Magda Wojtara ’22 and Samantha Ratner ’22
“Next to water, tea is the most consumed beverage worldwide with approximately 20 billion cups consumed daily,” which is almost 2000 olympic swimming pools.1,2 Tea has long been a staple in the diets of individuals all over the world and has been heralded for its health benefits.3 Lots of people have a cup of tea when they are sick, and recent studies have shown that tea might be able to prevent cancer. Much of the research about the potential anti-cancer effects of tea has focused on chemicals called polyphenols, which are the major active compounds in tea and are also responsible for the distinct flavors and aromas of tea. There are many common dietary sources of polyphenols, including berries, peppers, dark chocolate, red wine, and coffee, and they have a wide variety of health effects (Figure 1).4 These compounds are structurally diverse, but they all have multiple hexagonal, ring-like components called phenols, as shown in Figure 2. Different types of tea can contain different polyphenols.5 For instance, For instance, the major polyphenol in green tea is a catechin called (−)-epigallocatechin-3-gallate, or EGCG (Figure 2). Theaflavins and thearubigins are commonly found in black tea.5 Polyphenols are a promising candidate for advancing numerous anti-cancer innovations due to their accessibility through common dietary sources like tea and potential ability to combat cancer through both reversing epigenetic changes and improving the efficacy of cancer treatments.
In the United States, cancer is the second leading cause of death.4 Cancer is caused by uncontrolled cell division, which can be caused by both inherited and environmental factors. Sometimes cancer can run in families, meaning people can inherit an increased risk of cancer. However, environmental and behavioral factors like smoking can also increase an individual’s risk of cancer. One way that these risk factors cause cancer is through alterations to your DNA sequence, also called genetic changes. Each gene acts as a blueprint to make a specific product, which is usually a protein. To describe how often we use a particular gene to make its product, we use the terms activity and expression.7 Changes in your DNA sequence can increase or decrease the activity of a gene.4 Cancer is caused by altered expression in two main kinds of genes: proto-oncogenes and tumor suppressor genes. Proto-oncogenes promote cell division and prevent cell death. However, if these genes are too active, they can cause cells to divide more than they should and cause cancer. When proto-oncogenes are mutated, they are referred to as oncogenes. Tumor suppressor genes are the opposite of proto-oncogenes because they prevent cell division and promote cell death, so cancer can result from inactivation or reduced expression of these genes. When proto-oncogenes and tumor suppressor genes are functioning normally, they work together to regulate how often cells divide and when they should die.8,9
Another cause of cancer is epigenetic changes, which alter the expression levels of genes without disrupting the DNA sequence.4 If epigenetics do not cause changes in the DNA sequence, how do they work? If you are listening to music and you change the volume, it does not change the song itself. Similarly, epigenetic marks affect the expression of a gene without altering the gene itself. Genetics and epigenetics work together to make us who we are. All genes are present in every cell in the body, but not all genes are needed to make their corresponding protein in every cell all the time, so epigenetic marks are used to alter the expression levels of genes and can vary by cell type. In addition, epigenetic changes naturally occur over time and are caused by different experiences, exposures, and behaviors such as the foods you eat or exposure to pollution. Identical twins have the same DNA sequence, but they are not exactly the same people because of epigenetics.10
There are several types of epigenetic modifications to our genes that can contribute to cancer development. One type of epigenetic modification is called DNA methylation, which refers to the process of adding a chemical group called a methyl group, which is a carbon attached to three hydrogens, to your DNA. This modification turns down the expression of a gene without affecting the DNA sequence. Another type of epigenetic mechanism involves histones, which are proteins that help to compact the DNA. The DNA wraps around the histones like string, which makes it more compact. Like in DNA methylation, histone modifications involve adding a chemical group to change the volume. However, there are several types of histone modifications, and they can either increase or decrease the volume of the gene depending on the type of modification and where it is added. Some of them use methyl groups, which are generally used to turn down the activity, but some of them add an acetyl group, which is a small molecule made of carbon, hydrogen, and oxygen, to turn up the volume on a gene.11 Some epigenetic changes that could cause cancer are DNA methylation or histone methylation that turns down the expression of tumor suppressor genes, or histone acetylation that increases the expression of oncogenes. Alternatively, cancer could be caused by removing epigenetic marks. For example, removing acetyl groups from a histone associated with a tumor suppressor gene, would result in less expression of the gene and could cause cancer. These mechanisms are important because epigenetic changes are present in every human cancer and are critical for cancer development and progression.8,12
