Collagen IV derived "tumstatin" suppresses tumor growth.

Collagen IV, the basement membrane collagen is probably one of the oldest and most examined subtypes of collagen in oncology.  It is certainly not the only or most important collagen in cancer suppression, or other diseases, but Col4 has been proven to function as a barrier against metastasis in the fibrous capsule in several sophisticated and technically up-to-date studies.

Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression.

"Sudhakar A¹, Boosani CS.

Growing tumors develop additional new blood vessels to meet the demand for adequate nutrients and oxygen, a process called angiogenesis. Cancer is a highly complex disease promoted by excess angiogenesis; interfering with this process poses for an attractive approach for controlling tumor growth. This hypothesis led to the identification of endogenous angiogenesis inhibitors generated from type IV collagen, a major component of vascular basement membrane (VBM). Type IV collagen and the angiogenesis inhibitors derived from it are involved in complex roles, than just the molecular construction of basement membranes. Protease degradation of collagens in VBM occurs in various physiological and pathological conditions and produces several peptides. Some of these peptides are occupied in the regulation of functions conflicting from those of their original integral molecules. Tumstatin (alpha3(IV)NC1), a proteolytic C-terminal non-collagenous (NC1) domain from type IV collagen alpha3 chain has been highlighted recently because of its potential role in anti-angiogenesis, however its biological actions are not limited to these processes. alpha3(IV)NC1 inhibits proliferation by promoting endothelial cell apoptosis and suppresses diverse tumor angiogenesis, thus making it a potential candidate for future cancer therapy. The present review surveys the physiological functions of type IV collagen and discovery of alpha3(IV)NC1 as an antiangiogenic protein with a comprehensive overview of the knowledge gained by us towards understanding its signaling mechanisms."

Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. 

"

Hamano Y¹, Kalluri R.

Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen alpha3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to alphaVbeta3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors."

Collagen XIX is strongly anti-tumorigenic

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Mol Cancer Ther. 2007 Feb;6(2):506-14.

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Ramont L¹, Brassart-Pasco S, Thevenard J, Deshorgue A, Venteo L, Laronze JY, Pluot M, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls. Histologic examination of the tumors showed a strong decrease in tumor vascularization in treated mice. In vitro, NC1(XIX) inhibited the migrating capacity of tumor cells and their capacity to invade Matrigel. It also inhibited the capacity of human microvascular endothelial cells to form pseudotubes in Matrigel. This effect was accompanied by a strong inhibition of membrane type-1 matrix metalloproteinase (matrix metalloproteinase-14) and vascular endothelial growth factor expression. Collectively, our data indicate that the NC1 domain of type XIX collagen exerts antitumor activity. This effect is mediated by a strong inhibition of the invasive capacities of tumor cells and antiangiogenic effects. NC1(XIX) should now be considered as a new member of the basement membrane collagen-derived matrikine family with antitumor and antiangiogenic activity.

PMID: 17308049

 

The NC1 domain of type XIX collagen inhibits melanoma cell migration. 

Eur J Dermatol. 2010 Nov-Dec;20(6):712-8. doi: 10.1684/ejd.2010.1070. Epub 2010 Sep 14.
 The NC1 domain of type XIX collagen inhibits melanoma cell migration.

Toubal A¹, Ramont L, Terryn C, Brassart-Pasco S, Patigny D, Sapi J, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones. We previously demonstrated that the C-terminal NC1 domain of type XIX collagen inhibits tumor growth in vivo. In the present study, we analyzed the effects of the NC1(XIX) collagen domain on migratory behaviour of melanoma B16F10 cells. We found that NC1(XIX) do not inhibit melanoma cell proliferation. On the contrary, NC1(XIX) strongly inhibited the migratory capacities of melanoma cells in the scratch wound model and in Ibidi® devices: cell migration speed was 7.69 ± 1.49 μm/h for the controls vs 6.64 ± 0.82 μm/h for cells incubated with 30 μmol/L NC1(XIX) and 5.72 ± 0.67 μmol/h with 60 μmol/L NC1(XIX). Similar results were obtained with UACC 903 human melanoma cells. Further work will be necessary to elucidate the molecular mechanisms of this migration inhibition. It may, however, explain, at least partially, the inhibition of tumor growth that we observed in vivo.

