Inflammation - A Tell Tale Sign of Cancer?
Posted on April 02 2021
How Does Cancer Start?
Chronic inflammatory diseases are the most significant cause of death in the world. The World Health Organization ranks chronic diseases as the greatest threat to human health. The functional relationship between inflammation and cancer is not new. In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic inflammation, in part based on his hypothesis that some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance cell proliferation.
Chronic inflammation is also referred to as slow, long-term inflammation lasting for prolonged periods of several months to years. It is now accepted within both the medical and scientific community that chronic inflammation is a major underlying condition of many age-related diseases, such as atherosclerosis, arthritis, cancer, diabetes, osteoporosis, dementia, vascular diseases, obesity and metabolic syndrome (Yu and Chung, 2006). More specifically, there are several reviews suggesting a direct relationship between chronic inflammation and cancer (Oshima et al., 2003; Moss et al., 2005; Aggarwal et al., 2006; Lu et al., 2006).
Inflammation has been identified as a hallmark of tumorigenesis (1). In fact, many common cancers develop as a consequence of years of chronic inflammation. Increasing evidence indicates that the chronic inflammation may result from persistent mucosal or epithelial cell colonization by microorganisms. Persistent inflammation leads to increased cellular turnover, especially in the epithelium (tissues that line the outer surfaces of organs and blood vessels throughout the body, as well as the inner surfaces of cavities in many internal organs), and provides selection pressure that result in the emergence of cells that are at high risk for malignant transformation. Key molecular players that link inflammation to genetic alterations are prostaglandins, cytokines, nuclear factor NF-κB, chemokines, and angiogenic factors.(2)
It is suggested that age-related oxidative stress, consequent to chronic inflammation, contributes to the induction and progression of cancer.
Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of our body to detoxify these reactive products. ROS play several physiological roles (i.e. cell signalling), and they are normally generated as by-products of oxygen metabolism; despite this, environmental stressors such as UV, ionizing radiations, pollutants, heavy metals and some prescription drugs, contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress).(3)
It stands to reason then, that interventions that delay ageing or age‐related diseases and therefore inflammation, would greatly benefit health. One such supplement, Hydrolysed Collagen (HC), a hydrolysis product of collagen, has been widely used in food, cosmetic and pharmaceutical industries for decades. As a healthcare supplement, HC has a variety of interesting health benefits, such as antiatherosclerotic activity(4), antitumor activity(5) and preventing osteoporosis(6).
Hydrolysed Collagen Inhibits Tumor Growth
There are numerous published studies showing how Hydrolysed Collagen (HC) peptides can inhibit tumor growth.
One such study, conducted by Laing et al., reported HC intake inhibited spontaneous tumor incidence and increase life span in Sprague-dawley rats. (7)
The study showed that HC notably increased the mean life span, the life span of the last 30% of the survivors, and the maximal life span; it significantly decreased overall spontaneous tumor incidence of both sexes. The incidence of death from tumors was decreased in HC groups in comparison with the control group of both sexes. Scientists concluded that:
“HCs dose-dependently increase life span and decrease spontaneous tumor incidence in Sprague-Dawley rats. Moreover, the antioxidative property of HCs may be responsible for the increased life span and protection against tumor development”.
The results of a similar study published in the Journal of Cellular and Molecular Medicine(8), provide a mechanism underlying anti‐skin ageing by HCs intake and highlight potential application of HCs as a healthcare supplement to combat cancer and cardiovascular disease by inhibiting platelet release.
The authors of that study comment:
“ these results provide a possible mechanism underlying the anti tumor effect of Hydrolysed Collagen”.
Hydrolysed Collagen’s Role in Preventing Cancer
Hydrolysed collagen is a protein containing a unique Amino Acid profile. It is unlike any other protein. The Amino Acids glycine, proline, and hydroxyproline contribute to 57% of total amino acids in collagen, which accounts for one-third of proteins in the human body. Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brainstem, and a potent anti‐inflammatory, cytoprotective, and immune modulating substance.
Glycine is very effective in improving our health. There are overwhelming reports supporting the role of supplementary glycine in prevention of many diseases and disorders including cancer. Accumulating lines of evidence suggest a possibility that glycine is useful as a type of immunotherapy that enhance the body's immune response against cancer.
