Killing cancer cells and boosting immunity are the two cornerstones of fighting cancer. If it is also possible to inhibit cancer metastasis while having little or no toxic side effects, there is a greater chance of maximizing the anti-cancer effect and coexisting peacefully with cancer for a lifetime.

 

In April 2023, a study led by Professor Jia Li, director of the Marine Drug Research and Development Center at Minjiang University, and Associate Professor Lu Yusheng of the same center, was published in the journal Food and Chemical Toxicology. The study demonstrated the potential of GLE, an extract of Ganoderma lucidum, to fight cancer through a “three-pronged” approach using animal models of breast cancer cells and breast cancer lung metastasis.

 

The mechanism by which GLE kills cancer cells through “cell pyroptosis” and stimulates anti-tumor immune responses is in line with the new strategy of cancer immunotherapy that has attracted much attention in the medical community in recent years. This once again proves the timeless and evergreen value of Ganoderma lucidum.

 

 

Research team and experimental materials

 

In addition to the team members of the Marine Drug Research and Development Center at Minjiang University, this study was jointly conducted by researchers from several institutions, including the School of Basic Medicine at Gannan Medical College, the School of Pharmacy at Fujian University of Traditional Chinese Medicine, the Translational Research Centre in Onco-Hematology (CRTOH) at the University of Geneva in Switzerland, and Fujian Xianzhilou Biological Science and Technology Co., Ltd.

 

The Ganoderma lucidum extract (GLE, GanoExtra) used in the experiment was made by Fujian Xianzhilou Biological Science and Technology Co., Ltd. using specific strains of Ganoderma lucidum cultivated and extracted in a specific way. Each 100 grams of this extract contains 10 grams of Ganoderma lucidum crude polysaccharides and 8 grams of Ganoderma lucidum total triterpenes.

 

The test for GLE is human breast cancer cells (MCF-7) that are positive for both estrogen receptor and progesterone receptor (ER+/PR+), as well as mouse triple-negative (ER-/PR-/Her2-) breast cancer cells (4T1), both of which have metastatic aggressiveness.

 

Ganoderma lucidum extract can interfere with multiple steps of cancer metastasis.

 

The process of cancer metastasis is complex. First, the tumor must promote the growth of new blood vessels from nearby capillaries to penetrate the tumor tissue in order to obtain nutrients for growth and expansion. Furthermore, cancer cells that break away from the tumor must not only have the ability to invade and migrate, but also be able to break through the tissue barrier and advance into the surrounding blood vessel walls. They must also have the ability to adhere to endothelial cells on the blood vessel walls in order to enter the blood vessels and hitch a ride with the blood flow, and then be able to exit the blood vessels and colonize new territories. Finally, the pioneer units of cancer cells that are fortunate enough to escape immune sniping must also have the ability to form colonies in order to take root in new territories.

 

 

A schematic diagram of cancer metastasis and the five main steps of metastasis (https://www.mdpi.com/2073-4409/10/11/2815)

 

The suppression of any of the above abilities can increase the difficulty of cancer cell metastasis. However, according to the results of in vitro experiments from this study, Ganoderma lucidum extract GLE (50-200 μg/mL) can not only inhibit angiogenesis but also weaken the ability of breast cancer cells to survive, migrate, invade, adhere, and form colonies (as shown in the table below). Moreover, the inhibitory effect is positively correlated with the dose of GLE. This indicates that as long as the dose is appropriate, GLE has the potential to break through multiple points and comprehensively block the metastasis of breast cancer cells.

 

Oral administration of Ganoderma lucidum extract can promote anti-tumor immunity and reduce the rate of lung metastasis after breast cancer tumor resection. 

 

Researchers conducted a study to further investigate the anti-cancer effects of Ganoderma lucidum extract (GLE) in vivo. They implanted 4T1 breast cancer cells into the mammary fat pads of female mice. Once the tumors grew to a size of 100 mm³, they were surgically removed. The mice were then orally administered either 20 mg/kg or 200 mg/kg of GLE every day for a period of 30 consecutive days. The results showed that both groups had one-third fewer lung metastases compared to the control group that did not receive GLE. Additionally, there was a significant increase in the number of cytotoxic T cells in the peripheral blood and spleen, and the number of natural killer cells also increased significantly in the group that received 200 mg/kg of GLE. 