PMID: 20840910

 

 

Loss of Collagen XV Causes Muscle Tissue and Capillary Degeneration

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

From:

Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1194-9. Epub 2001 Jan 23.

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

Eklund L¹, Piuhola J, Komulainen J, Sormunen R, Ongvarrasopone C, Fássler R, Muona A, Ilves M, Ruskoaho H, Takala TE, Pihlajaniemi T.

Muscle histology: focal areas of degeneration, regeneration, and variation in fiber size. Hematoxylin and eosin-stained sections of the gastrocnemius (A), triceps brachii (B), paraspinal (C), and quadriceps (D) muscles of 6-month-old null mice showing cell degeneration (curved arrows, A and C) with macrophage infiltration (A), regenerative fibers (thin arrow, B), central nuclei (thin arrow, C), and increased variation in fiber size with atrophic muscle fibers (D, arrowheads) compared with age-matched wild-type mice (E). Original magnifications: A and D, ×300; B, ×200; C and E, ×80.

Ultrastructural changes in capillaries. Electron microscopy of heart capillaries from a wild-type (A) and a null mouse (B) with swollen endothelial cells (asterisks). The lumen is indicated by a white arrow. Skeletal muscle capillaries from a wild-type (C) and a mutant mouse (D) showing luminal narrowing and folding of endothelial cells.

Effect of isoproterenol stimulation on developed pressure in (A) 6-month-old and (B) 12-month-old mutant and wild-type mice. The responses to β-agonists were measured in terms of the ratio of the maximal value of the developed pressure (DP) to the basal level before the isoproterenol perfusion in Col15a1^−/− (●: A, n = 7; B, n = 11) and Col15a1^+/+ (□: A, n = 7; B, n = 8) mice. The symbols represent mean ± SEM. Significant differences between the Col15a1^−/− and Col15a1^+/+ mice are indicated by asterisks as follows: *, P < 0.05, **, P < 0.01. The basal pressure was 31.7 ± 5.0 and 27.3 ± 5.0 mmHg for the 6-month-old control and null mice, respectively, and 20.2 ± 3.4 and 20.8 ± 2.0 mmHg for the 1-year-old mice (mean ± SEM).

Partial and Total Loss of Arterial Collagen XVIII Causes Atherosclerosis

Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

Some factions claim that loss of arterial collagen is causal to atherosclerosis without being very specific about the mechanism (where? the adventitia? the endothelial basement?  The media?  how? immune side?  smc autophagic?  oxidative?  proteolytic? autolysis?) and refer to studies done before regarding deranged hepatic metabolism of cholesterol during scurvy which causes a certain hyperlipidemia by bile metabolism deficiency and consequent lack of fecosteroid excretion.  Others will look at ratios of Collagens I, III, IV, and even V in the atherosclerotic plaque and their ratios during atherosclerosis.  However, the specific mechanism of collagen loss and atherosclerosis has never been scientifically described in a definitive study until this one.  Through simple logic, (common sense), it follows that singular or combinatory losses of the other arterial collagen subtypes would provide the same result experimentally, either in vitro or in vivo.

The Maeda paper showing that scurvy causes Evans Blue extravasation and gross damage to the arterial wall did not describe any atheromas, hyperplasias, or plaques because the mice die from scurvy before they can incur cumulative atherosclerosis.  They did prove that scurvy causes arterial degradation to the extent that lipoproteins and anything else can enter the artery that can't transgress a healthy, vitamin C (ascorbate) replete artery wall.

The implied connection between atherosclerosis and scurvy is collagen.  While ascorbate isn't the only vitamin involved in collagen synthesis, it is the only one that when absent will prevent proper polymerization of hydroxyl residues.  There is nothing to debate in this regard.  No ascorbate = no assembled collagen.  There may be pro-collagen formation and its strands, but they will never be assembled correctly into their "stronger than steel" fibers without vitamin C, but remain a useless stockpile of components.

