The Multifaceted Role of Mast Cells in Cancer
When do mast cells inhibit cancer proliferation, and when do they contribute to it?
By Jacob Schor, ND, FABNO
About The Author
Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine and now practices in Denver. He served as president to the Colorado Association of Naturopathic Physicians, and is now on the board of directors of both the Oncology Association of Naturopathic Physicians and the American Association of Naturopathic Physicians. He is recognized as a Fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal.
Mast cells play a dual role in cancer, and their presence in tumor tissue may affect prognosis both positively and negatively. What isn’t clear is in which situations mast cells aid tumor growth and in which they suppress it. Published studies are reviewed in an attempt to provide a clinically useful understanding for the practitioner.
Mast cells may play an important role in cancer. They are potential triggers of allergic reactions, so stabilizing them has long been a therapeutic target in treating allergies, asthma, and anaphylaxis. It is time to shift attention to the role mast cells play in cancer and how we might use this understanding for therapeutic advantage.
Paul Ehrlich first described and named mast cells in his doctoral thesis in 1878. During his illustrious career, Ehrlich exhibited a talent for naming things, coining the terms chemotherapy and magic bullet. He also originated the term mast cell. Ehrlich mistakenly believed that mast cells fed the surrounding tissue and so came up with the name, Mastzellen, from the Greek masto, meaning “I feed.” Though the term mast cells stuck, luckily, his term to describe autoimmunity, horror autotoxicus, did not become popular.
Mast cells originate in the bone marrow and enter the circulation in immature form. Once settled into a tissue site, they mature, taking on characteristics specific for that tissue. There are two general types of mast cells: those found in connective tissue and those found in mucosal tissue. We usually think of mast cells in association with boundary areas, such as the skin but especially the mucosa of the lungs, digestive tract, mouth, nose, and eyes.
One image of mast cells is a cross between a sentry and a land mine posted around our perimeter. When triggered by antigens, they degranulate, releasing destructive enzymes and sounding chemical alarms that cause a series of chain reactions resulting in acute allergic inflammation. Often our therapeutic intent is to decrease allergen-triggered reactions.
Recent findings have challenged the view that mast cells are only important for their role in acute allergic reactions. Mast cells also play a role in allergen sensitization, and they actually may limit some types of allergic reactions. Mast cells also cause inflammation through non-histamine mediated routes.1 Research now implicates mast cells in a variety of inflammatory diseases affecting a variety of organs; mast cells may contribute to diseases such as asthma, atopic dermatitis, coronary inflammation, and inflammatory arthritis.2
Recent findings have challenged the view that mast cells are only important for their role in acute allergic reactions.
Mast cells and their progenitors are drawn to target tissues from the bone marrow by the ‘scent’ of a chemical attractant called stem cell factor (SCF). Okayama states in his review of mast cells, “SCF also elicits cell-cell and cell-substratum adhesion, facilitates the proliferation, and sustains the survival, differentiation, and maturation of mast cells. Therefore, many aspects of mast cell biology can be understood as interactions of mast cells and their precursors with SCF and factors that modulate their responses to SCF and its signaling pathways.”3
Mast cells mediate the process of antigen sensitization in the digestive tract. Without mast cells, increased intestinal permeability would not have consequences. However, with active mast cells present, proteins trigger sensitization and the development of food allergies.4
Mast cells also play a role in obesity and diabetes. Blocking mast cell action appears to be protective against both diseases.5
The Role Mast Cells Have in Tumor Growth
In a paper titled, “The role mast cells have in tumor growth,” Conti, Castellani, and colleagues point out that many tumors are surrounded by mast cell infiltrates. They present evidence that these mast cells secrete inflammatory cytokines that in some cases benefit the cancer. Once mast cells are attracted to tumors by chemo-attractants like SCF, they are then triggered to secrete molecules that act as growth factors aiding tumor growth, angiogenesis, and metastasis.6 The mast cells ‘remodel’ the tumor microenvironment so as to promote tumor growth. This increases secretion of inflammatory chemicals, increasing activity of NF-kappaB and increasing the tumor’s ability to suppress T cell and natural killer cell attacks against it.7