 

Cytotoxic T cells and natural killer cells are two major indicators of anti-tumor immunity. The former is a subgroup of T cells marked with CD8 molecules (CD8+), which can specifically kill targeted cancer cells. The latter, also known as NK cells, do not require instructions from other cells and can attack any cancer cell. GLE can strengthen the power of these two, indicating that the role of GLE in inhibiting breast cancer lung metastasis is also related to the enhancement of anti-tumor immunity.

 

The inhibitory effect of Ganoderma lucidum extract (GLE) on postoperative lung metastasis in breast cancer mice.

  

The regulatory effect of Ganoderma lucidum extract GLE on anti-tumor immunity in breast cancer mice after surgery.

 

In addition, evidence presented in this study shows that Ganoderma lucidum extract (GLE) can also kill breast cancer cells and boost the immune system through the induction mechanism of “cell pyroptosis”, adding another chip to the inhibition of tumor growth and metastasis.

 

Cell pyroptosis and cell apoptosis, which we often hear about, are both ways for cells to self-destruct. However, unlike the silent shrinking and withering of apoptotic cells, pyroptotic cells will “punch holes” in their cell membranes, allowing extracellular fluids and water to continuously flow in, causing the cells to swell like water-filled balloons until they burst. When the cell’s contents spill out, cytokines such as IL-1β and IL-18 synthesized during pyroptosis also flow out, triggering a beneficial anti-tumor immune response (as shown in the figure below).

 

Schematic diagram of increased anti-tumor immunity through cellular pyroptosis (https://www.nature.com/articles/s41420-020-00349-0)

 

One of the molecular pathways that initiates cell pyroptosis is the activation of caspase 3 (a key protease that regulates the cell suicide program), which then cleaves the pore-forming protein GSDME (Gasdermin E), releasing its N-terminal fragment GSDME-N, which can “punch holes” in the cell membrane.

 

In other words, activated caspase 3 and GSDME-N are molecular markers for the initiation of the pyroptosis mechanism in cells. When cells reach this stage, their appearance should swell like a balloon, and the lactate dehydrogenase (LDH) that flows out of the cell will also increase significantly due to severe damage to the cell membrane.

 

Since all of the above phenomena appear in the experimental results of treating breast cancer cells with Ganoderma lucidum extract (GLE) (as shown in the figure below), and breast cancer mice that were orally administered GLE for 30 consecutive days after tumor resection not only had a large amount of activated caspase 3 protein in their lung tissue but also had a large amount of cytotoxic T cell infiltration in their lung metastases (as shown in the figure below). The research team believes that “promoting cancer cell pyroptosis” is one of the mechanisms by which GLE inhibits breast cancer cell survival and enhances anti-tumor immunity.

 

The pro-pyroptotic effect of Ganoderma lucidum extract (GLE) on breast cancer cells

The regulatory effect of Ganoderma lucidum extract (GLE) on the postoperative tumor microenvironment in breast cancer mice

 

The above research results have proven the new function of Ganoderma lucidum extract (GLE) in “inhibiting breast cancer metastasis by promoting pyroptosis.” This allows us to have a better understanding of how Ganoderma lucidum fights tumors. However, the research team also found in vitro experiments that when they blocked the pyroptosis pathway, the death rate of breast cancer cells due to GLE only decreased by about 35%, indicating that GLE has other methods of killing cancer cells besides promoting pyroptosis.

 

The activated caspase 3 protein can initiate not only the “cell pyroptosis” program but also the “cell apoptosis” program (as shown in the figure below), causing the cell to end its life in a way of “DNA fragmentation, nuclear division, and subsequent cell shrinkage and decomposition.” Therefore, the research team inferred that GLE can also force cancer cells to the end of apoptosis.

