Abstract
This review discusses the immunological roles of 5 major mushrooms in oncology: Agaricus blazei, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, and Trametes versicolor. These mushrooms were selected based on the body of research performed on mushroom immunology in an oncology model. First, this article focuses on how mushrooms modify cytokines within specific cancer models and on how those cytokines affect the disease process. Second, this article examines the direct effect of mushrooms on cancer. Finally, this article presents an analysis of how mushrooms interact with chemotherapeutic agents, including their effects on its efficacy and on the myelosuppression that results from it. For these 5 mushrooms, an abundance of in vitro evidence exists that elucidates the anticancer immunological mechanisms. Preliminary research in humans is also available and is promising for treatment.
Medicinal mushrooms have been proposed as a novel therapy that may improve cancer treatment and patients’ survival. They have been used medicinally since at least 3000 bce. Mushrooms are reported to have antimicrobial, anti-inflammatory, cardiovascular-protective, antidiabetic, hepatoprotective, and anticancer properties. It is well-established that mushrooms are adept at immune modulation and affect hematopoietic stem cells, lymphocytes, macrophages, T cells, dendritic cells (DCs), and natural killer (NK) cells.1 Extensive research over the last 40 years has demonstrated that mushrooms have potent antineoplastic properties that slow growth of tumors, regulate tumor genes, decrease tumoral angioneogenesis, and increase malignant-cell phagocytosis. Additionally, evidence suggests that medicinal mushrooms may safely boost chemotherapeutic efficacy and simultaneously protect against bone marrow suppression.
Mushrooms represent a unique branch of botanical medicine and are classified in the kingdom of Fungi. They reproduce as spores. The fungal body can be a single cell or a structure called a hypha or mycelial threads. The fruiting body grows off the hyphae and produces spores for reproduction (Figure 1). The common and scientific names of the mushrooms discussed in this article are found in Table 1. The 5 mushrooms explored in this paper have many active constituents including, but not limited to, polysaccharides, polysaccharide peptides, proteins, terpenoids, and nucleotides . Many of the compounds studied have yet to be named and are often referred to by gel chromatography fraction when they are studied. The most common medicinally active ingredient among mushrooms is β-glucan.
Mushroom Anatomy
Table 1
Scientific and Common Names of Mushrooms and Their Major Constituents
| Scientific Name | Common Name | Specific Constituent | Type of Constituent |
|---|---|---|---|
| Agaricus blazei | Agaricus | β-d-glucan | Polysaccharide |
| Ganoderma lucidum | Reishi, lingzhi | Ganoderic acid | Protein |
| Danoderiol | Protein | ||
| Danderenic acid | Protein | ||
| Lucidenic acid | Protein | ||
| GLPS | Polysaccharide | ||
| Cordyceps sinesis | Cordyceps, caterpillar mushroom | Adenosine | Nucleotide |
| Cordycepin | Nucleotide | ||
| Trametes versicolor (formerly Coriolus versicolor) | Turkey tail | PSP | Polysaccharide peptide |
| PSK | Polysaccharide peptide | ||
| Grifolia frondosa | Maitake | Grifolan | Polysaccharide |
| D-fraction | |||
| MD-fraction | Polysaccharide | ||
Abbreviations: GLPS = Ganoderma lucidum polysaccharide; PSP = polysaccharide peptide; PSK = polysaccharide K.
Cancer Immunology
One of the myriad effects of mushrooms occurs through their ability to stimulate cytokine production. Cytokines are small, soluble proteins that act as intracellular mediators in an immune response. In the effort to understand cytokine responses and the interrelationships between cytokines, one approach has been to characterize a certain set of cytokines for responses to different situations. The cytokines involved in different types of responses are defined as cytokine patterns. Patterns of importance in cancer research include TH1, TH2, TH3/T regulatory (Treg) cells, and the proinflammatory pathways. Each of these defined patterns can have a different physiological effect in a cancer patient. Cytokines are cross-regulatory, and the expression of one pattern of cytokines can modulate other cytokine patterns. To evaluate the role of cytokines in disease, it is necessary to evaluate several cytokines from each pathway because the overall pattern may have a larger impact on the body than any individual cytokine.
