff and simply realize that there are activities going on within a cell that you can appreciate without understanding.   Don't sweat it!

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Figure 3.   Cycle of events leading to cell division is under strict genetic control. Resting cells are in the phase called Gap₀ (G₀).

During this period cells cannot divide, but they can differentiate by maturing and taking on the functions of the mature cell type.

When cells receive external cues to divide they enter the cycle at the Gap₁ (G₁) phase.

During G₁, cells manufacture cellular components, such as RNA and proteins, in preparation for division.

After a time, the cells enter the Synthesis (S) phase in which the cell's DNA is duplicated.

During the next phase, Gap₂ (G₂), the cell continues to manufacture proteins and RNA.

Finally, the cell undergoes Mitosis (M), during which each daughter cell receives a complete set of the cell’s genes, along with all of the other constituents it needs to function and mature.

To ensure that cell division equals apoptotic cell loss the cell’s response to growth cues is regulated, for example, by the protein Myc, encoded by the gene c-myc, which exerts its effects during the G₁ phase of the cycle.

In order that DNA be faithfully duplicated, checkpoints exist at certain steps of the cell cycle. The p53 protein mediates a checkpoint when the cell enters the S phase.

If all is well, the cell continues with the cycle. But if the DNA is damaged, the cell cycle is stopped to allow for DNA repair.

If the damage is so severe that it cannot be fixed, the cell exits the cycle and instead undergoes apoptosis.

Mutations in the c-myc gene, in the p53 gene or in any of the many other regulatory genes, or the genes that encode proteins that correct defects in DNA, alter the cell cycle. Alterations lead the cell to proceed through the cell cycle with damaged DNA, which contributes to the kinds of chromosomal anomalies seen in Figure 2.

[Karl Note:  Again these authors talk about "mutations" without ever even breathing the words "free radicals."  It is impossible to understand cancer fully without understanding "free radicals."  Perhaps another reason why they don't mention "free radicals" is that they know that both chemotherapy and radiation are designed to CREATE free radicals in your body, and that free radicals are killers.   Any alternative cancer therapy that does NOT explain ITS role in handling free radicals may "work" but doesn't have the type of full explanation that science is capable of providing.

These in turn lead to further deregulation of the cell cycle such that cellular proliferation is excessive, and apoptosis reduced. The net effect is an overabundance of cells, which is basically the situation in cancer.

Sticking Together, Coming Apart

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The impact of cellular adhesion in cancer is most clearly manifest in carcinomas—cancers of epithelial cells.

Epithelial cells exhibit a rich variety of molecular interconnections. One of these is a very specific cell-membrane structure called the adherence junction.

Karl Note:  If you want more technical data about these "junctions," read here and click for the source.

"We wanted to understand the molecular mechanisms that enable epithelial cells to bind to each other in order to form an impermeable barrier," said Valeri Vasioukhin, Ph.D., a postdoctoral fellow in the lab of Elaine Fuchs, Ph.D., Amgen Professor of molecular genetics & cell biology and biochemistry & molecular biology. Fuchs is an expert on epithelial cells and skin diseases. (source)

Primarily responsible for the junction is E-cadherin, a large protein that spans the membrane such that one end of the protein pokes out of the cell's surface, while the other end projects into the cell's interior. The external portion of E-cadherin forms interlocking bonds--like the teeth of a zipper—with E-cadherin molecules on neighboring cells. The internal portion hooks into the cell's interior protein skeleton, called the cytoskeleton. Recently, the proteins linking E-cadherin molecules to the cytoskeleton have been identified. These proteins are called catenins.

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Before a cell can even start to move about, it first must break this complex, multidimensional interlocking structure. The adherence junction must be disassembled. This might be achieved in one of three ways.