In their 2009 paper, the Italians Ribatti and Crivelatto suggest that mast cells could be a target for cancer treatment.8 Citing evidence that mast cells appear to play a significant role in tumor angiogenesis, they write, “In tumor models, mast cells have been shown to play a decisive role in inducing the angiogenic switch which precedes malignant transformation. There is, moreover, strong evidence that mast cells significantly influence angiogenesis and thus growth and progression in human cancers.”9 It would appear that if we could decrease mast cells we might inhibit both tumor angiogenesis and tumor growth.10
The title of a 2009 Dutch paper, “Mast cells as target in cancer therapy,” suggests that the Italians are not alone in pursuing this line of thought.11 Following is a review of some of the studies that have led to these proposals. In some cancers, mast cells clearly act to support tumor growth. Ribatti demonstrated a direct correlation between mast cells and disease progression in multiple myeloma in 1999.12 Nakayama was able to show this effect was mediated at least in part by mast cell production of angiopoietin-1 (Ang-1).13 Mast cells aid the development of squamous cell carcinoma. Coussens et al reported in 1999 that mast cells, “infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas,” and then release the mast cell–specific proteases chymase and tryptase—the former acting as a mitogen and the latter being angiogenic to skin fibroblasts. In experiments, tumor angiogenesis was stopped when implanted in mice genetically devoid of mast cells. Cancer progression in their experiment required an inflammatory response to tissue abnormality. In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are drafted to reorganize stromal architecture and hyperactivate angiogenesis. Without mast cells, progression halted.14
Studies on human pathology samples that have looked to mast cell numbers for prognostic power provide stronger arguments for the possible role for mast cells in cancer.
In 1989 Fisher et al reported that in biopsies from more than 300 rectal cancer patients, they found that patients who had low mast cell counts fared better than patients with high counts.15
Increased mast cells are associated with progression from common nevi to malignant melanoma. The higher the mast cell counts in the tissue, the deeper the penetration into the dermis and the more likely the tumor is to undergo metastasis.16 Increased mast cells are also associated with squamous cell cancers. A correlation between mast cell numbers and poor outcome was reported in a 2003 paper on oral squamous cell carcinoma.17 A 2009 paper reports high concentrations of tryptase produced by mast cells in squamous cell carcinoma of the lip.18
Imada et al reported in 2000 that they had found large differences between the numbers of mast cells in different types of non-small cell lung cancer (NSCLC). Mast cells and vascular endothelial growth factor (VEGF) were detected in a higher proportion of adenocarcinoma tumors than squamous cell lung tumors. There were not just more mast cells in VEGF-expressing tumors compared with VEGF-negative tumors, but almost all mast cells expressed VEGF. Increased numbers of mast cells correlated with poor prognosis in patients with stage I NSCLC.19 Mast cells may be an important source of VEGF in some early tumors. Results on lung cancer are not consistent.
In a more recent paper, mast cells were beneficial in NSCLC. In a 2005 paper, Welsh et al report on 175 patients with surgically resected NSCLC. They identified and counted the tryptase-positive mast cells and CD68+ macrophages in the tumors. Both mast cells and macrophages were independent favorable prognostic indicators.20
In a 2005 paper, Ribatti et al reported a correlation between mast cell tryptase, angiogenesis, and tumor progression in endometrial cancer.21
Some studies have found that mast cells play an important role in promoting pancreatic cancer and suggest blocking mast cell activity. Esposito et al reported in 2004, “There were significantly more mast cells and macrophages in pancreatic cancers than in normal pancreas and the number of mast cells directly correlated with the presence of lymph node metastases.”22
