Skin cancer prevention

Posted on July 26, 2011 by Dr. Jonathan

More can be done to prevent skin cancer than shield against excessive exposure to ultraviolet radiation. There is a growing body of evidence supporting the effectiveness of substances taken internally for skin protection and health. Consider a paper published in the journal Photochemical & Photobiological Sciences in which the authors observe:

“Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer…Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis…A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties.”

They examined selected chemopreventive including apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against cancer causing UV radiatoin in laboratory and living systems. Having attended to the mechanism of chemopreventive action of these dietary botanicals they concluded:

“We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.”

A paper published last year in Archives of Dermatological Research updated the data on polyphenols and other phytochemicals as skin cancer chemopreventive agents with special reference to the effect of suboptimal immunefunction on vulnerability to skin cancer . The authors state:

“Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc.. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse, or retard the process of these harmful events in the UV-exposed skin.”

They examined data from a number of studies on the photoprotective effects of green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, particularly in reference to UV-induced skin inflammation, oxidative stress, and DNA damage. The authors conclude:

“The laboratory studies conducted in animal models, suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.”

Of great interest is a paper published in the journal Cancer Letters that specifically considers the role of UV radiation-induced immune suppression. The authors note:

“Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression…Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis.”

Their summary of studies investigating the photoprotective efficacy of dietary agents included green tea polyphenols, grape seed proanthocyanidins and silymarin. Based on this body of data they…

“…present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) The induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) Stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis….The supplementation of the use of sunscreens with these dietary agents may provide an effective strategy for the prevention of melanoma and nonmelanoma skin cancers in humans. The dietary botanical agents discussed are considered to be non-toxic and pharmacologically safe for human consumption.”

More recently there have been investigations of the chemopreventive properties of specific agents, such as a paper published in Experimental Dermatology on an extract of Curcuma longa (turmeric).

“…[partial purification from C. longa (PPC)] was used to investigate the alpha-melanocyte-stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway…In cells stimulated α-MSH, PPC inhibited cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein (TRP)…was activated by PPC in α-MSH-stimulated B16F10 cells…MEK/ERK or Akt activation by PPC may contribute to reduced melanin synthesis via MITF and its downstream signal pathway including tyrosinase and TRPs in α-MSH-induced melanogenesis.”

In other words, the turmeric extract was shown to regulate pathways intrinsic to the production of melanoma in a way that would inhibit its development. More evidence for the inhibitory effect on melanogenesis of curcumin, the principal medicinal extract of turmeric, was recently reported in the journal Phytotherapy Research. The authors observe:

“Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells.”

They specifically investigated whether curcumin affects the development of melanoma in cultured human melanocytes. Additionally, they sought to elucidate the molecular mechanisms by assessing the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins, tyrosinase, tyrosinase-related protein 1 and 2, and the activation of a number of melanogenesis-regulating signals in human melanoma cells. The data they obtained is very promising:

“The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3β, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis.”

Thus they concluded…

“These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3β, ERK or p38 MAPK signaling pathways.”

And another study just published in the International Journal of Molecular Medicine demonstrates the same findings.

”The present study was designed to assess the potential inhibitory activity of curcumin on the α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway in B16F10 melanoma cells. The molecular mechanism of curcumin-induced inhibitory activity on the α-MSH-stimulated melanogenesis signal pathway, including expression of melanogenesis-related proteins and activation of melanogenesis-regulating proteins, was examined in B16F10 cells.”

The authors report essentially the same effects of curcumin as described in the earlier paper, including the influence of tyrosinase activity, the expression of melanogenesis-related proteins, and melanogenesis-regulating signals. They state in conclusion:

“Our results suggest that the suppressive activity of curcumin on α-MSH-stimulated melanogenesis may involve the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt.”

Evidence has been accumulating for some time that green tea polyphenols also protect against skin carcinogenesis. A paper published in Photodermatology, Photoimmunology & Photomedicine reported that green tea constituents protect against UV-induced DNA damage. The authors state:

“Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (−)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells.”

Of special interest is that…

“This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion.”

They compared DNA damage induced by UVR in cultured human cells with and without EGCG, and then conducted the same assay on peripheral white blood cells isolated from 10 adult human volunteers before and after drinking 540 ml of green tea. What did the data show?

“The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet A (UVA) radiation.”

Thus they conclude:

“The studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion.”

