Metastasis is the general term used to describe the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is a primary cause of cancer morbidity and mortality.(Source).
Metastasis involves a complex series of sequential and interrelated steps. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulation and lymphatic system, evade immune attack, extravasate at a distant capillary bed, and invade and proliferate in distant organs (Source).
Metastatic cells also establish a microenvironment that facilitates angiogenesis and proliferation, resulting in macroscopic, malignant secondary tumors. A difficulty in better characterizing the molecular mechanisms of metastasis comes in large part from the lack of animal models that manifest all steps of the cascade. Although the major steps of metastasis are well documented, the process by which metastatic cells arise from within populations of non-metastatic cells of the primary tumor has not been well elucidated. (Source). The ACR Institute is working on this problem.
Nutritional and Supplementation Recommendations
1. Modified Citrus Pectin or MCP: Typical adult dose ranging from 6-30 grams divided throughout the day. 15 grams is usually the normal doses, divided in three daily doses. But because of the metastasis-angiogenesis promoting surgery and the accompanying stress, it may be wise to increase that dose to 20-25 grams per day. If the bloodwork and biomarkers show no signs of cancer progession and if the Circulating Tumor cell test also shows no sign of CTC (circulatiog tumor cells) activity, then we can go back down to 10-15 grams. But without knowing, it’s important to have a good amount of this substance floating in the bloodstream most of the time to avoid the cancer adhesion molecules from taking effect.
Action mechanism: In order for metastasis to occur, cancerous cells must first bind or clump together. The molecule called galectin is thought responsible for much of cancer’s metastatic potential by providing the binding site (Guess et al. 2003). MCP appears small enough to access and bind tightly with galectins, inhibiting (or blocking) aggregation of tumor cells and adhesion to surrounding tissue (Kidd 1996). Deprived of the capacity to adhere, cancer cells fail to metastasize.
Evidence of efficiency: Research shows that metastasis of breast cancer cell lines requires aggregation and adhesion of the cancerous cells to tissue endothelium in order for it to invade neighboring structures (Glinsky et al. 2000). To test the anti-adhesive properties of MCP, researchers evaluated (in an in vitro model) breast carcinoma cell lines MCF-7 and T-47D. The study concluded that MCP countered the adhesion of malignant cells to blood vessel endothelium and subsequently inhibited metastasis (Naik et al. 1995). MCP decreased metastasis of melanoma to the lung by more than 90% in laboratory animals (Platt et al. 1992). Men with prostate cancer who took 15 grams of MCP a day, they had a slowdown in the doubling time of their PSA levels. (Lengthening of doubling time represents a decrease in the rate of cancer growth.) According to Dr. Kenneth Pienta (leader of the Michigan Cancer Foundation), MCP may be the first oral method of preventing spontaneous prostate cancer metastasis (Pienta et al. 1995; Guess et al. 2003).
Evidence of safety: Modified citrus pectin (MCP), also known as fractionated pectin, is a complex polysaccharide obtained from the peel and pulp of citrus fruits. Through pH and temperature modifications, the pectin is broken down into shorter, nonbranched, galactose-rich, carbohydrate chains. The shorter chains dissolve more readily in water, making them better absorbed than ordinary, long-chain pectin. The short polysaccharide units afford MCP its ability to access and bind tightly to galactose-binding lectins (galectins) on the surface of certain types of cancers. By binding to lectins, MCP is able to powerfully address the threat of metastasis (Strum et al. 1999). No signs of adverse effects have been reported.
Research has shown that cancer surgery, among other deleterious effects, increases tumor cell adhesion (Kate, 2004). Therefore, it is critically important for the person undergoing cancer surgery to take measures that can help to neutralize the surgery-induced increase in cancer cell adhesion. MCP can help to do that.
The treatment of cancer usually aims to destroy and/or stop the growth of the primary tumor. Major improvements in the methods of surgery, radiation and chemotherapy have taken place, but corresponding improvements in patient survival have not always followed. Treatments that focus on the primary cancer typically do not address metastasis.
