Glioblastoma - Comments on Żwierełło et al., 2023

Comments on current issues in fluoride/thyroid research.
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Glioblastoma - Comments on Żwierełło et al., 2023

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Copied from Research Forum on Feb 24, 2023

STUDY:
Żwierełło W, Maruszewska A, Skórka-Majewicz M, Gutowska I - "Fluoride in the Central Nervous System and Its Potential Influence on the Development and Invasiveness of Brain Tumours - A Research Hypothesis" Int J Mol Sci 24(2):1558 (2023) doi: 10.3390/ijms24021558
https://www.mdpi.com/1422-0067/24/2/1558

PFPC Commentary:

Żwierełło et al. provide an excellent and welcome review of the effects of fluoride on pathways implicated in the formation and clinical course of brain cancer, particularly glioblastoma.

The authors discuss many pathways and the effects of fluoride, yet they do not appear to appreciate the fact that these same pathways are controlled by thyroid hormones. Our website lists detailed information on almost all of the various pathways discussed in the paper [i.e. TNF-α, IL-8, IL10, NF-κB, etc.]

While the authors provide a brief paragraph on the issue of fluoride and thyroid hormones, outlining a.o. Nauman's outstanding 2015 review on the role of thyroid hormones in the central nervous system (CNS) and their effect on glioblastoma, they fail to consider the most plausible primary pathway identified so far - the involvement of reverse T3 (rT3) and its corresponding deiodinase, D3.


FLUORIDE & rT3

During the early 1990s, Lin Fa Fu and colleagues found that increased fluoride intake in areas with endemic fluorosis in China correlated with elevated levels of rT3. They suggested using rT3 as a diagnostic marker for fluoride poisoning (Lin et al., 1991, 1992). The use of rT3 as a diagnostic marker has since been confirmed in other studies (Shashi & Singla, 2013a, b).

Increased rT3 levels are also found in glioma patients and are used as a prognostic marker.


WHAT IS rT3?

rT3 is a metabolite of thyroxine (T4), similar to T3, but is considered to be metabolically inactive. Elevated levels of rT3 can be observed in conditions such as severe illness, stress, malnutrition, and at higher altitudes. rT3 is synthesized in peripheral tissues, outside the thyroid gland, through the process of deiodination catalyzed by the deiodinase D3. This enzymatic conversion restricts the availability of T4 for the formation of T3, which is considered the 'active' thyroid hormone. Consequently, the reduced availability of T3 to thyroid receptors leads to a slower metabolic rate. Additionally, D3 plays a vital role during gestation by regulating thyroid hormone levels to prevent excessive exposure to the developing fetus.

  • The deiodinases regulate the activity of thyroid hormones by converting them into active or inactive forms. These enzymes are essential in maintaining the balance of thyroid hormones in the body and play a role in various physiological processes such as metabolism, growth, and development. Abnormalities in deiodinase function can lead to thyroid disease and many other health problems.

    There are three types of deiodinases - type 1 (D1 --> DIO1), type 2 (D2 --> DIO2), and type 3 (D3 --> DIO3), each with distinct properties and functions.


rT3, D3 and CANCER

Recent research has postulated that D3 (rT3) activity is required to facilitate tumor cell proliferation, as D3 expression has been found in oligodendromas, astrocytomas, gliosarcomas, glioblastomas, TSH-secreting pituitary adenomas, basal cell carcinomas, colon adenomas, and carcinomas (see Luongo et al., 2013).

Earlier, Nauman and colleagues discovered that the activity of D3 was increased in 8/8 cases of gliosarcoma and in 9/10 cases of glioblastoma (Nauman et al., 2004).

In 2019, studies by Lin et al. showed that in vitro, rT3 increased the proliferation of 50% to 80% of human breast cancer and glioblastoma cells, further suggesting that rT3 may be a host factor supporting cancer growth (Lin et al., 2019).

The "low T3 syndrome", caused by increased rT3 levels, has been found a "strong independent predictor of unfavorable clinical outcomes and depressive symptoms" and experts advise that the "diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors." (Bunevicius et al, 2013).

On the other hand, increased activities of D1 and D2, leading to greater T4 to T3 conversion, have been found associated with survival in glioma patients (Bunevicius et al., 2019).