 

Schematic diagram of caspase 3 protein initiating cell apoptosis and pyroptosis mechanisms (https://www.nature.com/articles/s41420-020-00349-0)

 

Ganoderma lucidum extract promotes cancer pyroptosis through GSDME, which has the dual significance of “avoiding drug resistance” and “immunotherapy”.

 

According to current scientific research, when the caspase 3 protein in cancer cells is activated, it will initiate the apoptosis program in principle. However, if the expression level of the perforin GSDME in the cell is high enough, the caspase 3 protein will instead initiate the pyroptosis program. The problem is that most tumor cells do not express GSDME very much, but the Ganoderma lucidum extract (GLE) in this study can increase the expression of GSDME in breast cancer cells, making the impossible “pyroptosis” possible. 

 

Since the mechanism of many chemotherapy drugs to kill cancer cells is achieved by “promoting apoptosis”, “anti-apoptosis” has become a common cause of drug resistance in cancer cells. Therefore, the “two-handed strategy” of Ganoderma lucidum extract (GLE) can undoubtedly lead those anti-apoptotic cancer cells to pyroptosis, reducing the occurrence of failure.

 

In addition, since promoting pyroptosis can simultaneously activate anti-tumor immune responses mainly mediated by cytotoxic T cells, which is in line with the definition of cancer immunotherapy “attacking cancer through the patient’s own immune system”, “promoting pyroptosis” is also hailed as a new generation of cancer immunotherapy and is highly anticipated.

 

This study confirms that Ganoderma lucidum extract (GLE) has three major advantages in fighting cancer (https://doi.org/10.1016/j.fct.2023.113654)

 

The consumption of Ganoderma lucidum extract is safe and can improve anemia caused by tumors.

 

Ganoderma lucidum extract (GLE) has been shown to have multiple anti-tumor effects, from interfering with the various steps of tumor metastasis to killing cancer cells by promoting pyroptosis and stimulating immunity. This provides some explanation for the unexpected gains observed by some people who use Ganoderma lucidum extract as an adjunct to cancer treatment.

 

More importantly, the effectiveness of Ganoderma lucidum extract (GLE) does not conflict with its safety. According to observations made by a research team on mice with breast cancer lung metastasis after 30 days of continuous oral administration of GLE, GLE not only had no negative impact on the heart, liver, spleen, and kidneys but also improved anemia caused by tumors (as shown in the figure below). This suggests that Ganoderma lucidum extract is quite different from the general drugs we are familiar with.

 

Ganoderma lucidum extract (GLE) can improve anemia indicators in mice with breast cancer.

 

Cancer treatment is not simply a matter of killing all cancer cells or choosing the medication that is considered to be the less harmful of the two. Instead, it requires a comprehensive approach that takes into account immune balance, protection of tissue cells, and maintenance of organ function in order to accumulate the energy needed for restoration of health.

 

The ancient Ganoderma has never been outdated. It is hoped that the organization of this research will help everyone understand the benefits of Ganoderma and that good Ganoderma can lend a helping hand to friends who are dancing with cancer.

 

References:
1. Chunlian Zhong, et al. Ganoderma lucidum extract promotes tumor cell pyroptosis and inhibits metastasis in breast cancer. Food Chem Toxicol. 2023 Apr;174:113654. doi: 10.1016/j.fct.2023.113654.

2. Jenna A. Dombroski, et al. Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis. Cells. 2021; 10(11): 2815.

3. Mingxia Jiang, et al. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Review Cell Death Discov. 2020;6:112.

4. Nancy Fliesler. Gasdermin E: A new approach to cancer immunotherapy. Boston Children’s Hospital Website. Posted on 2020 March 11.

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★ The original text of this article was written in Chinese by Wu Tingyao and translated into English by Alfred Liu. If there is any discrepancy between the translation (English) and the original (Chinese), the original Chinese shall prevail. If readers have any questions, please contact the original author, Ms. Wu Tingyao.