Soucek et al reported in 2007 that the Myc oncogene protein in mice induces rapid development of pancreatic islet tumors and is dependent on mast cells’ being present to have this effect. Myc is a transcription factor that contributes to tumor angiogenesis, growth, proliferation, and stromal remodeling. Myc activation rapidly induced release of mast cell attractants. Mast cells were the only inflammatory cell to increase in the vicinity of tumor cells. The increased concentrations of mast cells correlated with expansion of islet tumors. Mast cell presence was required for maintenance of established tumors. Treatment of the mice with the mast-cell stabilizer cromolyn sodium led to tumor hypoxia and tumor-cell apoptosis. Moreover, tumors could not be induced in mast-cell–deficient mice.23,24
Another study suggests cromolyn sodium, the classic mast cell inhibitor, may have a positive effect on pancreatic cancer, inhibiting tumor growth and increasing the effectiveness of gemcitabine.25 The well-known study 2008 study by Dhillon suggested another mast cell inhibitor, curcumin, may offer benefit in treating pancreatic cancer.26
In an April 2010 paper, Strouch et al sum this up: “Tumor-infiltrating mast cells are associated with worse prognosis in pancreatic cancer. In vitro, the interaction between mast cells and pancreatic cancer cells promotes tumor growth and invasion.”27
An August 2010 paper by Ribatti et al added gastric cancer to our list of tumor types promoted by mast cells. Specimens of primary gastric adenocarcinomas from 30 patients were investigated and showed that stage IV gastric carcinoma has a higher degree of vascularization than other stages, and that both tryptase- and chymase-positive mast cells increase in parallel with malignancy and are highly correlated with the extent of angiogenesis.28
In November 2010, Oncogene published a paper by Melillo et al that tells us that mast cells promote the growth of thyroid cancer. The researchers started by comparing the density of tryptase-positive mast cells in 96 papillary thyroid carcinomas to thyroid tissue from 14 healthy individuals. Mast cell density was higher in 91 of the 95 cancers (95%) than the control tissues. They then showed that thyroid cancer secretes soluble factors that induce mast cell activation and attracts them to the tumor. Mast cells triggered cancer cell invasive ability, survival, and DNA synthesis in vitro. Injecting thyroid cancer cells into the tails of rats recruited mast cells and accelerated the growth of thyroid cancer cell grafts by increasing tumor vascularization and proliferation. The mast cell effects were canceled out by cromolyn sodium.29
We see evidence that increased mast cells are correlated with enhanced tumor cell growth in
Squamous cell carcinoma of mouth and lip
NSCLC adenocarcinomas (studies are contradictory)
Follicular lymphoma (but not with diffuse B-cell lymphoma)
In recent years several general concepts have been talked about to explain carcinogenesis. The first was that chronic inflammation might predispose a person to cancer. There is also a theory suggesting that cancer is a long unhealed wound. These mast cell studies suggest we could view cancer as a chronic allergic reaction mediated by mast cells. In our eagerness to see mast cells as a target for attack, it is easy to overlook inconsistent results seen in a number of studies on mast cells that have not been mentioned above.
A More Complex Role for Mast Cells
Before refocusing all our therapeutics to eradicate all mast cells in cancer patients, we must consider a 2008 article by Daliah Galinsky and Hovav Nechushtan from Hadassah Hebrew University in Jerusalem. This is the most balanced review of the literature to date. The authors suggest that the role mast cells play may be more complex than other writers have appreciated; the effect of mast cells on tumors varies, perhaps with tumor types. In some tumors, mast cells encourage growth, angiogenesis, and metastasis; in other tumor types, mast cells limit tumor growth by killing tumor cells. Galinsky and Nechushtan review an interesting series of studies suggesting mast cells can have both tumor-promoting and antitumor effects. Studies on certain cancers certainly correlate increasing numbers of mast cells with increasingly poor prognosis. Yet studies on other types of cancer show that increasing mast cells had no effect on prognosis, and studies on yet other cancers correlated increasing mast cell numbers with longer survival. Effect seems to vary with type of cancer.
Reports on lymphoma have been inconsistent. In 2002 and 2004, Swedish researchers reported that in Hodgkin’s lymphoma patients with higher mast cell numbers had shorter disease-free survival.30,31 The same researchers were unable to find evidence that mast cells had an angiogenic effect on lymphoma.