SUMMARY

Since the 1950s has it been shown that fluoride affects deiodination, and may dose-dependently interfere with the activity of all three deiodinases in a tissue-specific manner.

Fluoride has been identified to raise rT3 levels and cause "low T3 syndrome" in adults and children, in addition to raising TSH levels with increasing intake.

Anything that raises rT3 or TSH levels should not be put into the water supply or salt or used carelessly in any other intervention. The high fluoride content in some foods and beverages such as grape products and tea must be urgently addressed, and public advisories should be issued.

Patients suffering from brain cancer should be advised that fluorides may cause increased rT3 levels, thereby contributing to cancer growth and unfavourable outcomes.

PFPC Canada, February 2023


REFERENCES

Buccarelli M, Lulli V, Giuliani A, Signore M, Martini M, D'Alessandris QG, Giannetti S, Novelli A, Ilari R, Giurato G, Boe A, Castellani G, Spartano S, Marangi G, Biffoni M, Genuardi M, Pallini R, Marziali G, Ricci-Vitiani L - "Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3" Neuro Oncol 22(12):1771-1784 (2020) doi: 10.1093/neuonc/noaa127
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746944/
"Patients with imprinting defects in the DLK1-DIO3 region suffer from a range of abnormalities, including growth delay, skeletal malformations, developmental delay/intellectual disability, and even perinatal death...These results suggested that deregulated expression of the transcripts contained in the DLK1-DIO3 region could be involved in GBM [glioblastoma] pathogenesis."

Bunevicius A, Laws ER, Saudargiene A, Tamasauskas A, Iervasi G, Deltuva V, Smith TR, Bunevicius R - "Common genetic variations of deiodinase genes and prognosis of brain tumor patients" Endocrine 66(3):563-572 (2019) doi: 10.1007/s12020-019-02016-6
https://pubmed.ncbi.nlm.nih.gov/31452060/

Bunevicius A, Deltuva V, Tamasauskas S, Tamasauskas A, Laws ER Jr, Bunevicius R - "Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery: a pilot study: clinical article" J Neurosurg 118(6):1279-87 (2013) doi: 10.3171/2013.1.JNS121696
https://pubmed.ncbi.nlm.nih.gov/23480214/

Faghih-Jouybari M, Naderi S, Mashayekhi S, Padeganeh T, Abdollahzade S - "Hypothyroidism among patients with glioblastoma multiforme" Iran J Neurol 17(3):149-151 (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420696/

Freitas BC, Gereben B, Castillo M, Kalló I, Zeöld A, Egri P, Liposits Z, Zavacki AM, Maciel RM, Jo S, Singru P, Sanchez E, Lechan RM, Bianco AC - "Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells" J Clin Invest (2010) 120(6):2206-17. doi: 10.1172/JCI41977
https://pubmed.ncbi.nlm.nih.gov/20458138/
"We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease."

Hackney AC, Feith S, Pozos R, Seale J - "Effects of high altitude and cold exposure on resting thyroid hormone concentrations" Aviat Space Environ Med 66(4):325-9 (1995)
https://pubmed.ncbi.nlm.nih.gov/7794224/

Hercbergs A, Johnson RE, Ashur-Fabian O, Garfield DH, Davis PJ - "Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study" Oncologist 20(1):72-6 (2015) doi: 10.1634/theoncologist.2014-0308
https://academic.oup.com/oncolo/article/20/1/72/6399261

Kress E, Samarut J, Plateroti M - "Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality?" Mol Cell Endocrinol 313(1-2):36-49 (2009) doi: 10.1016/j.mce.2009.08.028.
https://pubmed.ncbi.nlm.nih.gov/19737599/
"This interplay comprises a crosstalk between sonic Hedgehog (Shh) and the thyroid hormones (Bianco, 2008). The Shh pathway determines patterns of cell growth and differentiation in a wide variety of developmental and disease processes, including cancer, as well as in continuously remodeling organs such as skin (Briscoe and Therond, 2005)."

Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, and Aiken - "High-fluoride and Low-iodine Environment and Subclinical Cretinism in Xinjiang" Endemic Diseases Bulletin 6(2):62-67 (1991)
viewtopic.php?p=596

Lin Fa-Fu - "A Study on the Relationship between Serum rT3 and Environmental Iodine or Fluoride Levels" Endem Dis Bull 7(2):68-70 (1992)
http://poisonfluoride.com/phpBB3/viewtopic.php?p=632
Image

Lin HY, Tang HY, Leinung M, Mousa SA, Hercbergs A, Davis PJ - "Action of Reverse T3 on Cancer Cells" Endocr Res 44(4):148-152 (2019)
https://pubmed.ncbi.nlm.nih.gov/30943372/
"In the present studies, we show that rT3 caused increases of proliferation in vitro of 50% to 80% (P < 0.05-0.001) of human breast cancer and glioblastoma cells. Conclusion: rT3 may be a host factor supporting cancer growth."

Liu GY, Chai CY, Kang SL - "Effects of fluoride on the activity of deiodinase in the liver of chickens" Chin J Vet Med 39:14-5 (2003)
http://www.cqvip.com/qk/92143x/200305/7939505.html
First, fluoride causes an increase in D1, then, after 90 days, a severe decrease. When D1 is downregulated, there is less conversion of T4 to T3, and as a result, T4 is more likely to be converted into rT3. (Compare to Zhao et al., 1998;1992)
Image

Luongo C, Trivisano L, Alfano F, Salvatore D - "Type 3 deiodinase and consumptive hypothyroidism: a common mechanism for a rare disease" Front Endocrinol (Lausanne) 4:115 (2013) doi: 10.3389/fendo.2013.00115. PMID: 24027558; PMCID: PMC3761349.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761349/
"D3 expression has been widely documented in a variety of malignancies; it is turned-on in some malignant cell lines and in a number of human tumors, i.e., oligodendromas, astrocytomas, gliosarcomas, glioblastoma multiforme, TSH-secreting pituitary adenomas, basal cell carcinomas, colon adenomas, and carcinomas. It has been postulated that D3 activity is required to facilitate tumor cell proliferation.."

Majos A, Sewerynek E, Grząsiak O, Ciesielski W, Hogendorf P, Hołyński J, Strzelczyk J, Durczyński A - "FT3 to FT4 Conversion Ratio May Be an Independent Prognostic Factor in Pancreatic Cancer Patients" Biomedicines 11(1):77 (2022) doi: 10.3390/biomedicines11010077
https://www.mdpi.com/2227-9059/11/1/77
"We conclude that the importance of fT4 into fT3 conversion means not just its standard metabolic effects as the final products of thyroid gland activity. We hypothesize that it is linked to the progression of pancreatic malignancies, either via thyroid hormone receptors or indirectly, by interaction with cancer cells product."

Mikhailets ND, Balabolkin MI, Rakitin VA, Danilov IP – “Thyroid function during prolonged exposure to fluorides” Problemy Endokrinologii 42 (1):6-9 (1996)
https://www.probl-endojournals.ru/jour/ ... view/11890
"Hence, the syndrome of low T3 and reduced absorption of I131may be considered as diagnostic signs of fluorosis."

Nappi A, De Stefano MA, Dentice M, Salvatore D - "Deiodinases and Cancer" Endocrinology162(4):bqab016 (2021) https://doi.org/10.1210/endocr/bqab016
(Review: "It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interplay between deiodinases and cancer and how this family of enzymes is relevant in cancer progression.")

Nauman P, Bonicki W, Michalik R, Warzecha A, Czernicki Z - "The concentration of thyroid hormones and activities of iodothyronine deiodinases are altered in human brain gliomas" Folia Neuropathol 42(2):67-73 (2004)
https://pubmed.ncbi.nlm.nih.gov/15266780/
"The activity of 5-D3 was increased (in 8/8 cases of gliosarcoma and in 9/10 cases of glioblastoma multiforme) or decreased (in 3/3 cases of astrocytoma II, 5/5 cases of astrocytoma III) when compared to mean activity of this enzyme found in non-tumoural brain tissue. In summary, our results suggest that the concentration of brain iodothyronines and metabolism of thyroid hormones in the examined human brain tumours are altered. These changes may be related to malignant progression."