Metastasis suppressors act by different mechanisms than tumor suppressors and do not affect primary tumors. Tumor suppressors, however, also inhibit metastasis, since metastasis is dependent upon tumorigenicity.
Metastasis suppressors were first identified using microcell-mediated chromosome transfer (MMCT), which introduces chromosomes into intact recipient cells. Chromosomes 1, 6, 7, 8, 10, 11, 12, 16 and 17 harbor metastasis suppressor genes.
MicroRNAs (miRNAs) are a class of gene regulators that bind the 3′ untranslated regions of target messenger RNAs, leading to either suppression of their translation or acceleration of their degradation. In cell MDA-MB-231 and its metastatic variant, six miRNAs displayed lower expression in metastatic cells. Among them, miR-335 and miR-126 suppress metastasis without affecting primary tumor growth. miR-335 targets multiple pathways, including SOX4, MERTK, PTPRN2and TNC, which contribute to metastasis-suppression. miR-335 expression is correlated with metastasis-free survival in clinical breast cancer.
Metastasis suppressors can potentially serve as prognostic markers, therapeutic targets and predictors for treatment response.
High NM23 expression is correlated with good prognosis in multiple tumor types, including breast cancer. KAI1, PEBP1 and RECK expression correlate with improved survival in multiple tumor types, including colorectal cancer. High expression of CTGF is correlated with improved survival in colorectal cancer, non-small cell lung carcinoma and gallbladder cancer, but the correlation is reversed in esophageal cancer and glioma.
Patients with NM23 -positive ovarian cancer respond better to cisplatin than patients with NM23-negative tumors and esophageal squamous cell carcinoma. NM23 expression is correlated with increased survival after cisplatin treatment following surgery.
Unlike tumor suppressors, most metastasis suppressors are downregulated in clinical tumor samples rather than mutated. Activation of these metastasis suppressors can potentially block metastasis and improve survival. The promoter region of NM23 contains glucocorticoid response elements that can elevate NM23 expression. Treating human breast cancer cells with dexamethasone medroxyprogesterone acetate (MPA) increases NM23 expression.
Genes for about a dozen metastasis-suppressing proteins are known in humans and other animals, including BRMS1, CRSP3, DRG1, KAI1, KISS1, NM23 and various TIMPs. Most act by altering aspects of signal transduction.
- NM23 is a suppressor active in melanoma, breast and colon cancers and apparently inhibits the functioning of a kinase enzyme that promotes cell division. NM23 has eight family members. NM23-H1 and NM23-H2 suppress metastasis in multiple tumor types. NM23 expression can serve as a potential prognostic marker for survival in breast, ovarian, melanoma, gastric, hepatocellular and non-small cell carcinoma. It affects the MAPK and cytoskeleton-organizing cellular pathways, which contribute to its metastasis-suppressing functions.
- MKK4 is a suppressor active in prostate and ovarian cancers It apparently functions by facilitating apoptosis, or death of abnormal cells such as cancer cells.
- KAI1 is found in prostate and breast cancers. It forms complexes with proteins called integrins. Integrins link cells together. The complex formation may inhibit detachment and migration of cancer cells.
- BRMS1 promotes the activity of the gap junctions of cells. BRMS1 suppresses metastasis in multiple tumor types including ovarian, bladder, melanoma and non-small cell lung carcinoma. Clinically BRMS1 expression correlates with survival in breast cancer and non-small cell lung carcinoma.
- KISS1 is found in melanoma and breast cancers. It acts by synthesizing a protein receptor.
- RHoGD12 is active in bladder cancer and inhibits proteins that aid in cancer cell migration. RhoGDI2 suppresses endothelin 1 (ET1), a vasoconstrictor correlated with higher clinical stage in bladder cancer.
- CRSP3 and VDUP1 are both active in melanoma. CRSP3 is a co-activator of genes involved in cancer growth, while VDUP1 inhibits a protein involved in cell proliferation.