A paper more recently published in the Journal of Photochemistry and Photobiology adds further evidence that green tea can protect against DNA damage from ultraviolet radiation. The authors state:

“Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet A and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin.”

They too exposed white blood cells drawn from healthy human volunteers to UV irradiation after ingestion of green tea and measured the levels of DNA damage. They conclude:

“The findings…indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure.”

Ellagic acid, another polyphenol found in pomegranate and berries, has also been studied for its ability to reduce skin damage due to UV-B irradiation. The authors of a paper published in Experimental Dermatology state:

“This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts.”

Interestingly, in regard to wrinkle production ellagic acid…

“…attenuated UV-B-triggered skin wrinkle formation and epidermal thickening…In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis.”

The skin inflammation due to UV exposure noted in the authors’ conclusion is a contributing cause for skin cancer:

“These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries [and pomegranate] rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing.”

Sulforaphane, a compound found in cruciferous vegetables, has also been shown to reduce carcinogenic inflammation as documented in a paper just published in Molecular Carcinogenesis. The authors state:

“Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2)…Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against…UVB-induced skin inflammation.”

To do this they induced skin inflammation by UVB irradiation in two groups of mice, with and without the Nrf2 genes that respond to sulforaphane. What did they find?

“SFN treatment of Nrf2 WT ['wild type', with Nrf2 genes] but not Nrf2 KO ['knockout', without Nrf2 genes] mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin.”

In other words, sulforaphane (SFN) from cruciferous vegetables like broccoli, Brussels sprouts and cabbages activated the Nrf2 genes that conferred protection against UVB-induced inflammation.

While there is evidence that polyphenols, green tea EGCG, curcumin, sulforaphane and other single agents protect against skin cancer, a combination of multiple agents may work best. The authors of a paper published in the journal Dermatologic Surgery note:

“The endogenous antioxidant system of the skin scavenges reactive oxygen species and combats ultraviolet induced oxidative skin damage. Supporting this cutaneous defense system with topical or oral antioxidants may provide a successful strategy for the treatment and prevention of skin cancer.”

They undertook a review of the evidence available in 2002 for treatment and prevention of melanoma and nonmelanoma skin cancers using antioxidants and vitamins. Their findings were mixed:

“Review of the literature demonstrates that the administration of synthetic retinoids has not proved beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium supplementation has reduced the incidence of several internal malignancies but not of nonmelanoma skin cancer. Synergistic use of β-carotene with vitamins C and E has demonstrated prophylaxis against reactive oxygen radicals involved in nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25-dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent in the regression of the early stages of melanoma in specific cell lines.”

They support the use of a combination approach:

“Delivery of exogenous antioxidants in combination appears to be a more successful strategy for enhancing the cutaneous antioxidant system than the administration of isolated antioxidants alone. Vitamin D analogs may have a role in the medical therapy of melanoma.”

The authors of a paper published recently in the journal Seminars in Cutaneous Medicine and Surgery also assert that combining multiple agents may be significantly more effective than single agents in prevention of UV-induced skin cancer:

“With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.”

Along these lines a promising study just published in the journal Nutrition and Cancer offers evidence that the multiherbal formulation Zyflamend inhibits melanoma growth. By way of background…

“Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer.”

They further observe:

“Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation.”

The authors designed their study to test the effect of Zyflamend on melanoma proliferation. They found that…

“Zyflamend inhibits melanoma growth by regulating the autophagy–apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer.”

Interestingly, two earlier studies published in the same journal report that Zyflamend induces apoptosis (programmed cell death) of prostate cancer cells and inhibits malignant bone destruction and invasion while potentiating cytotoxicity.

A sound strategy for skin cancer prevention requires a comprehensive examination of the various possible contributing causes that addresses the unique needs of the individual. That being said, there is ample evidence that beneficial agents are available to play a role in protection from UV-induced irradiation that are worthy of consideration.

Immunepheresis: a vastly under-utilized cancer therapy that deserves far more attention

Posted on August 2, 2010 by Dr. Jonathan

It has long been known that tumor cells defy destruction by immune cells by producing cytokine ‘decoys’ called soluble TNF-α (tumor necrosis factor-alpha) receptors. TNF-α is a ‘guidance system’ for the immune attack that seeks its receptors on malignant cell membranes. The soluble receptors (TNF-R) shed by tumor cells into their local environment divert the TNF-α by binding them. A paper published sixteen years ago in the British Journal of Cancer documents their presence in breast cancer:

“The expression of tumour necrosis factor alpha (TNF-alpha) and its two distinct receptors, TNF-R p55 and TNF-R p75 [soluble receptors], was…was not detectable in normal breast tissue or in non-malignant breast tissue adjacent to the tumours.”