Some studies have shown that polyphenols may reverse some of the epigenetic markings associated with cancer. The most active polyphenol in green tea is EGCG (Figure 2). This polyphenol can attach to the protein that adds a methyl group to DNA to prevent methylation. As a result, the gene is more expressed because it is not methylated. This activity was shown to reverse excessive methylation caused by cancer.13 EGCG has also been shown to increase the activation of tumor suppressor genes by inhibiting the activity of a protein called histone deacetylase, or HDAC. This protein typically removes acetyl groups from histones, which usually activate genes. By inhibiting this protein, acetyl groups are not removed from the histone, so the volume of this gene remains high.11 However, EGCG in green tea is not the only polyphenol with anti-cancer epigenetic effects. For example, curcumin, a component of turmeric, has been shown to remove methylation from the region of DNA that controls expression of a tumor suppressor gene called DLC1, thereby turning up the volume of this gene in breast cancer cells.14 These studies show multiple epigenetic mechanisms supporting the anti-cancer effects of polyphenols.
In addition to directly combating the effects of cancer, the epigenetic effects of polyphenols may also be able to improve cancer treatment. Specifically, EGCG has been shown to potentially address one of the major current challenges in cancer treatment, which is hormone receptor negative cancers. These cancers do not express hormone receptors, which are proteins that bind to hormones like estrogen and progesterone. These cancers tend to grow faster and do not respond to some existing cancer treatments that target hormones.15 EGCG has been shown to increase the expression of the ERα gene, which makes an estrogen receptor, and makes cells sensitive to hormone directed therapies. As a result, polyphenols may be a promising avenue for future research on optimizing cancer treatment.16
The studies showing anti-cancer effects from polyphenols mostly used experiments on cells grown in a lab (cell culture) or on mice (mouse models), and there are limited studies in humans. Studies in humans are typically preferable to mouse models and cell culture because a particular treatment might be really effective when tested using these methods, but might not work the same way in humans. Non-human studies can be informative, but they are often used as a gateway to clinical trials because studies in humans can 1) corroborate findings when the same results occur in both formats and 2) can provide information that is more applicable to the audience. Most of the studies discuss the effects of polyphenols in a particular pathway or mechanism but do not show the potential clinical significance. There is not a clear consensus about the ideal dosages of polyphenols or which types are the most effective. As a result, we do not know whether the amount of tea people regularly consume would have a significant impact. One study in humans showed that increased green tea consumption was correlated with better outcomes in people diagnosed with stage I or II breast cancer.17 However, further studies are necessary to determine whether this is causal. Based on research thus far, the accuracy of these findings appears to be high since it has been corroborated with the work of many different researchers. Many of these papers are review articles, meaning that they summarize the findings of multiple studies about a particular topic, so there seems to be agreement amongst several papers that polyphenols may have anti-cancer effects. There are, however, a large number of different polyphenols so there is a possibility that some polyphenols may have a more significant anti-cancer effect than others due to differences in structure.
Although some studies have demonstrated the anti-cancer effects of polyphenols, more research should be done on this topic, especially the role of epigenetic mechanisms on the impact of polyphenols. Drinking tea or consuming foods that contain polyphenols would be an accessible and easy way to prevent cancer and improve treatment outcomes. Although drinking tea alone is likely not enough to cure cancer, it may be an easy intervention to supplement and improve the response to existing treatments. More work should also be done to determine if certain polyphenols are more effective than others and how much is needed for a significant anti-cancer effect.