- Ectopic expression of Krüppel-like factor 17 (KLF17) in highly metastatic 4T1 cells suppresses their metastatic potential without affecting primary tumor growth in a mouse model. KLF17 suppression promotes tumor cell epithelial-mesenchymal transition (EMT), which leads to metastasis. Transcription factor Id1 is a direct target of KLF17 and mediates its metastatic functions. KLF17 expression is significantly downregulated and Id1 expression is upregulated in breast cancer metastasis.
- GAS1 is found in melanoma. In poorly metastatic B16-F0 mouse melanoma cells, GAS1 knockdown promoted metastasis without affecting primary tumor growth. GAS1 suppresses metastasis by promoting apoptosis in disseminated cancer cells at secondary organs. Its expression is downregulated in metastatic clinical samples.
- Primary tumor samples of colorectal cancer patients with liver metastasis showed gain of chromosomes 7p, 8q, 13q and 20q and loss of chromosomes 1p, 8p, 9p, 14q, 17p and 22q. Genes that are located in the regions of chromosomal loss include MAP2K4, LLGL1, FBLN1, ELAC2, ALDH3A2, ALDH3A1, SHMT1, ARSA, WNT7B, TNFRSF13B, UPK3A, TYMP, RASD1, PEMT and TOP3A. These genes can potentially serve as metastasis suppressors.
- In a basal-like primary breast cancer, mutations in SNED1 and FLNC influenced metastasis.
Metastasis suppressor genes may offer mechanistic insight for guiding specific therapeutic strategies, which may include drug-induced reactivation of metastasis suppressor genes and their signaling pathways. Clinical assessment of metastasis suppressor gene product status in disseminated cancer cells may improve prognosis accuracy in patients with clinically localized disease. These proteins are different from ones that act to suppress tumor growth.
- Olle, David (September 9, 2009). “Metastasis Suppressors”. Suite 101. Missing or empty
- Sobel, Mark E. (1990). “Metastasis Suppressor Genes”. Journal of the National Cancer Institute. 82 (4): 267–76. doi:10.1093/jnci/82.4.267. PMID 2405170.
- Yan, Jinchun; Yang, Qin; Huang, Qihong (2013-03-01). “Metastasis Suppressor Genes”. Histology and histopathology. 28 (3): 285–292. ISSN 0213-3911. PMC 3910084. PMID 23348381.
- Shevde, Lalita A.; Welch, Danny R. (2003). “Metastasis suppressor pathways—an evolving paradigm”. Cancer Letters. 198 (1): 1–20. doi:10.1016/S0304-3835(03)00304-5. PMID 12893425.
- Jackson, Paul (2007). New Developments in Metastasis Suppressor Research. Nova Publishers. ISBN 978-1-60021-603-9.[page needed]
- Kauffman, Eric C.; Robinson, Victoria L.; Stadler, Walter M.; Sokoloff, Mitchell H.; Rinker-Schaeffer, Carrie W. (2003). “Metastasis Suppression: The Evolving Role of Metastasis Suppressor Genes for Regulating Cancer Cell Growth at the Secondary Site”. The Journal of Urology. 169 (3): 1122–33. doi:10.1097/01.ju.0000051580.89109.4b. PMID 12576866.
- Yoshida, Barbara A.; Sokoloff, Mitchell M.; Welch, Danny R.; Rinker-Schaeffer, Carrie W. (2000). “Metastasis-Suppressor Genes: a Review and Perspective on an Emerging Field”. Journal of the National Cancer Institute. 92(21): 1717–30. doi:10.1093/jnci/92.21.1717. PMID 11058615.
- Kauffman, Eric C.; Robinson, Victoria L.; Stadler, Walter M.; Sokoloff, Mitchell H.; Rinker-Schaeffer, Carrie W. (2003). “Metastasis Suppression: The Evolving Role of Metastasis Suppressor Genes for Regulating Cancer Cell Growth at the Secondary Site”. The Journal of Urology. 169 (3): 1122–33. doi:10.1097/01.ju.0000051580.89109.4b. PMID 12576866.