It was a different story for the tumors examined:

“TNF-R p55 was expressed by a population of stromal cells in all the tumours examined, and a varying proportion of neoplastic cells in 75% of these tissues. TNF-R p75 was detected in about 70% of the tumours…”

It has been known for just as long that the presence of soluble tumour necrosis factor receptors can predict the outcome for a cancer patient. A paper published in The Lancet around the same time references a number of earlier studies on the topic.

A couple years later a similar observation was reported in a paper published in the European Journal of Cancer for melanoma. The authors note:

“It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer.”

They proceed to describe increased concentrations of soluble TNF receptors in association with adhesion molecules that also participate in tumor development:

“We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-Rl levels were detected only in patients with metastatic melanoma compared with normal controls, whereas sTNF-R2 levels were increased both in primary and metastatic melanoma…A correlation between sTNF-Rs and sICAM-1 concentrations in patients’ sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.”

These observations were soon followed by research that further confirmed the blockade of anti-tumor immune mechanisms by soluble TNF receptors. A paper published in the journal Immunology also mentions early trials of ultrapheresis (another term for immunepheresis = filtering from the blood of soluble TNF receptor ‘decoys’):

“Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour immunity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis, an experimental extracorporeal treatment for cancer.”

The authors designed their study to resolve definitive proof that sTNFRI specifically blocks immune efforts at tumor removal (full text available here):

“While the considerable clinical benefit provided by Ultrapheresis is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits immune mechanisms which mediate tumour cell elimination.”

Their findings proved that soluble TNF receptor (sTNFRI)-secreting tumor cells resisted destruction by TNF:

“These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.”

We have another interesting study published just weeks ago in the journal Clinical Chemistry and Laboratory Medicine that adds more evidence that soluble tumour necrosis factor receptor type I concentrations are a powerful predictor of outcome in breast cancer.

“The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer.”

The authors surveyed cytokines in breast cancer patients including interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)and followed them for ten years. Their data led them to this conclusion:

“…a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer… Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.”

In other words, the soluble TNF receptors, the worse the breast cancer patient will do. But what about other types of cancer? A research article published in the Journal of Surgical Oncology shows the link between serum cytokine receptor levels and bone sarcoma:

“We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors (interleukin 6 (IL-6); interleukin 8 (IL-8); interleukin 10 (IL-10); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); macrophage colony-stimulating factor (M-CSF); granulocyte colony-stimulating factor (G-CSF); interleukin 1 receptor antagonist (IL-1ra); sIL-2R; tumor necrosis factor receptor I (TNF RI), and TNF RII) with clinico-pathological features and survival of patients with bone sarcomas.”

They used multiple metrics to show the association between cytokines and soluble receptors and tumor characteristics along with overall outcome. Their data led to this conclusion:

“These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.”

A research article published in the journal Tumor Biology finds the same kind of evidence for colorectal cancer. While they found a correlation with a number of circulating cytokines, their summary observations are the most striking:

“sTNF RI (soluble TNF receptor 1), IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF RI was found elevated in the greatest percentage of all CRC [colorectal cancer] patients, in the greatest proportion of stage I patients and presented the best diagnostic sensitivity. In addition, the sTNF RI level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor.”

And another paper published in the same journal concludes with concordant evidence for solid carcinomas in general:

“…for the soluble tumor necrosis factor (TNF) receptors type I (p55) and type II (p75) and IL·2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors plasma levels of TNF receptor p75 and IL·2 receptor were not significantly different from the controls.”

A study published around the same time in the journal Oncology makes the same case for non-small cell lung cancer (NSCLC) as well, with an interesting comparison to the standard markers:

“…increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers…A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor.”

We also have the evidence from a study published in the journal Cellular Immunology in which the authors blocked the decoy effect of soluble tumor necrosis factor receptor type I (sTNFRI)receptors with neutralizing antibodies and observed the effect. Their data led to this conclusion:

“These data demonstrate that sTNFRI directly influences tumor formation and persistence in vivo and suggest the selective removal and/or inactivation of sTNFRI as a promising new avenue for cancer immunotherapy.”