Table 2
Basic Cytokine Patterns
| Pattern | Cytokines | Pattern Effect |
|---|---|---|
| TH1 | IFN-γ, IL-12, TNF-α | Stimulates immune response to cancer |
| TH2 | IL-4, IL-5, IL-13 | Decreases TH1 |
| TH3/Treg | TGF-β | Modulates TH1 |
| Proinflammatory | IL-1, IL-6, IL-8, TNF-α | Causes inflammation |
The cytokine pattern associated with a beneficial immune response to cancer is TH1. The dominant TH1 cytokine is IFN-γ, which is responsible for stimulating the cellular immune response. Cellular immunity is important in an antitumor response since NK and CD8+ T cells, as well as tumoricidal macrophages, can destroy tumor cells. In addition, a number of cellular functions, such as presentation of tumor-specific antigens and production of tumoricidal cytokines, are increased by IFN-γ. Thus, therapies, including use of mushrooms that increase IFN-γ and drive a TH1 response, are beneficial for cancer patients.
In contrast to a TH1 response, a TH2 response is not typically associated with an immune response to cancer. TH2 responses are associated with allergies and asthma and involve the cytokines IL-4, IL-5, IL-13, and sometimes IL-10. Most important, IL-4 and IFN-γ cross-regulate each other. IFN-γ decreases production of IL-4, and IL-4 decreases production of IFN-γ. Thus, a TH2 response can be detrimental to cancer patients because it decreases IFN-γ and decreases the cellular immune response to cancer.
Regulation of the T-cell response is accomplished by Treg cells, also called TH3 or Treg cells. While many categories of Treg cells exist, most Tregs produce TGF-β (transforming growth factor β). This cytokine was discovered through its ability to increase the growth of tumor cells, mediated by decreasing the TH1 response. TGF-β can also decrease TH2 responses. Because it can decrease both TH1 and TH2, TGF-β is most commonly associated with tolerance and is found in high levels in the intestine and lungs, where large doses of innocuous antigens are frequently introduced. While it is beneficial to have a Treg response to self-antigens, Treg responses do not lead to cancer clearance.
When associated with cancer, proinflammatory cytokines can contribute to inflammatory symptoms. These cytokines are released early in the immune response to infectious agents and are responsible for driving fever and stimulating the innate immune system. Many symptoms related to sickness—malaise, anxiety, and hostility, which are observed during infection are a result of these cytokines. For example, radiotherapy increases IL-1, IL-6, and TNF-α. A recent quantitative review of 1037 patients with cancer-related fatigue that partially resulted from radiotherapy demonstrated that IL-6 and IL-1RA were associated with fatigue; however, IL-1β and TNF-α were not linked to fatigue.
In summary, when considering immunomodulatory effects of mushrooms, those that stimulate TH1 responses may be beneficial in cancer treatment, as are those that decrease TH2 and Treg responses. Mushrooms that decrease inflammation may have the added benefit of decreasing fatigue, anxiety, and other symptoms by decreasing inflammatory cytokines.
Few studies examining immunological outcomes have been conducted within the clinical trial framework. That framework is the key to moving the knowledge of mushroom immunology out of the lab and animal models and into both physically well and diseased human populations. A recent phase 1, dose-escalation, clinical trial of turkey tail evaluated dosing safety and immune function in women with breast cancer Turkey tail extract was well-tolerated and was immunomodulatory at higher doses (6 g or 9 g) by increasing CD8+ T cells and CD19+ B cells. The researchers also found that the radiation-induced decline in NK cells was improved by a 6-gram dosing per day of turkey tail.
Agaricus has also been tested by Ohno et al in a phase I clinical study of safety with participants in cancer remission. At all doses—1.8, 3.6, and 5.4 g/d for 6 months, Agaricus was well-tolerated, with a 12% rate of adverse events that were digestive in nature, such as nausea. While Agaricus was deemed safe, the study did not follow immune outcomes for the enrolled patients.
Gao et al studied the use of reishi polysaccharides in late-stage cancer patients and late-stage, lung cancer patients. In participants with late-state lung cancer treated with 5.4 g/d of a proprietary reishi extract (Ganopoly), IL-2, IL-6, and IFN-γ increased. Great variability in patients’ responses occurred, with some participants having a very significant increase while others had minimal changes. This finding suggests that subgroups of patients may respond more favorably to reishi, although the mechanisms of such a difference have not been studied at this time. When Ganopoly was studied in late-stage cancer patients, it was found that a dose of 5.4 g/d increased IL-2, IL-6, and IFN-γ and decreased TNF-α and IL-1. This dosage also increased NK cells (CD56+ cells) and NK activity.