Renowned Biologist Ray Peat Ph D, comments (9) that,
"...When cells are stressed, they form extra collagen, but they can also dissolve it, to allow for tissue remodeling and growth. Invasive cancers over-produce this kind of enzyme, destroying the extracellular matrix which is needed for normal cellular differentiation and function. When collagen is broken down, it releases factors that promote wound healing and suppress tumor invasiveness. Glycine itself is one of the factors promoting wound healing and tumor inhibition. It has a wide range of antitumor actions, including the inhibition of new blood vessel formation (angiogenesis), and it has shown protective activity in liver cancer and melanoma. Since glycine is non-toxic (if the kidneys are working, since any amino acid will contribute to the production of ammonia), this kind of chemotherapy can be pleasant."
Angiogenesis is the mechanism in cancer that permits the creation of new blood vessels to supply cancerous tumors and ensure their growth. It is a recognized hallmark of cancer and is confirmed in melanoma, where vascular proliferation is associated with increased aggressiveness and poorer prognosis. This sprouting of capillaries from pre-existing blood vessels, or by splitting of blood vessels is among the key events in destructive pathological processes such as tumor growth, metastasis, arthritis, age related macular degeneration etc.(10)
This study (11) published in 2016 evaluated the anti-angiogenic effects of glycine in colorectal cancer. Scientists found that tumor growths (proliferation, migration, and capillary formation) were completely neutralised by Glycine. Compared to the control group, tumor volume, weight, and vessel density decreased up to 55 % in glycine-fed animals. Scientists concluded that Glycine inhibits angiogenic signaling of endothelial cells and tumor growth and is a promising additive to standard and targeted cancer therapies.
Another study (12) investigated the effects of glycine on angiogenesis during embryogenesis, wound healing and tumor growth. Scientists observed that tumor growth decreased by 15% and tumor micro-vessel density dropped by 20% with dietary glycine compared to controls. They concluded that dietary glycine is a potent anti-angiogenic agent that can reduce tumor growth.
This study (13) also reported that dietary glycine inhibits the growth of tumors. The authors of the study conclude that glycine can be used not only for treatment of inflammation, but also for chemoprevention and treatment of carcinoma.
Glycine (14) plays an important role in metabolic regulation, anti-oxidative reactions, and neurological function. Thus, this nutrient has been used to: prevent tissue injury; enhance anti-oxidative capacity; promote protein synthesis and wound healing; improve immunity; and treat metabolic disorders in obesity, diabetes, cardiovascular disease, ischemia-reperfusion injuries, cancers, and various inflammatory diseases.(15).
Glycine is a conditionally essential amino acid in humans because we are unable to synthesize enough glycine to satisfy metabolic requirements. The average adult human (70 kg; 30-50 years; sedentary) requires nearly 15 grams of glycine per day. However, glycine synthesis is limited to about 2.5 grams per day, suggesting that we require about 12 grams of dietary glycine to satisfy daily metabolic requirements. Although, in humans, the normal serum level of glycine is approximately 300 μM, increasing glycine intake can lead to blood levels of more than 900 μM that increase its benefic actions without having harmful side effects.(16).
Advances in Lung and Brain Cancer
Lung and brain (glioblastoma) cancer are among the deadliest. The 5-year survival rates for both are below 20%. There is a growing realisation that cancers are highly metabolically deranged. Two separate and quite different studies found that increased catabolism of Glycine (and thus lower levels) leads to tumor formation and aggressive phenotype. Inhibiting the enzyme that degrades Glycine was highly therapeutic. The same effect can be achieved by supplying extra Glycine through supplementing with Hydrolysed Collagen.
In the first study (17), Biologists at MIT and the Whitehead Institute for Biomedical Research discovered a vulnerability of brain cancer cells that could be exploited to develop more-effective drugs against brain tumors.
The study found that a subset of glioblastoma tumor cells is dependent on a particular enzyme that breaks down the amino acid glycine. Without this enzyme, toxic metabolic by-products build up inside the tumor cells, and they die.
Lead author of the study, Dohoon Kim says, "Blocking this enzyme in glioblastoma cells could offer a new way to combat such tumors", which appears in the April 8 online edition of Nature (18).
The second study (19) explains how lung carcinoma tumors contain high levels of glycine decarboxylase (GLDC), an enzyme that breaks down glycine. Overexpression of GLDC stimulates the generation of tumors and the proliferation of self-renewing tumor-initiating cells (TIC), and high GLDC levels are associated with poor survival rates in patients.