It is important to note that the correct ratios of the various collagens is exceedingly important.  While much focus has been made on COL4 basement membranes in conferring tensile strength and resistance to metastasis, too much of COL4 without the other collagens in balance can cause mitochondrial death by integrin signaling abnormalities, as well as aberrant vitamin A processing.  It is not as simple as to say "the more collagen the better."  Not whatsoever is it that simple, and such a conclusion could be disastrous in clinic.  Fibrosis is a disorder of too much of the wrong collagen in the wrong place at the wrong time and is a devastating disorder. 

However, if the intrinsic collagens in the artery, such as COLXVIII, vanish, arteries become much more prone to lipid intrusion and the chain of events that occur after that.  As such, the normal constituency of arterial collagens, many of them not even recognized by conventional histopathology stains and immunohistochemistry, prevent large particle lipoprotein intrusion.  Collagen XVIII is a subtype that is virtually ignored in cardiology, yet possibly one of the most important subtypes.  It logically follows that deficiencies in the most commonly acknowledged collagens of the arterial media and basement membrane, COLI, COLIII, and COLIV, would cause similar problems of pathological permeability to both the clotting cascade biomolecules as well as the whole gamut of lipoproteins.  This deposition of foreign matter is understood for over five decades as being the causal moment of atherosclerosis, but it is still not widely accepted in 2015 that the collagenous and protein barrier of the artery built by vitamin C dependent enzymes is important to prevent this permeability event.

 

Cholesterol in the CNS: Right Place At The Right Time

Cholesterol is indispensable to the brain and nerves.  Native non-oxidized cholesterol is much more important to the nervous system than other organ systems for which such normal levels of cholesterol may be excessive in that system.  So much so that the brain has its own isolated supply separated from the blood by the notoriously hard to cross blood brain barrier (BBB) which relies on collagen to make it selectively impenetrable to certain molecules.  Any excess is turned into a hydroxy- soluble form which is released from the brain into the blood circulation.  However, when it runs low for whatever reason, cholesterol can be and is actively transported across the BBB from the hepatic supply.  Nowdays, the statin industry has introduced some confusion by entering into the science of Alzheimer's disease.  The big million dollar question is how interfering with the mevalonate pathway can help reduce the causal protein tangles when lowering cholesterol below normal is very toxic to neural function.  There are some elucidations regarding isoprenoids involvement, independent of cholesterol.  Perhaps in some instances with specific ApoE isoforms this is true, but in the majority of instances lowering CNS cholesterol damages it instead of benefitting it.  The tangible outcome of cholesterol depletion in the human brain are problems like amnesia, and the very symptoms of Alzheimer's itself.  The question to answer is probably what optimal cholesterol synthesis is to the brain, as compared to that in the blood supply, just as the "normal" brain ascorbate pool (2000-10,000uM)  is much much higher than that of the bloodstream (60-150uM).

Brain-Derived Neurotrophic Factor Regulates Cholesterol Metabolism for Synapse Development

Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2

Dr. Robert F. Cathcart III, M.D. was right...in 1975

While combinations upon the base of high dose Vitamin C are fairly new, the application of high dose Vitamin C against viral ailments is a very old idea that was actually put into practice by Dr. Cathcart.  As with most things in medicine, things that are both cheap and effective tend to get buried by the new widget or pill for sale.  Cathcart was no crank, or belligerent lecturer, but a practicing physician with very strong credentials.

His experience as an actual practicing doctor in the USA, employing Vitamin C as a medicine, clearly shows that a little sprinkle (91 mgs) is quite far away from what you need as a therapeutic dose.

He explains this clearly, unambiguously, in 1981 in the Orthmolecular Psychiatry, one of the few non-corporate aligned outlets that would display an efficacious medicine for humanity that would not bankrupt it.  Yes, we should constantly remember that while people are well-meaning, well-meaning people working for a business are lead by business interests not human interests.  So then the chicken chase goes on for the patent drug, the newest widget and pill to be able to sell at the same time a widely available and safe cure might exist. 