The immune-stimulating impact that mushrooms can exert on NK cells, macrophages, and T cells can also provide a protective effect against chemotherapeutic myelosuppression, one of the most serious deleterious effects of chemotherapy. Because severe myelosuppression neutropenia often truncates treatment and requires hospitalization before full therapeutic effects can be achieved, reducing myelosuppression would allow for better response to chemotherapy. One promising study examined the effect of the MD-fraction from the maitake mushroom on cisplatin-induced myelosuppression in a mouse model. Mice given 8 mg/kg/d while treated with cisplatin did not experience a decrease in NK cells, DCs, and macrophages. These mice also maintained body weight and spleen weight compared to those treated with cisplatin alone.28 Another study demonstrated that mice that had been immunosuppressed with cyclophosphamide and then subsequently treated with a water-soluble extract from reishi had an increase in red blood cells (RBCs), white blood cells (WBCs), NK T cells, splenic NK cells, and a number of bone marrow cells.56 Given the need to find treatments for this difficult side effect, human studies are needed at this time that examine whether mushrooms are protective against myelosuppression during chemotherapy.
Mushrooms With Antineoplastic Agents
In addition to treating chemotherapeutic myelosuppression, studies have shown that medicinal mushrooms can be used in conjunction with antineoplastic agents to increase the efficacy of chemotherapeutic agents and radiation, the mainstay treatments for most cancers.
Chemotherapy must penetrate the tumor and accumulate within each cell to induce cell cycle arrest and apoptosis. Each of the mushrooms discussed within this review has been shown to increase the effects of chemotherapy, usually by increasing the dose of chemotherapeutic agent that accumulates within a cell (Table 6). For example, when an Agaricus extract high in β-glucan is used in conjunction with doxorubicin, a chemotherapeutic agent, the effectiveness of the drug is increased. Doxorubicin combined with Agaricus is accumulated at higher doses within hepatocellular carcinoma cells and increases apoptosis compared to doxorubicin alone.
Table 6
Mushrooms and Chemotherapeutic Agents
| Chemotherapeutic Agent | Indicated Mushroom | Reference |
|---|---|---|
| Trastudzumab | PSK (turkey tail) | Lu et al, 2011b37 |
| Cyclophosphamide | Reishi | Zhu et al, 200756 |
| Cisplatin | Maitake, Cordyceps, reishi | Masuda et al, 200928; Yao et al, 201257 |
| Docetaxel | PSK (turkey tail) | Kinoshita et al, 200958; Wenner et al, 201259 |
| Doxorubicin | Agaricus | Lee and Hong, 201148 |
Abbreviations: PSK = polysaccharide K.
Similarly, PSK extracted from turkey tail increases the efficacy of the drug docetaxel in the treatment of human gastric carcinoma. Within an in vitro and an in vivo model, Kinoshita et al found that PSK inhibited NF-κB, and survivin, an antiapoptotic molecule.58 The researchers were able to use a lower dose of the drug to induce similar levels of apoptosis. Other studies confirm this observation in a human prostate cancer model.59 Extracts from reishi in the form of ganoderic acid A were recently found to increase accumulation of the chemotherapeutic agent cisplatin inside tumor cells. Specifically, ganoderic acid A sensitized the cancer cell line HepG2 to cisplatin by suppressing Janus kinase/signal transducers and activators of transcription (JAK/STAT3), allowing cisplatin to amplify the apoptosis rate.57
Akin to the effects of reishi, cytotoxicity from cisplatin also increased significantly when Cordyceps extract was added.60 To understand the mechanism of this increased cytotoxicity, researchers can examine a study in which Cordyceps was used in an in vitro model of nonsmall-cell lung cancer (NSCLC), a treatment resistant form of cancer that accounts for 80% of that cancer. Cordyceps extract decreased vascular endothelial growth factor (VEGF) and basic fibrogrowth factor (bFGF) in vitro. Thus, Cordyceps can decrease blood supply to the cancer cell and increase the ability of cisplatin to exert cytotoxic effects.