First, an alteration [notice the absent reference to free radicals] in the structure of E-cadherin could be introduced that would prohibit it from forming proper connections. [This would be a change that inhibits matrix function, or a change which CREATES something that destroys the matrix!] Such an alteration would imply that the gene encoding E-cadherin had become mutated, corrupted in such a way that it encoded a less functional or even a nonfunctional protein. Surprisingly, mutations in the E-cadherin gene are relatively rare.

Second, there could be a decrease in the number of E-cadherin molecules on the cell surface. And, indeed, studies have shown that this is the case in many cancer cells.

What is actually shown is that there are SOME of these molecules that contain free radical forms of the metal which is an essential part of these molecules. There are also OTHER molecules where the atom of metal in it is NOT in a free radical form.  The same means of testing might not detect both types!  In any event, when the proportion of these molecules with free radicals atoms of metal start exceeding the molecules which are "normal," you have trouble.!

Finally, the linking proteins—the catenins—might be absent or nonfunctioning. This has in fact been found in an increasing number of cancers. The breakdown of cellular junctions not only diminishes the connections between epithelial cells, but it is also related to the cell's increasing internal disorganization.

[Again, free radicals are at the heart of this problem, and are deliberatly, or ignorantly, overlooked by these authors!]

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It has long been noted that the internal architecture of cancer cells is irregular and disorganized. In general, E-cadherin expression is closely related to cellular differentiation. When they do occur, mutations in the E-cadherin gene often result in poorly differentiated cancer cells whose internal architecture no longer resembles the original structure. Furthermore, the lack of E-cadherin expression alters the relation of cells to each other. The same holds true for catenin mutations.

Of the three forms of catenin molecule, β-catenin has received the most attention. Work in the Johns Hopkins laboratory of Bert Vogelstein has shown that β-catenin not only helps to maintain tissue architecture, it also participates in the cell's internal chemical signaling system. Normally, β-catenin hooks up with another protein called APC (for adenomatous poliposis coli), whose function is to eliminate cells with mutations via apoptosis. A mutation in the APC protein leads to the growth of polyps, small benign tumors in the colon. For people who inherit mutations in APC, the risk is rather large that these polyps will become cancerous.

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When acting alone, β-catenin has the potential to initiate cell division. The complex of β-catenin bound to APC prevents this from happening. In this way, cell growth is inhibited. Sometimes one or the other of the proteins in this complex becomes altered—owing to a mutation in the genes encoding them—and the complex cannot be formed. In that case, β-catenin, now unrestrained by APC, interacts with the cell's DNA and activates several genes that cause the cell to re-enter the cell cycle. Abnormal cell growth ensues.

Just as E-cadherins link cells to one another, molecules called integrins link cells to proteins such as collagen in the surrounding connective tissue. Like E-cadherin, the integrins span the cell's membrane, forming connections with connective-tissue proteins outside the cell as well as with proteins in the cell's cytoskeleton, inside the cell. One important difference between normal and cancer cells on the brink of metastasizing is that the cancer cells produce fewer integrins capable of linking with connective tissue than do the normal cells.

Researchers very quickly picked up on the fact that this test not only gave a patient's outcome. But blocking of integrins could also be used to fight cancer.

The intergin seems to act on a molecular level and can encode the DNA and allow angiogenesis to occur in that manner. What they used in the test to block the integrin was a cyclic peptide intravenously. The results showed "regression of human tumors transplanted onto chick cloriallantoic membrane."  (source)

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As long as tumor cells continue to need oxygen to survive, we have a chance to knock cancerous tumors out. (source)

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A review of published information fails to support a cancer-causing or growth-enhancing effect by Hyperbaric Oxygen Treatment. (Source)

Interestingly, not all integrin synthesis stops. On the contrary: In cancer cells integrins are still being produced, but these constitute a set of integrin proteins different from those on normal cells. The so-called invasive cells on their way to becoming metastatic produce integrins that seem to help them migrate through the connective tissue or blood-vessel wall. Specifically, the migratory cells extend cytoplasmic protrusions (like the pseudopods of an amoeba) into the matrix of connective tissue. These protrusions latch on to proteins in the matrix with the help of the new integrin molecules and pull themselves through.