The Method of Determining Proper Doses of Vitamin C for the Treatment of Disease by Titrating to Bowel Tolerance

Anyone who tries to revert back to little sprinkles of Vitamin C does not understand the topic and worse will not achieve a cure or effect.  Might as well do nothing then...

Here is the PubMed entry which documents his experience in healing patients with Vitamin C:

Vitamin C in the treatment of acquired immune deficiency syndrome (AIDS).

If someone thinks a viral disease which can be spread through needle sticks somehow has something to do with morality, they should discuss this idea with their medical doctor or nurse and listen to what they have to say about plagues that arise by "immorality."  Better yet, find one of the many children born with the disease and tell them how they are immoral before they know the meaning of it.  Now that the inane and tedious medieval fingerpointers have been given their aggrandizements, the science can be returned to:

Here is the body of the text in regular html on Vitamincfoundation.org:

VITAMIN C IN THE TREATMENT OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)


"Why eradicate a disease when you can profit by selling non-working pills for it and weaponize its stigma as a sociopolitical gambit" - The body of fiscal corporate thought.

IMPROVE-IT study: Desperation of the Statin Industry

IMPROVE-IT touts ezetimibe and simvastatin therapy results as guidance to load up patients with ever higher doses of statins, satisfying the mythical NNTI of 100 patients dosed per 2 magical, precise, exact reductions of CVD incidence over 6 years.  Common sense would indicate that if you did nothing, normal variation would generate the same results given that there will never be 100% incidence of anything.  The impact of various statins piled one on top of each other in cardiovascular medicine is already being exaggerated based on a literal 1% decrease in incidence which could also easily be had by statistical manipulation. 

Stopping short of cutting cholesterol synthesis altogether, the ever lower recommendations for LDL to definitive hypocholesterolemia levels, which generates its own set of diseases such as increased infection and hemorrhagic type cerebral stroke, the ludicrous idea offered seriously to lower LDL levels in the populace to 60mg/dL and below will cause a whole swath of new death by low cholesterol.  What it says to the astute observer is that the normal range of LDL has never been culprit to atherosclerosis leading to ischemic events and that other unrecognized factors are causal, such as oxidation of cholesterol and proteins.

We're not seeing a remarkable 50% reduction here, just a flutter.  Moreover, the rate of death is exactly the same, barring a 0.1% difference.  For other drugs in oncology, this would be considered an unmet endpoint, and the drug would be canned, but not for the statin industry, whose sales must always increase year over year in order to inflate their stock price like other unrelated products.

IMPROVE-IT results

The real world data is that serum cholesterol levels are not related to CVD disease....at all.  Other factors associated with its transport do, but not cholesterol levels.  It is misdirected effort to reduce LDL-cholesterol across the board to hypocholesterolemia levels, especially as it pertains to the importance of cholesterol synthesis to cognition.  The thing with statins is that they are not targeted to particles, proteins, glycoproteins, etc.  They are designed to poison the mevalonate pathway, indiscriminately lowering cholesterol synthesis everywhere, having nothing to do with ApoB, ApoA, ApoE, ApoC, ApoJ, apo(a), triglycerides, phospholipids, plasmalogens, particle number, particle size, etc.  They have been proven dozens of times to have zero effect on the particle that is extremely more atherogenic than LDL, Lp(a), which nobody seems to check for.  One day in the future, it will be considered medical negligence not to check for Lp(a).  Statins do sometimes offer an anti-inflammatory mechanism, which may actually be their mode of action rather than poisoning the cholesterol synthesis enzyme chain.  The fact that lowering cholesterol lower and lower and lower had no benefit against heart disease says something to the tune of "obvious."

cholesterol-heart-disease-there-is-a-relationship-but-its-not-what-you-think

Real world data: Zero correlation (0.0) between cholesterol and heart disease.