Some anticancer therapies are dependent on NK-cell function to induce apoptosis. One such drug is trastuzumab, a HER2-targeted monoclonal antibody therapy. When PSK from turkey tail was given with trastuzumab, cell-mediated cytotoxicity was greatly increased.37 Interestingly, when PSK and trastuzumab were used alone, they had similar rates of tumor inhibition. Combined, these 2 treatments decreased cell growth in tumors by 96%.
In addition to chemotherapy, researchers are seeking to improve the deleterious side effects of radiation therapy using mushrooms. β-Glucan isolated from reishi significantly improves mouse survival postradiation. Pillai and Devi studied mouse survival, hematology, liver GSH (reduced glutathione), liver malondialdehyde (MDA) and bone marrow chromosomal aberrations in mice exposed to a 4-Gy or 8-Gy radiation dose with or without β-glucan.61 They found that β-glucan rescued 66% of mice from death, compared to 100% mortality when no radioprotective agent was used. When combined with the radioprotective drug amifostine, survival increased to 83%. They also found a significant decrease in bone marrow aberrations in mice pretreated with β-glucan.
Discussion
The evidence base for using mushrooms in cancer treatment has greatly increased in the past 5 years. Many researchers are working to purify and study individual constituents of mushrooms to understand their effects on apoptosis, cell cycle arrest, and immune modulation.This research is allowing researchers to move from lab bench to bedside. As this review has demonstrated, mushrooms show great promise as adjunctive treatment used in conjunction with typical care for patients with cancer, as well as treatment to stimulate the immune response to cancer. Research to date has shown a high safety profile of for mushrooms and a lack of negative interactions. As the science continues to emerge, it is likely that the efficacy and safety will justify medicinal mushrooms as an adjunct treatment. summarizes potential clinical applications.
Table 7
Summary of Potential Clinical Applications
| Type of Cancer | Indicated Mushroom |
|---|---|
| Nonsmall-cell lung cancer | Cordyceps |
| Lung cancer | Reishi |
| Gastric cancer | PSK (turkey tail) |
| Hepatocellular carcinoma | Agaricus, reishi |
| Leukemia | Agaricus, reishi |
| Lymphoma | Cordyceps |
| Breast cancer | Reishi, maitake, turkey tail |
| Colon cancer | Maitake, reishi, turkey tail |
| Prostate cancer | Reishi |
| Sarcoma | Reishi |
Abbreviations: PSK = polysaccharide K.
The mushrooms discussed in this review elicit effects on cytokine production. The authors know that immune stimulation during cancer can be beneficial in terms of tumor regression and patients’ survival.2 Upon diagnosis, most patients are treated with antineoplastic therapy and are immunosuppressed. Emerging evidence suggests that mushrooms may reverse myelosuppression, which makes them a promising adjunct therapy to optimize overall treatment outcomes.
Anytime an adjunct therapy is added to a conventional therapy, drug-botanical interaction must be addressed. Interestingly, mushrooms appear to increase the effects of chemotherapy. This important finding must be considered when patients are using mushrooms for myelosuppression or other symptoms.
While the immunological findings are promising, ultimately this information must be applied to patients and clinical outcomes, as the goal when working with any patient with cancer is to improve quality of life and ultimately improve survival. To that end, the meta-analysis of turkey tail by Eliza et al demonstrated an increased rate of survival for cancer patients who took this mushroom, especially participants with breast, gastric, and colorectal cancers.The articles examined in this meta-analysis did not obtain immunologic outcomes and were thus not included in the current article. Similarly, a retrospective case series of patients who were treated for hepatocellular carcinoma with a combination of 11 different integrative therapies, which included Cordyceps and β-glucan from Agaricus, showed a significant correlation between the number of treatments used and survival. Patients given ≥4 agents had a survival of 40.2 vs 6.4 months for those given ≤3 agents (P < .001). Of these individuals, participants whose combination therapy included Cordyceps had the longest survival.
Conclusions
As the treatment of various cancers continues to evolve, mushrooms should be considered as an adjunct therapy. As with any phytochemical, the dose, concentration, absorption, and extraction methods play a role in the pharmacological effects, and these factors will be important in future studies. With more research and a better understanding of how different mushrooms elicit varied effects, it will be increasingly important that integrative clinicians work with oncologists to determine the appropriate treatment for each individual. Research into underlying mechanisms of mushrooms will continue to help in devising new strategies for treating cancer, preventing its long-term complications, and increasing survival.