- Pecorino, Lauren. Molecular Biology of Cancer. 2nd ed. New York: Oxford UP, 2005. Print.
- “Understanding Cancer Series: Cancer“. National Cancer Institute. U.S. National Institutes of Health. Web. 21 November 2009.
- “Understanding cancer“, cancer.gov.
- “Metastasis”, wordnetweb.princeton.edu, WordNet Search 3.0. Web. 19 November 2009.
- “‘Super natural killer cells’ destroy cancer in lymph nodes to halt metastasis”. Kurzweil Accelerating Intelligence. Newsletter. November 16, 2015. Retrieved 2016-04-23.
A metastasis suppressor is a protein that acts to slow or prevent metastases (secondary tumors) from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.
BMC Cancer. 2010; 10: 175.
Published online 2010 Apr 30. doi: [10.1186/1471-2407-10-175]
Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid
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This article has been cited by other articles in PMC.
Advanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways. Chinese herbal cocktail which contains various phytochemicals may target multiple dys-regulated pathways in cancer cells and thus may provide an alternative/complementary way to treat cancers. Previously we reported that the Chinese herbal cocktail Tien-Hsien Liguid (THL) can specifically induce apoptosis in various cancer cells and have immuno-modulating activity. In this study, we further evaluated the anti-metastatic, anti-angiogenic and anti-tumor activities of THL with a series of in vitro and in vivo experiments.
Inhibition of cancer cell invasion and metastasis by genistein.
Genistein is a small, biologically active flavonoid that is found in high amounts in soy. This important compound possesses a wide variety of biological activities, but it is best known for its ability to inhibit cancer progression. In particular, genistein has emerged as an important inhibitor of cancer metastasis. Consumption of genistein in the diet has been linked to decreased rates of metastatic cancer in a number of population-based studies. Extensive investigations have been performed to determine the molecular mechanisms underlying genistein’s antimetastatic activity, with results indicating that this small molecule has significant inhibitory activity at nearly every step of the metastatic cascade. Reports have demonstrated that, at high concentrations, genistein can inhibit several proteins involved with primary tumor growth and apoptosis, including the cyclin class of cell cycle regulators and the Akt family of proteins. At lower concentrations that are similar to those achieved through dietary consumption, genistein can inhibit the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms, including the transforming growth factor (TGF)-beta signaling pathway. Several in vitro findings have been corroborated in both in vivo animal studies and in early-phase human clinical trials, demonstrating that genistein can both inhibit human cancer metastasis and also modulate markers of metastatic potential in humans, respectively. Herein, we discuss the variety of mechanisms by which genistein regulates individual steps of the metastatic cascade and highlight the potential of this natural product as a promising therapeutic inhibitor of metastasis.
Inhibition of breast cancer metastases by a novel inhibitor of TGFβ receptor 1.
Transforming growth factor beta (TGFβ), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs.
To identify specific inhibitors of TGFβ receptor 1 (TGFβR1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGFβR1 kinase assays. Affymetrix GeneChip expression analysis of mRNA levels and real-time polymerase chain reaction were performed to determine expression changes of TGFβ-mediated, metastasis-associated genes in breast cancer cells after treatment with the small-molecule inhibitor YR-290. YR-290 was also examined for its effects on breast cancer migration, invasion, and metastasis using transwell and epithelial-to-mesenchymal transition (EMT) assays in vitro and three different mouse (BALB/c and NU/NU nude) models (n = 10 per group). Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided.
YR-290 interacted with the kinase domain of TGFβR1, abrogated kinase activity (half maximal inhibitory concentration = 137nM, 95% confidence interval = 126.4 to 147.6nM) and inhibited the TGFβ-mediated downstream signaling pathway and metastasis-associated genes in breast cancer cells. YR-290 inhibited TGFβ-modulated breast cancer cell migration and invasion. In tumor metastasis mouse models, YR-290 almost completely blocked cancer metastasis. Numbers of lung tumor nodules of mice treated with 1mg/kg and 5mg/kg YR-290 were reduced by 74.93% (95% confidence interval = 61.45% to 88.41%) and 94.93% (95% confidence interval = 82.13% to 100%), respectively, compared with control mice. Treatment with YR-290 also statistically significantly prolonged the survival of tumor-bearing mice.
