"Killing cancer cells" and "boosting immunity" constitute the two cornerstones of cancer treatment. If one can also achieve "inhibiting cancer metastasis" simultaneously, along with minimal toxic side effects, there is a greater likelihood of maximizing the efficacy of cancer treatment and of coexisting peacefully with cancer throughout one’s lifetime.

 

In April 2023, Director and Professor Jia Li, along with Associate Professor Lu Yusheng, both affiliated with the Marine Drug Development Center at Minjiang University, led a study published in "Food and Chemical Toxicology". Their research, utilizing breast cancer cells and animal models of breast cancer lung metastasis, demonstrated that Ganoderma lucidum extract (GLE) does have a "three-pronged" anti-cancer potential.

 

The mechanism by which GLE kills cancer cells through "cellular pyroptosis" and triggers anti-tumor immune responses is in line with recent strategies in cancer immunotherapy, which have garnered significant attention in the medical community. This once again underscores the timeless efficacy and enduring relevance of Ganoderma lucidum.

 

Research Team and Experimental Materials

 

In addition to the team members from the Marine Drug Development Center of Minjiang University, this study also involved researchers from the School of Basic Medicine at Gannan Medical University, the School of Pharmacy at Fujian University of Traditional Chinese Medicine, the Translational Research Center in Onco-Hematology (CRTOH), Faculty of Medicine, University of Geneva, Geneva, Switzerland, as well as researchers from Fujian Xianzhllou Biological Science and Technology Co., Ltd., among other institutions.

 

The Ganoderma lucidum extract (GLE or GanoExtra) used in the experiments was produced by Fujian Xianzhilou Biological Science and Technology Co., Ltd. using specific Ganoderma lucidum strains, cultivation methods, and extraction processes. Each 100 grams of the extract contains 10 grams of crude polysaccharides and 8 grams of total triterpenes from Ganoderma lucidum.

 

The touchstones used to test GLE are estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) human breast cancer cells, namely MCF-7 cells, as well as triple-negative (ER-, PR-, HER2-) mouse breast cancer cells, known as 4T1 cells, both displaying metastatic invasiveness.

 

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

 

The process of cancer metastasis is highly complex. Firstly, the tumor must stimulate adjacent capillaries to grow new blood vessels that penetrate the tumor tissue, in order to obtain nutrients for proliferation and growth. Secondly, cancer cells that detach from the tumor must not only possess the ability to invade and migrate to break through tissue barriers and advance toward the periphery of blood vessel walls but also have the capability to adhere to endothelial cells on the blood vessel wall, enabling them to enter the bloodstream and hitchhike on the blood flow, and eventually extravasate from the blood vessels to colonize new territories. Finally, those fortunate enough to evade the vanguard immune attacks must also possess the ability to form colonies in order to successfully establish themselves in new locations.

 

Illustration of Cancer Metastasis and the Five Key Steps

（https://www.mdpi.com/2073-4409/10/11/2815）

 

Suppression of any of the aforementioned abilities increases the difficulty of cancer cell metastasis. However, based on the results of in vitro experiments in this study, Ganoderma lucidum extract (GLE) at concentrations of 50–200 μg/mL not only inhibits angiogenesis but also diminishes breast cancer cell survival, migration, invasion, adhesion, and colony formation (as shown in the table below). Furthermore, the inhibitory effect of GLE is positively correlated with the dosage, indicating that with appropriate dosing, GLE has the potential to comprehensively hinder breast cancer cell metastasis.

 

Oral administration of Ganoderma lucidum extract enhances anti-tumor immunity and reduces lung metastasis rates after breast cancer tumor resection.

 

Researchers further investigated the anticancer effects of GLE (Ganoderma lucidum extract) in vivo: First, they implanted 4T1 breast cancer cells into the mammary fat pad of female mice. Once the tumors reached a size of 100 mm³, they were surgically removed. The mice were then orally administered GLE at doses of either 20 mg/kg or 200 mg/kg daily for 30 consecutive days. The results showed that both groups treated with GLE had one-third fewer lung metastatic tumors compared to the tumor control group that did not receive GLE. Additionally, there was a significant increase in cytotoxic T cells in peripheral blood and spleen, with the GLE 200 mg/kg group showing a notable augmentation in natural killer cell count.

 

Cytotoxic T cells and natural killer (NK) cells are the two major indicators of anticancer immune response. The former, marked by the CD8 molecule (CD8+), specifically targets and kills cancer cells that have been identified. NK cells, on the other hand, do not require additional cellular instructions and can launch attacks against any cancer cells. Ganoderma lucidum extract (GLE) has the potential to enhance the strength of both these cell types, indicating its role in inhibiting breast cancer lung metastasis and contributing to improved antitumor immunity.

Inhibitory Effect of Ganoderma Lucidum Extract (GLE) on Postoperative Lung Metastasis in Breast Cancer Mice

Modulatory Effect of Ganoderma Lucidum Extract (GLE) on Postoperative Antitumor Immunity in Breast Cancer Mice

 

Ganoderma lucidum extract initiates the pyroptosis pathway in cancer cells: simultaneously eliminating cancer cells and enhancing immunity.

 

Furthermore, according to the evidence proposed by this study, Ganoderma lucidum extract (GLE) can also poison breast cancer cells through the induction mechanism of "pyroptosis", improve immunity, and add chips to the suppression of tumor growth and metastasis.

 

Pyroptosis and the commonly heard term apoptosis are both cellular self-destructive mechanisms. However, unlike apoptosis, where cells wither away silently, pyroptotic cells create pores in their cell membranes, allowing extracellular fluids and water to continuously flood in. This leads to cell swelling akin to an inflating balloon until rupture occurs. At the moment of cell rupture, proinflammatory cytokines synthesized during pyroptosis, such as IL-1β and IL-18, are released, triggering a favorable immune response against tumors (as depicted in the figure below).