No therapeutic agents have been developed against GLDC until now.
Surana and Wee identified short synthetic RNA sequences (steric hindrance antisense oligonucleotides, or shAONs) that suppressed the production of GLDC protein in human lung cancer cells, hindering their proliferation and preventing tumor formation. The article can be found here (20).
So, the fact that this approach worked in two very different cancer types, which oncology considered completely unrelated, suggests that it is a general feature of cancer cells and can be exploited against any tumor type.
Hydrolysed Collagen and Skin Cancer
In 1999 scientists designed an experiment to test the hypothesis that dietary glycine would inhibit the growth of tumors arising from B16 melanoma cells implanted subcutaneously in mice (21). They found that 65% of tumor growth of melanoma cells was inhibited by glycine indicating that glycine has anticancer properties. The study reported that B16 tumors grew rapidly in mice fed control diet; however, in mice fed glycine diet, tumor size was 50–75% less. At the time of death, tumors from glycine-fed mice weighed nearly 65% less than tumors from mice fed control diet. After 14 days, tumors from mice fed dietary glycine had 70% fewer arteries. Furthermore, glycine inhibited the growth of endothelial cells.
Hydrolysed Collagen and Liver Cancer
Liver cancer is the third leading cause of cancer-related death in the world with no curative treatment options available.
Two very good tumor promoters are polyunsaturated fatty acids (22) (found in vegetable and seed oils) and peroxisomal proliferators (nongenotoxic rodent carcinogens), as they increase cell proliferation.
Peroxisome proliferators (known as WY-14,643) cause liver cancer in rodents by unknown mechanisms. Their ability to sustain elevated rates of hepatocyte DNA synthesis is most likely pivotal in the ultimate development of tumors.
So Peroxisome proliferators act as tumor promoters by increasing cell proliferation. Scientists also know that Hepatic Kupffer cells (specialized cells localized in the liver) represent a rich source of mitogenic cytokines (e.g., tumor necrosis factor alpha, TNF alpha) and are stimulated by the peroxisome proliferators.
Since glycine prevents activation of Kupffer cells, this experiment (23) tested the hypothesis that a diet containing glycine could block the mitogenic effect of the peroxisome proliferator.
And the results - After 3 weeks, dietary glycine reduced basal rates of cell proliferation by about 50% and completely prevented the sustained 5-fold increase in cell proliferation. Moreover, the 3-fold increase in TNF alpha mRNA caused by WY-14,643 was blocked completely by the glycine-enriched diet. The results demonstrate that a glycine-enriched diet prevents stimulated cell proliferation most likely by inhibiting TNF alpha production and raise the possibility that dietary glycine will be effective in preventing cancer caused by nongenotoxic carcinogens.
In another experiment (24) scientists confirmed the previous findings by testing the hypothesis that dietary glycine would inhibit the hepatocarcinogenic effect of WY-14,643. The results were amazing. After 51 weeks of dietary exposure to WY-14,643, glycine prevented formation of small (0-5 mm diameter) tumors by 23% and inhibited the development of medium size (5-10 mm) tumors by 64%. Furthermore, glycine prevented the formation of the largest tumors (>10 mm) by nearly 80%. Thus, glycine significantly decreased the progress to tumors. Moreover, the inhibitory effect of glycine was greater with increasing tumor size.
These studies demonstrate that dietary glycine prevents the development of hepatic tumors caused by the peroxisome proliferator WY-14,643 consistent with the idea that it may be an effective chemopreventive agent.
In fact, the authors of this study (25) say that:
“Glycine might have additional benefit effects in conventional chemotherapy options”
They conclude that Glycine is a potent, indirect inhibitor of in vitro tumor angiogenesis.
The incidences of many diseases, such as vascular diseases, cancer, arthritis and osteoporosis, rise rapidly with age. So, interventions that delay ageing or age‐related diseases greatly benefit health. To date, healthcare supplements that delay ageing or age‐related diseases have received great attention. Of these, Hydrolysed Collagen has been widely used in food, cosmetic and pharmaceutical industries for decades. However, it is only in more recent times that we are discovering the wide and varied benefits of this miraculous supplement in the treatment and prevention of cancer.