Outside of its role in the anti-cancer response, there is the potential for multiple avenues of future research. Polyphenols have been reported to prevent decline in brain function which occurs in many different neurodegenerative diseases like Parkinson’s Disease, and they can promote the generation of new neurons, which are a type of cell that is important for sending signals for movement and sensing the environment.18 Parkinson’s Disease is a progressive loss of neurons that respond to dopamine, an important neurotransmitter that helps to control movement, memory and pleasure. This loss of neurons happens in a region of the brain called the substantia nigra, which is a small region in the midbrain and is responsible for a variety of functions including voluntary movement.19 Additionally, polyphenols in tea may prevent cardiovascular disease and reduce stroke risk, but more evidence is needed.3
Based on this research, tea and the polyphenols it contains may have some health benefits, such as cancer prevention, that should be explored further. More studies on humans should be performed in order to determine the clinical significance of these findings including the optimal doses and ideal dietary sources of polyphenols. In addition, there is a lot of current research on other dietary compounds and their impacts on human health. This research has significant real-world impacts because simple dietary changes may be able to prevent diseases or improve treatments. Future research on this topic could be used to inform policy changes such as subsidizing foods with known health benefits. Overall, researching the health impacts of polyphenols will hopefully lead to more research on how what we eat impacts our health.
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- Tea | The Nutrition Source | Harvard T.H. Chan School of Public Health. https://www.hsph.harvard.edu/nutritionsource/food-features/tea/.
- Arora, I., Sharma, M. & Tollefsbol, T. O. Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy. Int. J. Mol. Sci. 20, 4567 (2019).
- Khan, N. & Mukhtar, H. Tea Polyphenols in Promotion of Human Health. Nutrients 11, 39 (2018).
- Bigelow, R. L. H. & Cardelli, J. A. The green tea catechins, (−)-Epigallocatechin-3-gallate (EGCG) and (−)-Epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells. Oncogene 25, 1922–1930 (2006).
- Gene Expression. Genome.gov https://www.genome.gov/genetics-glossary/Gene-Expression.
- Baylin, S. B. & Jones, P. A. Epigenetic Determinants of Cancer. Cold Spring Harb. Perspect. Biol. 8, a019505 (2016).
- Oncogenes and Tumor Suppressor Genes | American Cancer Society. https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html.
- Flintoft, L. Identical twins: epigenetics makes the difference. Nat. Rev. Genet. 6, 667–667 (2005).
- Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention – ScienceDirect. https://www.sciencedirect.com/science/article/pii/S0304383514005291#bib0190.
- Özyalçin, B. & Sanlier, N. The effect of diet components on cancer with epigenetic mechanisms. Trends Food Sci. Technol. 102, 138–145 (2020).
- Tea Polyphenol (−)-Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase and Reactivates Methylation-Silenced Genes in Cancer Cell Lines | Cancer Research | American Association for Cancer Research. https://aacrjournals.org/cancerres/article/63/22/7563/510678/Tea-Polyphenol-Epigallocatechin-3-Gallate-Inhibits.
- Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter | SpringerLink. https://link.springer.com/article/10.1007/s11010-016-2861-4.
- Breast Cancer Hormone Receptor Status | Estrogen Receptor. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
- Li, Y., Yuan, Y.-Y., Meeran, S. M. & Tollefsbol, T. O. Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells. Mol. Cancer 9, 274 (2010).
- Nakachi, K. et al. Influence of Drinking Green Tea on Breast Cancer Malignancy among Japanese Patients. Jpn. J. Cancer Res. 89, 254–261 (1998).
- Di Meo, F. et al. Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration. Int. J. Mol. Sci. 21, 2564 (2020).19. Thangapazham, R. L., Sharad, S. & Maheshwari, R. K. Phytochemicals in Wound Healing. Adv. Wound Care 5, 230–241 (2016).