YR-290 is a novel inhibitor of tumor metastasis that works by blocking TGFβ signaling pathways.
Chronic Inflammation Inhibition
One of the key driving forces behind cancer metastasis is systemic inflammation. It is suspected that chronic inflammation is the primary cause of 25% of all human cancers. Inflammatory conditions contribute to the ability of cancer cells to rapidly grow, form tumors, and even resist cancer treatment drugs.
Inflammation increases tissue damage and is a major cause of epigenetic changes. While scientist once thought that the genes we were given at birth were unchangeable, the field of epigenetics provides evidence that environmental factors we are exposed to (ie. nutrition, toxins, stress) can turn genes off and on causing genetic abnormalities.
Genetic alterations result in the following consequences:
• Activation of EMT Activity: EMT (epithelial-mesenchymal transition) activity is turned on, triggering a series of pathways that maintain chronic inflammation. EMT pathways boost tumor cell migration by breaking down adhesive anchors to cancers cells, thus increasing their ability to move and invade new tissue.
• Transcriptional Changes: Many transcription factors that act as on/off switches for the expression of genes are altered under conditions of inflammation. These controlling factors have the ability to repress E-cadherin activity normally responsible for maintaining the adhesive properties that binds a cell to a location.
• Immune Cell Secretion: Inflammatory cells like lymphocytes and neutrophils infiltrate tumors causing the release of other cellular agents that promote metastasis including cytokines and growth factors.
• Overexpression of LOX: LOX or lysyl oxidase changes enzymatic activity associated with cellular adhesion. As a result, increased LOX expression induces several of the influences mentioned above including EMT activation and the suppression of E-cadherin activity.
Factor #2: Modified Nrf2 Signaling
Nrf2 (nuclear factor-E2-related factor 2) signaling is involved in numerous functions in the body associated with healing. Nrf2 aids in DNA repair and has anti-inflammatory properties that regulate cellular adhesion. It also regulates enzyme activity and apoptosis and otherwise acts as a super antioxidant defense system.
This transcription factor is intrinsically involved in maintaining homeostasis throughout the body via stress management. Three major stress molecules including reactive oxygen species (ROS), hydrogen peroxide (H202), and reactive nitrogen species (RNS) are toxic to biological systems and are regulated by Nrf2.
Oxidative stressors ultimately degrade Nrf2 preventing its ability to block genetic mutations from occurring while aiding cells to appropriately manage stress.
Factor #3: Secretion of Connective Tissue-Dissolving Enzymes
The overexpression of metalloproteinases or MMPs is indicative of cancer metastasis. MMPs are a family of enzymes that break down the extracellular matrix within a cell. Typically, a healthy cell utilizes this connective network of tissue to communicate with other cells and its environment while also providing structure and various physiological functions.
When this matrix is degraded, there is an increased risk of malignant tumor growth. This is due to increased cellular permeability, response changes to surrounding stimuli including angiogenesis (new blood vessel growth), and increased systemic inflammation. Of the 21 MMPs recognized in the development of chronic conditions and disease, a select few are used as biomarkers in identifying aggressive cancer types.
MMP-13 activity is prevalent in metastatic breast cancers, urinary cancer, as well as skin, head, and neck cancers. MMP-11 is evident in invasive breast and skin cancer. MMP-2 and MMP-9 play a key role in cancer malignancy because they are associated with increasing tumor growth.
Specifically, these MMPs support metastatic growth factors like angiogenesis. They act as traffic controllers sending signals to inflammatory compounds and light the path to receptors. Once MMPs bind to these receptors they activate numerous other metastatic influences.