Obviously an intervention that gets rid of the ‘decoy’ receptors so the immune system can effectively attack the tumor makes excellent sense. In a paper published in the Proceedings of the National Academy of Sciences (USA) we have early evidence that the soluble tumor necrosis factor receptors can be filtered out of the blood of human cancer patients:

“Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro.”

The investigators proceeded to show that the blocking factor is derived from malignant cell membrane TNF receptors. They further observed that:

“Purified BF blocks the lytic [malignant cell destroying] activity of recombinant human and mouse TNF-alpha…The BF also inhibits the necrotizing activity of recombinant human TNF-alpha… The BF may have an important role in…interaction between the tumor and the host antitumor mechanisms…”

A paper published in 2002 by a leader in the field of immunepheresis in the journal Therapeutic Apheresis and Dialysis documents the emerging insights and outstanding outcomes with cancer patients that were already being accomplished:

“Immunosuppression is a hallmark of advanced malignancies in man. Over the past 40 years, many investigators have identified soluble immunosuppressive factors in blood, serum, ascitic fluid, and pleural fluid from cancers in man and other species. Suppressive factors have also been identified that are produced by tumors.”

The author also draws attention to the similarity of immunologic tolerance in cancer and pregnancy (which has also been referred to as the ‘trophoblastic theory‘):

“The description of immunosuppressive factors in the blood of vertebrates who either have cancer or who are pregnant is significant, for only in pregnancy and cancer does a seemingly normal immune system tolerate immunogenic neoantigen. Tumor necrosis factors (TNFs) are …thought to be suppressed in patients who have cancer or who are pregnant. Recently, elevated blood levels of soluble tumor necrosis factor receptors (sTNFRs) have been reported in the blood in a variety of cancers and pregnancy.”

He notes that much evidence has accumulated validating the connection between elevations of sTNFRs and a poor prognosis:

“In 1990, after our initial publication of the discovery of sTNFRs in the serum and low molecular weight ultrafiltrates of serum from a variety of cancer patients, others confirmed significant elevations of sTNFRs in cancer patients. This elevation was found to correlate with a poor prognosis.”

The author then reviews the suppressive role of soluble receptors shed from tumor cells and the positive effects of ultrapheresis—filtering the blood to remove reduce these suppressive molecules. A few years a ago a paper published in the same journal reported advances in the filtering technology:

“Using these methods, an improvement in performance status and clinical symptoms and reduction of tumor size have been observed.”

Two years ago further advances and positive clinical outcomes were reported in Therapeutic Apheresis and Dialysis in a paper presented by the same pioneer mentioned above:

“Mean reductions in sTNF-R1 (48%), sTNF-R2 (55%), and sIL2-R levels (72%) were observed … Clinical findings indicated tumor inflammation and necrosis in most patients. Side-effects were low-grade fever, flu-like symptoms; tumor pain and redness, warmth, tenderness, and edema. The column demonstrated safety and efficacy in lowering plasma sTNF-R1, sTNF-R2, and sIL2-R levels.”

Personally I know of patients who have undergone this procedure who have had outstanding outcomes characterized by dramatic reductions in tumor mass.

Is this a safe treatment? A paper published in the Journal of Clinical Apheresis reports that, in contrast with chemotherapy, short term side-effects of immune activation were only mild-moderate, and there were no long-term side-effects at all:

“The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment…Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects.”

Immunepheresis (therapeutic apheresis, ultrapheresis) is worthy of far more research resources and clinical utilization. For more information see the International Immunology Foundation. Treatment is available for suitable candidates from M. Rigdon Lentz, M.D. (an American oncologist and immunepheresis pioneer) and Kiran Lentz, M.D. at their clinic in Prien am Chiemsee, Bavaria, Germany. As usual, the papers presented above are a small selection from a much larger body of literature. A 170 page report by Dr. Ralph Moss of Cancer Decisions on the work of Dr. Lentz is available here.

Note: Removal of soluble receptor blockade to permit immune destruction of malignant cells is an elegant physiological intervention to reduce tumor burden. Practitioners and patients alike must also bear in mind the need to investigate and treat from a functional medicine perspective the underlying causal factors that develop malignancies in the first place and promote their recurrence.

These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.