Other Swedes, Hedström et al, reported in 2007 that high mast cell numbers were a predictor of a favorable outcome in diffuse large B cell lymphomas.32 In 2008, however, Finnish researchers reported finding that high levels of mast cells in follicular lymphoma were linked with a poor prognosis.33 One of the genes they identified strongly correlated with poor survival odds coded for the microphthalmia transcription factor (MITF). This transcription factor is highly expressed in mast cells and regulates genes that are found only in mast cells.34
Renal Cell Cancer
There are studies in which mast cell numbers, though they appear to promote tumor growth, do not affect prognosis (eg, studies on mast cells and renal cell cancer). In 2006, Turkish researchers reported that kidney cancers tend to have high numbers of mast cells and increased vascular density, greater angiogenesis, and faster tumor growth. Yet the number of mast cells and these related undesirable tumor characteristics did not correlate with a change in patient survival.35 A 2009 report from Iran yielded similar findings in renal cell cancer: Although mast cells have an angiogenic effect, there is no correlation to any other disease factors.36 Renal cell cancers themselves usually express high levels of VEGF. Since the tumor itself supplies the VEGF, it doesn’t rely on mast cells for VEGF, and thus mast cells may play little role in tumor growth in this particular cancer.
A January 2010 Swedish study examining histologic samples from 61 patients with esophageal cancer found no significant correlation between mast cells and survival.37
Diseases in which increased mast cell number has been correlated with improved prognosis:
NSCLC (studies are contradictory)
Mast cells can also limit tumor growth. A 2005 paper suggests that degranulating mast cells can inhibit tumor growth by releasing heparin.38 Whatever is going on here is more complex than some of these papers would suggest.
Heparin released by mast cells negatively affects cancer tumors that contain fibroblasts alongside cancer cells. Heparin-containing mast cells are found in breast, head and neck, lung, and ovarian cancers, and also in Hodgkin’s and non-Hodgkin’s lymphoma.39 Mast cell heparin reduces the number of and size of tumors that are growing alongside fibroblasts, but not of tumors growing alone. Samoszuk et al reported on their interesting work in 2003. In their experiment, they used mice with implanted breast cancer tumors and treated them with very low dose imatinib to kill off mast cells. Removing the mast cells resulted in more rapid tumor growth. Tumor growth was also more rapid in a group of mice with mast cells that were genetically unable to make heparin.40 There is other evidence that heparin has an anticancer effect.
Agnes et al reported in 2005 on 602 cancer patients who suffered from thromboembolisms and who were then treated with either heparin or coumarin. The heparin made a significant impact on survival. “Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin [heparin] group, as compared with 36% in the oral anticoagulant [coumarin] group.” In patients with metastatic cancer, no difference in mortality between the treatment groups was observed.41
Mast cell–generated heparin may be protective in breast cancer, though early studies didn’t find this. Fisher et al reported nearly a quarter a century ago that when they looked for a correlation between mast cell numbers and survival in breast cancer patients, they were unable to find any relationship. Yet they noted that their count of mast cells did not include degranulated mast cells, and that they were mistaken in not including this factor that would have been most correlated to effect.42
Some research has suggested that it is the release of histamine from the mast cells that hinders tumor growth.43 One example given in support is a study on histidine decarboxylase (HDC) and its effect on myeloid cells. HDC is an enzyme responsible for histamine generation that is highly expressed in myeloid cells. HDC-knockout mice, which are unable to generate histamine, show a high rate of colon and skin carcinogenesis. Exogenous histamine induces the differentiation of immature myelocyte cells (IMCs) and suppresses their ability to support the growth of tumor allografts. Thus in certain situations, HDC and histamine increase myeloid cell differentiation and hinder early cancer development.44 If this idea holds true, one might hypothesize that triggering histamine-generating reactions by antigenic exposure might hinder cancer growth.
A July 2010 paper suggests that the opposite may occur. Exogenous histamine stimulated human melanoma cell proliferation rather than suppressed it. Treatment with terfenadine, an antihistamine used for the treatment of allergic conditions, in vitro induced melanoma cell death by apoptosis and in vivo treatment significantly inhibited tumor growth.45
Another example that argues against the theory that histamine generation underlies the anticancer potential of mast cells is the anticancer effect of cimitidine, a histamine antagonist, that has been promoted as an ‘alternative’ cancer therapy for decades. A March 2010 paper reported that cimetidine exhibits antitumor effects in gastric cancer cells by induction of apoptosis.46
A January 2011 paper reports that histamine dihydrochloride (Ceplene), a synthetic derivative of histamine, may be useful when used in combination with interleuken-2 (IL-2) for the treatment of acute myeloid leukemia (AMK).47 These studies on both heparin and histamine, while intriguing, have not reached a consensus that explains the varying effects mast cells have on cancer.