[Karl Note:  What a wonderful missed opportunity these people had to mention whether or not "oxygen" might have any effect on this situation.  If you are trying to get data about "oxygen therapy" you won't find it here where it could have and should have been.

Remodeling

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In order for a cell to make protrusions, its cytoskeleton has to be configured for motility. But as already noted, most cancer cells start out as sedentary cells and are neither programmed genetically for motility, nor is their basic skeletal structure conducive to it.

Before a cancer cell can walk away from an organ, its cellular skeleton must be restructured for movement. And it is. The idea that a cell can alter its internal architecture is akin to suggesting that a fish can grow leg bones and walk off. And yet, biologists have long observed that cells do in fact change shape through the course of cancerous transformation.

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In their normal state, epithelial cells come in several shapes—cylindrical, cuboid or flattened.

Their cancerous counterparts become somewhat star-shaped and elongated and more closely resemble fibroblasts than they do epithelial cells. (Fibroblasts are the cells in the connective tissue that form a wall around epithelia and produce the matrix of connective-tissue proteins.)

Interestingly, similar fibroblastic morphology is also observed in epithelial cells during embryonal development. This raises the interesting point that many characteristics of tumor cells resemble those normally seen only during the very early stages of embryonic development.

The internal cell structure is not the only thing that must be remodeled before the metastatic cell can leave its host organ. The matrix of proteins forming the connective tissue is like a wall without doors. Somehow, the metastatic cells must pass through this wall. This means that either the wall must be altered, or the cancer cells must acquire the ability to bore through tissue.

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The latter scenario seems to take place. Cancer cells penetrate and pass through this barrier by dissolving it.

[How misleading this is -- as if the causative agent is an evil cancer cell. The true cause is a free radical (possibly from cigarette smoke?) that changes the atom in the middle of this enzyme to be a free radical, thus changes the function of the molecule, and damages the matrix which had been holding the cancer cells "in place."

For this purpose, cancer cells use proteases, enzymes that break down proteins, to degrade the mortar of the connective-tissue wall.

[Again, how misleading.  The cancer cells are not "using" anything -- but rather the person has been living a life style that increases the number of free radiclas in his body -- some of them cause changes in the molecule that inibits the degradation of the matrix!

It is probable that expression of active proteases is precisely coordinated in time as well as in extracellular location. For example, fibroblasts produce and degrade the matrix continuously, and under normal circumstances, this process is in equilibrium with other factors that rebuild the matrix. At the moment, it is not entirely clear whether the cancer cell releases its own proteases, or whether it stimulates protease release from other cells, or whether both processes take place sequentially or simultaneously. What is known is that certain messenger molecules alter the balance. It is possible that cancer cells have acquired the ability to synthesize these messenger molecules.

[No matter HOW this happens, the action is through the operation of a free radical -- drugs do not reduce free radicals, but increase them.  Oral chelation removes the metals that are free radicals, and which create more free radicals.

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All proteases share a common feature: They are synthesized by cells in an inactive form, which must be chemically processed before they become active. Processing requires other proteases to chew away at a portion of the precursor protein, called a proprotein, in order to expose the active site of the protease. Complicating the balance is the fact that cells producing proteases may also produce natural protease inhibitors. Sometimes, chemicals in the environment can inhibit the protease inhibitors.

[Such a vital comment -- hidden in obscurity here!  Yes, there are "chemicals in the environment can inhibit the protease inhibitors" but why not admit that these "chemicals" are free radicals.

So, the ability of a cancer cell to pass through its host tissue depends on some constellation of events that either promotes the synthesis and/or the activation of proteases or prohibits protease inhibition. The net effect is that proteases chew through the connective tissue, allowing the metastatic cancer cells to pass through. (Proteases secreted by endothelial cells may play a role in the angiogenesis required for the growth and metastasis of the primary tumor.)

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