 

Illustration of Pyroptosis Enhancing Antitumor Immunity（https://www.nature.com/articles/s41420-020-00349-0）

 

One of the molecular pathways that initiates pyroptosis involves the activation of caspase 3, a critical protease in regulating programmed cell death. Subsequently, activated caspase 3 cleaves the "GSDME (Gasdermin E)," releasing the N-terminal fragment GSDME-N capable of creating pores in the cell membrane.

 

In other words, activated caspase 3 and GSDME-N serve as molecular markers for initiating the pyroptosis pathway in cells. When cells reach this stage, their appearance is akin to swollen balloons, and the amount of lactate dehydrogenase (LDH) flowing out of the cells will also increase significantly due to severe cell membrane damage.

 

The observed phenomena mentioned above were all present in the experimental results of treating breast cancer cells with Ganoderma lucidum extract (GLE) (as shown in the figure below). Additionally, when mice with breast cancer underwent continuous oral administration of GLE for 30 days after tumor removal, not only did their lung tissues exhibit abundant activated caspase 3 protein, but the lung metastatic tumors also showed significant infiltration of cytotoxic T cells (as depicted in the figure below). Consequently, the research team posits 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

 

Regulatory Effects of Ganoderma Lucidum Extract (GLE) on the Tumor Microenvironment in Postoperative Breast Cancer Mice

 

The action of Ganoderma lucidum extract in killing breast cancer cells is not only reliant on "promoting pyroptosis" but also on "inducing apoptosis".

 

The aforementioned research findings demonstrate a novel role of Ganoderma lucidum extract (GLE) in inhibiting breast cancer metastasis through promoting pyroptosis. This enlightens us further on how Ganoderma lucidum contributes to anticancer mechanisms. However, the research team also discovered in in vitro experiments that when they blocked the cell pyroptosis pathway, the rate of breast cancer cell death due to GLE decreased by approximately 35%. This suggests that besides promoting pyroptosis, GLE also employs other methods to combat cancer.

 

Since the activated caspase 3 protein can not only initiate the "pyroptosis" program, it can also initiate the "apoptosis" program (as shown below), causing cells to end their lives by "DNA fragmentation, nuclear division, and cell atrophy and decomposition." Therefore, the research team concluded that GLE can also push 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）

 

The Ganoderma lucidum extract (GLE) induces cancer cell pyroptosis via GSDME, serving a dual purpose of avoiding drug resistance and enhancing immunotherapy.

 

According to current scientific research, when caspase 3 protein within cancer cells is activated, it theoretically initiates the apoptosis program. However, if the current expression level of the GSDME within the cell is sufficiently high, caspase 3 protein switches to inducing pyroptosis instead. The challenge lies in the fact that most tumor cells express GSDME at low levels. However, the Ganoderma lucidum extract (GLE) used in this study enhances GSDME expression in breast cancer cells, thereby transforming the seemingly impossible "pyroptosis" into a viable outcome. 

 

Due to the fact that many chemotherapy drugs achieve their anticancer effects by inducing apoptosis, resistance to apoptosis has become a common cause of drug resistance in cancer cells. Therefore, Ganoderma lucidum extract (GLE) employs a dual strategy, undoubtedly directing those apoptosis-resistant cancer cells toward the path of pyroptosis, thereby reducing the occurrence of treatment failure.

 

Furthermore, due to its ability to simultaneously activate an antitumor immune response dominated by cytotoxic T cells, pro-pyroptosis aligns with the definition of cancer immunotherapy as leveraging the patient's own immune system to combat cancer. Consequently, pro-pyroptosis is hailed as a promising next-generation cancer immunotherapy.

Based on this research, it has been confirmed that Ganoderma lucidum extract (GLE) has three key points that contribute to its anticancer properties.

（https://doi.org/10.1016/j.fct.2023.113654）

 

Ganoderma lucidum extract (GLE) is safe for consumption and can improve anemia caused by tumors.

 

From interfering with various steps of tumor metastasis to promoting pyroptosis in cancer cells and enhancing immune responses, Ganoderma lucidum extract (GLE) has indeed proven to be more than just single-pronged. It partially explains the unexpected benefits some individuals have experienced when using GLE as an adjunct in cancer treatment.

 

Importantly, the efficacy of Ganoderma lucidum extract (GLE) does not conflict with its safety. Based on observations by the research team, continuous oral administration of GLE to mice with breast cancer lung metastasis for 30 days after surgery not only had no adverse effects on the heart, liver, spleen, and kidneys but also improved anemia caused by tumors (as shown in the figure below). This highlights the remarkable divergence between Ganoderma lucidum extract and conventional pharmaceuticals.

 

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

 

Cancer treatment is not solely about eradicating cancer cells; nor can it be accomplished by merely opting for the lesser of two harmful drugs. Instead, it necessitates a holistic approach that takes into account immune balance, tissue cell protection, and maintenance of organ function to accumulate the energy required for recovery.

 

The ancient Ganoderma lucidum has never been out of date. May the compilation of this research help everyone understand the benefits of Ganoderma lucidum, and may this remarkable fungus lend a helping hand to friends 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 manuscript of this article was authored in Chinese by Wu Tingyao and subsequently translated into English by Alfred Liu. In the event of any inconsistencies between the English translation and the original Chinese text, the latter shall take precedence. For any queries, pls reach out to the original author, Ms. Wu Tingyao.