Other groups have found a positive correlation between mast cell numbers and breast cancer survival. Aaltomaa and his Finnish colleagues reported in 1993 that they had seen such an effect when they compared mast cell counts in 187 breast cancer biopsies: “In survival analysis a high mast cell count was related to a favorable prognosis.”48
In 2004 Canadian researchers reported on a study of tissue samples from 348 breast cancer patients. Follow-up data on these patients was gathered for an average of almost 15 years. Analysis yielded a strong correlation between presence of mast cells and a favorable prognosis. Mast cells were not correlated with hormone status, Her-2 status, or tumor grade. Presence of mast cells was an independent predictor of outcome.49 Mast cells were not correlated with immune system activity. Thus in breast cancer, mast cells appear to act in a way that is the reverse from their action in rectal cancer.
Exactly what mast cells do to breast cancer is still not clear. Sodium cromolyn, a chemical well known for stabilizing mast cells and limiting their activity, appears to be useful in treating breast cancer.
Samoszuk and Corwin in a 2003 paper tell us that cromolyn increases blood clotting and hypoxia in breast cancer tissue. Human breast cancer is heavily infiltrated with mast cells that contain the anticoagulants heparin, tryptase, and chymase. These researchers measured the levels of mast cell tryptase in the blood of 20 women with varying stages of breast cancer. The mean level of tryptase in the women with breast cancer was 10.3 mcg/L compared to 3.0 mcg/L in 50 controls without breast cancer. The researchers then carried out an experiment, giving mice that had been implanted with breast cancer tumors 5 daily injections of sodium cromolyn. About a third of the treated mice developed large ‘lakes’ of clotted blood surrounding the tumor. An equal percentage of the mice developed areas of hypoxia as well; the tumors were ‘suffocating.’50 Something similar appears to occur with prostate cancer.
Early research suggests mast cells play a protective, antitumor role in prostate cancer. Increasing numbers and density of mast cells correlate with a better prognosis. In 1999 it was reported that mast cell concentration nearly doubled close to prostate cancer tissue suggesting that mast cells aggregate around the periphery of prostate adenocarcinomas.51 Japanese researchers reported in the British Journal of Cancer in 2007 that not only did mast cell number correlate with clinical stage, but also higher mast cells numbers were prognostic of the length of survival with undetectable levels of PSA in prostate cancer patients.52
In the summer of 2009, a German paper confirmed that increasing numbers and density of mast cells was associated with more favorable tumors, having lower preoperative PSA, lower Gleason score, and lower tumor stage than tumors with low mast cell densities. “Prostate-specific antigen recurrence-free survival decreased with decline of mast cell density, showing poorest outcome for patients without intratumoral mast cells. In multivariate analysis, mast cell density narrowly missed to add independent prognostic information for prostate-specific antigen recurrence.”53 Breast and prostate cancer are not the only cancers in which mast cells improve survival. The most striking benefit is in ovarian cancer.
Chan et al reported on their evaluation of ovarian cancer tissues from 44 patients, again looking for the possible prognostic influence of mast cells. The number of mast cells alone in the tissues they examined was not clearly correlated with increased survival. However those patients whose tumors had higher microvessel density (interpreted as mast cell angiogenic effect) and high mast cell infiltration had a mean survival of 80.3 months compared to only 37.8 months in patients whose tumors either had low mast cell density or low microvessel density.54 Thus in ovarian cancer, this small trial suggests the potential benefits of the presence mast cells.
If we take all of this data at face value we are left with two lists, cancers that are helped by mast cells and cancers that are limited by mast cells. We want to decrease mast cell numbers and effects in rectal cancer, melanoma, squamous cell carcinoma, and myeloma. It’s unclear what goal we want in lymphoma and lung cancer. We may want to increase mast cell activity in breast, prostate, and ovarian cancers.