Factor #4: Angiogenesis
The development of new blood vessels to an abnormal cell naturally promotes aggressive tumor development. Angiogenesis provides a cancer cell with adequate blood flow and nutrients required to invade new tissue.
This energy fuels a tumor to create biological changes once it invades and interacts with endothelial cells. Thin layers of endothelial cells lines blood and lymphatic vessels. Once interaction with these cells is initiated, cancer has the ability to circulate throughout the body and invade distant tissue.
As infection increases and the cancer grows, conditions of hypoxia increases, further inducing LOX and giving rise to a cascade of adverse but favorable conditions to the tumor. Chronic inflammation leads to inflamed cells, prolonged oxidative stress, and the inability of the body to identify and eliminate the infectious cancer growth.
Cancer Tumor Prevention Strategies
The following strategies will increase the chemoprotective properties of your cells and limit cellular toxicity that stimulates cancer metastasis.
#1. Limit MMP Activity
Improving the regulation of MMP activity in cells is essential to reducing the breakdown of connective tissue within a cell and combating cancer metastasis. Some of the best dietary compounds that inhibit MMP activity and promote detoxification in the body are:
• Polyphenols: EGCG (epigallocatechin-3-gallate) found in green tea, resveratrol in dark grapes and berries, and curcumin-active turmeric
• Flavonoids: Quercetin, predominantly found in citrus fruits as well as apples
• Isothiocyanates: Sulfur-containing compounds including sulforaphane concentrated in broccoli and a variety of cruciferous veggies
Incorporating more of these antioxidants into your diet has been shown to effectively treat colon, prostate, kidney, and liver cancer − to name only a few. Simultaneous dietary phytochemicals provide significant cancer protective benefits to healthy cells and create cytotoxic effects to tumor cells. You can also support cellular integrity by consuming foods rich in zinc, magnesium, and vitamin C.
#2. Consume an Anti-Inflammatory Diet
Consuming an anti-inflammatory chemopreventive diet is the best way to prevent the aggressive behavior of cancer metastasis. These nutrients inhibit inflammatory enzymes and suppress carcinogenic activity:
• Berberine: Natural antibiotic with powerful anti-inflammatory properties. Found in goldenseal root and Oregon grape root
• Luteolin: Suppresses cancer by stimulating enzymes and supports elimination of toxins. Found in chamomile tea, celery, and green peppers
• Curcumin: Blocks TNF (tumor necrosis factor) therefore decreasing tumor growth activity. Active component in turmeric
• Kaempferol and Quercetin: Inhibits uric acid synthesis. Abundant in blackberries, spinach, onions, and cucumbers
• Apigenin: Scavenges free radicals and supports detoxification pathways. Concentrated in onions, oranges, and grapefruit
The key to preventing chronic inflammation and suppressing cancer growth is to limit foods high in sugar and starch. Genetically modified grains have flooded the marketplace and fuel cancer growth by supplying a steady feed of glucose.
Rather than feeding cancer, starve it by consuming foods that help maintain low blood sugar levels. These foods include 100% grass-fed beef and raw cheeses, and organic pasture-raised poultry. Adding low-carb fermented foods and beverages to your diet will help to provide an alkalizing environment in your tissue and organs inhibiting the development and spread of cancer.
<img class=”size-full wp-image-21155 alignright” src=”https://d2v4vjmuxdiocn.cloudfront.net/wp-content/uploads/anti-inflammation-diet-foods.jpg” alt=”Anti-inflammation Diet Foods to prevent Cancer” width=”900″ height=”1536″ />#3. Support the NRF2 Pathway
It is critical to strengthen the anti-inflammatory mechanisms regulated by Nrf2 signaling in order to protect your cells against oxidative damage and free radical activity. This is why the nutrients abundant in a plant-based diet have such powerful chemopreventive properties. Phytochemicals in fruits and vegetables prevent cancer development by upregulating antioxidant enzymes and detoxification processes.
Dietary phytochemicals support the Nrf2 defenses in the following ways:
•Inhibit the release of inflammatory promoting agents that induce metastasis
•Protect against genetic mutations and epigenetic alterations
•Turn off factors that keep cancer cells in a constant state of proliferation thus shutting down their ability to grow and divide
•Shut down transcription factors responsible for turning off the body’s defense mechanisms to fight against infection
Key dietary compounds that support the Nrf2 Pathway include curcumin, resveratrol, green tea extract, and sulforaphane, among others.
1Consume dietary compounds that inhibit MMP activity and promote detoxification in the body including EGCG found in green tea, resveratrol in dark grapes and berries, and turmeric; quercetin found in citrus fruits and apples; sulforaphane concentrated in broccoli and cruciferous veggies
2Consume nutrients that inhibit inflammatory enzymes and suppress carcinogenic activity such as berberine, luteolin, curcumin, kaempferol, quercetin and apigenin
3Strengthen the anti-inflammatory mechanisms regulated by Nrf2 signaling with curcumin, resveratrol, green tea extract, and sulforaphane
[-] Sources and References
PUBLIC RELEASE: 12-FEB-2018
Researchers inhibit cancer metastases via novel steps
Blocking action of gene enhancers halts spread of tumor cells
CASE WESTERN RESERVE UNIVERSITY
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In one of the first successes of its kind, researchers from Case Western Reserve University School of Medicine and six other institutions have inhibited the spreading of cancer cells from one part of the body to another. In doing so, they relied on a new model of how cancer metastasizes that emphasizes epigenetics, which examines how genes are turned on and off.
In a study published in Nature Medicine, the investigators–including scientists from the National Cancer Institute and Cleveland Clinic– used innovative epigenetic-centered techniques to halt the spread of bone cancer (osteosarcoma) cells to the lungs in mice. The large majority of deaths associated with osteosarcoma are due to the spreading of the cancer to the lungs, a process known as metastasis. Most human osteosarcoma cases occur in children and young adults between the ages of 10 and 30, with teens the most frequently affected age group. Clinical outcomes for patients with osteosarcoma have not improved for more than 30 years and there are currently no approved targeted anti-metastatic therapies for the disease in wide clinical use.
“More than 90 percent of all cancer deaths are the result of tumor metastasis, not primary-site tumors,” said the study’s senior author, Peter Scacheri, PhD, professor of genetics and genome sciences at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center. “While many of the genes responsible for metastasis have been identified, the mechanisms that control these genes are not well defined. Our findings demonstrate that altered gene-enhancer activity is fundamental to a cancer cell’s ability to metastasize.”
Gene enhancers are short segments of DNA that, when bound by specialized proteins called transcription factors, function like switches to activate genes. This process is critical for normal development, as when a single fertilized egg develops into the many different cell types which comprise the body. There are tens of thousands of gene enhancers in each cell, far more than the number of genes; they will be in different “on” and “off” positions in, for example, eye and heart cells, (or gradients thereof, like a dimmer switch’s effects on the brightness-level of a light). These distinctive “on and off” profiles lend cells their unique characteristics, even though they all have the same DNA. But faulty enhancer regulation appears to contribute to tumor-formation and subsequent spreading of cancer cells. In addition, different cancers are distinguishable by different enhancer patterns. In this new study, the authors show that the on-off switches of cancer cells that have metastasized are in different positions than in the cells of the source tumor.
“Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumors to form in the first place,” said the study’s lead author, James J. Morrow, PhD, a medical student in the Medical Scientist Training Program at Case Western Reserve University School of Medicine. “Unfortunately, searching for gene mutations that drive metastasis has not substantially improved outcomes for patients with metastatic disease. Five-year survival rates for cancer patients with regional or localized disease have significantly improved for many types of cancer. But with few exceptions, outcomes for patients with metastatic cancer have remained stagnant. It is well established that primary tumor formation is driven by a combination of genetic and epigenetic events. So based on the knowledge that enhancers drive both normal cell development and tumor-formation, we hypothesized that they may play a similar role in the transition of cancer cells from one developmentally distinct tissue to another during metastatic progression.”