We know of some dietary supplements that limit mast cell activity and relatively little about what agents will increase mast cell activity. Many of the nutritional supplements and botanical extracts that are employed by naturopathic doctors to treat cancer patients affect mast cells, decreasing their activity.
Table: Partial List of Supplements That Affect Mast Cells
Effects on Mast Cells
“In mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration.”55
“Data support the hypothesis of a physiological role of 1,25(OH)2D3 in mast cell development.” A deficiency of vitamin D increases mast cell effect.56
Flavonoids (eg, rutin, quercetin).
Commonly used to treat allergies, these affect mast cells.57 Quercetin is considered useful in cancer for its pro-apoptotic effects but is also commonly employed for its moderating effect on mast cells.58
Has potential at regulating mast cells and a role in treating allergies.59
EGCG interferes with mast cell activities.60
Found in green tea, oak leaves,61 and gallnuts.
Apparently useful in treating allergies because something in them, maybe the quercetin, stabilizes mast cells.62
Stabilizes mast cells, providing an anti-allergic benefit.63
Stabilizes mast cells, preventing anaphylactic reactions.64
Panax ginseng isolates
Possess anti-allergic effects, presumably through mast cell stabilization.65
Has probably the strongest evidence supporting its use to stabilize mast cells. Inhaled cromolyn is suggested to decrease the attendant cough triggered by lung tumors.66 It has an antitumor effect in both pancreatic and breast cancers.67,68,69
The Samoszuk and Corwin 2003 paper that tells us that cromolyn triggers hypoxia in breast cancer tumors would suggest that decreasing mast cell action might be useful in treating breast cancer. This suggestion contradicts the apparent fact that increased mast cell numbers improve prognosis for breast cancer patients.
Mast cells appear to have 2 very different actions in regard to cancer, and it appears to vary with cancer type. Mast cells appear to promote the growth of several tumor types, especially increasing angiogenesis through generation of VEGF and other cytokines. This seems especially true in rectal cancer, pancreatic cancer, and melanoma. Blocking mast cell action using sodium cromolyn appears useful in pancreatic cancer. Yet there are other cancers—breast, prostate, and ovarian—that appear to be hindered by mast cells and high mast cell counts would seem to improve survival of these patients.
Given the current information on mast cells and cancer, the safety of some of the supplements commonly employed in cancer treatment needs to be questioned.
Summarizing these studies yields three lists:
Cancers in which greater mast cell numbers appear to be beneficial.
Cancers in which greater mast cells appear to be detrimental.
Cancers in which sodium cromolyn has an anticancer effect.
Increased mast cell numbers or density is correlated with tumor development or disease progression in these cancers:
Squamous cell carcinoma of mouth and lip
NSCLC adenocarcinomas (studies are contradictory)
Follicular lymphoma (but not with diffuse B-cell lymphoma)
Mast cells increase angiogenesis in renal cell carcinoma but do not apparently change survival times. Mast cells appear to increase survival in ovarian, breast, prostate and maybe lung cancer. Now that we are aware of this, we must question whether agents that reduce mast cell activity would be contraindicated. Following this logic would mean that patients with these cancers should not take quercetin, a supplement often recommended for various cancers. It is not just quercetin that is called into question. The list of questionable supplements to use with these cancers would include at a minimum quercetin, curcumin, vitamin E, vitamin D, and green tea. Cromolyn sodium inhalers, which we have long thought as useful, should be avoided in lung cancer because of their unknown effect on the tumor, despite their apparent usefulness at ameliorating tumor-triggered coughs.70
This of course is assuming that biology is simple and straightforward—two traits that experience suggests cannot be depended upon. The fact that cromolyn appears potentially beneficial for hindering breast cancer growth suggests that something about the whole relationship between mast cells and cancers is still not understood. Of course, when applying any natural or prescriptive agent against cancer, it’s not just about mast cell effect. It’s about the cumulative effect of all the actions these agents will have on the cancer. Unfortunately we do not have the sort of live subject data that would allow us to make these decisions with any type of clinical certainty.
For more research involving integrative oncology, click here.
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