Through epigenomic profiling experiments, the Case Western Reserve-led researchers consistently identified certain bunched clusters of enhancers – known as metastatic variant enhancer loci (Met-VELs) – near cancer genes in lung metastases of patients with osteosarcoma, indicating that they were central to the metastatic process. Using experimental mouse models, the researchers then showed that growth of osteosarcoma cells in the lung can be mitigated by using BET inhibitors (anti-cancer drugs currently in clinical trials), which broadly interrupt the function of Met-VELs in driving gene expression.
Second, they demonstrated that the metastatic capacity of osteosarcoma cells can be diminished by blocking expression of individual genes regulated by Met-VELs or the transcription factors driving that regulation. They verified that a particular Met-VEL-linked gene, Tissue Factor (F3), is essential for metastatic colonization. Specifically, interrupting the signaling and pro-coagulant (blood clotting) functions of F3 with antibodies inhibiting these functions was sufficient to prevent metastasis. Additionally, they showed that deleting a single Met-VEL regulating F3 expression via the TALEN gene-editing process achieved a similar effect. “Our experiments show that removing a single enhancer of the F3 gene in tumor cells virtually eliminates their ability to metastasize in mice,” said Scacheri. “Collectively, our findings establish that enhancer elements endow tumor cells with metastatic capacity and that targeted inhibition of genes associated with enhancer alterations, or deleting altered enhancers themselves is sufficient to block metastatic colonization and proliferation. While our work focused on lung metastasis in osteosarcoma, the findings have implications for other types of metastatic cancer as well.”
The Case Western Reserve University School of Medicine focus on epigenetics in the new study represents a break with the prevailing model for metastasis, which largely explores mutations in the genes – not if or how certain genes are turned on or off. And the preponderance of current cancer research takes place on the early stages of disease, such as how tumors are formed and on what distinguishes cancer cells from normal cells, and not on metastasis. Additionally, most cancer medications and treatments today were developed to kill primary tumors, not cancer cells that have spread elsewhere.
In addition to Case Western Reserve University School of Medicine, researchers from the following institutions participated in the study: Altius Institute for Biomedical Sciences, Seattle, Washington; Cleveland Clinic, Cleveland, Ohio; Istituto Ortopedico, Bologna, Italy; Leiden University Medical Center, Leiden, Netherlands; National Cancer Institute of the National Institutes of Health, Bethesda, Maryland; University of Washington, Seattle, Washington.
This work was supported by the Case Comprehensive Cancer Center, Liddy Shriver Sarcoma Initiative, QuadW Foundation, Sarcoma Foundation of America, and the National Institutes of Health.
For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
Phyto-polyphenols as potential inhibitors of breast cancer metastasis
Dimiter AvtanskiEmail author
and Leonid Poretsky
https://doi.org/10.1186/s10020-018-0032-7© The Author(s) 2018
Received: 27 April 2018Accepted: 27 May 2018Published: 5 June 2018
Breast cancer is the most common cancer among women as metastasis is currently the main cause of mortality. Breast cancer cells undergoing metastasis acquire resistance to death signals and increase of cellular motility and invasiveness.
Plants are rich in polyphenolic compounds, many of them with known medicinal effects. Various phyto-polyphenols have also been demonstrated to suppress cancer growth. Their mechanism of action is usually pleiotropic as they target multiple signaling pathways regulating key cellular processes such as proliferation, apoptosis and differentiation. Importantly, some phyto- polyphenols show low level of toxicity to untransformed cells, but selective suppressing effects on cancer cells proliferation and differentiation.
In this review, we summarize the current information about the mechanism of action of some phyto-polyphenols that have demonstrated anti-carcinogenic activities in vitro and in vivo. Gained knowledge of how these natural polyphenolic compounds work can give us a clue for the development of novel anti-metastatic agents.
There are many other holistic techniques to put in place both preventively and when the metastatic cascade is ongoing. For more details, the viewer can set up a coaching session.
Christian Joubert (ACRI director)