Nauman P - "Thyroid hormones in the central nervous system (CNS) and their effect on neoplasm formation, particularly on the development and course of glioblastoma multiforme - research hypothesis" Endokrynol Pol 66(5):444-59 (2015) doi: 10.5603/EP.2015.0055
https://journals.viamedica.pl/endokryno ... view/42604

Sabatino L, Vassalle C, Del Seppia C, Iervasi G - "Deiodinases and the Three Types of Thyroid Hormone Deiodination Reactions" Endocrinol Metab (Seoul) 36(5):952-964 (2021). doi: 10.3803/EnM.2021.1198
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566136/
"Upon entering cells, THs can be activated or inactivated by deiodinases...The three enzymes have different subcellular locations; DIO1 and DIO3 are found at the plasma membrane, whereas DIO2 is found at the endoplasmic reticulum, making it very proximal to the nucleus. The DIO1 and DIO2 catalytic globular domains face the cytosol, whereas DIO3 molecules, including the catalytic domain, mostly protrude towards the extracellular space...DIO2 is upregulated in patients with hypothyroidism and downregulated in those with hyperthyroidism suggests that changes in DIO2 contribute to the general effort of maintaining T3 homeostasis, both at circulating and tissue levels, in these two opposite pathological conditions. Instead, DIO3 only catalyzes the inner ring deiodination of T4, resulting in the formation of the inactive product rT3...Furthermore, the high expression of DIO3 in the placenta and pregnant uterus suggests that this enzyme plays an important role in the development process."

Shashi A, Singla S - "Clinical and Biochemical Profile of Deiodinase Enzymes and Thyroid Function Hormones in Patients of Fluorosis" Australian Journal of Basic and Applied Sciences 7(4):100-107 (2013a)
http://poisonfluoride.com/phpBB3/viewtopic.php?t=552
"...the level of rT3 showed a stepwise elevation with increase in water fluoride concentration."

Shashi A, Singla S - "Syndrome of Low Triiodothyroinine in Chronic Fluorosis" International Journal of Basic and Applied Medical Sciences 3(1):152-160 (2013b)
"The study demonstrate that abnormalities in thyroid function characterized by a low level of T3, high rT3 and a slight increase of the TSH with normal to low T4 indicating low T3 syndrome in cases of chronic fluoride intoxication."

Wang YF, Heng JF, Yan J, Dong L- " Relationship between disease severity and thyroid function in Chinese patients with euthyroid sick syndrome" Medicine (Baltimore) 97(31):e11756 (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081175/

Zhang Y, Xie L, Li X, Chai L, Chen M, Kong X, Wang Q, Liu J, Zhi L, Yang C, Wang H - "Effects of fluoride on morphology, growth, development, and thyroid hormone of Chinese toad (Bufo gargarizans) embryos" Environ Mol Mutagen 59(2):123-133 (2018) doi: 10.1002/em.22147
https://pubmed.ncbi.nlm.nih.gov/29024016/
"According to real-time PCR results, exposure to fluoride upregulated Dio3 and TRβ mRNA expression and downregulated Dio2 and TRα mRNA level."

Zhao H, Chai L, Wang H - "Effects of fluoride on metamorphosis, thyroid and skeletal development in Bufo gargarizans tadpoles" Ecotoxicology. 22(7):1123-32 (2013)
http://poisonfluoride.com/phpBB3/viewtopic.php?t=555
"In conclusion, our study suggests that 50 mg L−1 fluoride could damage follicular cells in thyroid gland and induce a sharp reduction in thyroid hormone probably through the up-regulation of D3 mRNA expression, and these influences on thyroid system may delay metamorphosis as well as ossification in bone tissue by inhibiting calcium deposition."

============

In vitro experiments: The effects of fluoride on glioma cells:

Kagaya A, Uchitomi Y, Kugaya A, Takebayashi M, Nagaoka I, Muraoka M, Yokota N, Yamawaki S - "Differential regulation of intracellular signaling systems by sodium fluoride in rat glioma cells" J Neurochem 66(4):1483-8 (1996). doi: 10.1046/j.1471-4159.1996.66041483.x
(Gq/11)

Deng C, Xu L, Zhang Y, Zhao L, Linghu Y, Yu Y - "The value of the hedgehog signal in osteoblasts in fluoride-induced bone-tissue injury" J Orthop Surg Res 16(1):160 (2021) doi: 10.1186/s13018-021-02287-8
https://pubmed.ncbi.nlm.nih.gov/33637095/
"The mRNA expressions of Ihh, Smo, Gli2, and Runx2 in bone tissue of the F group were significantly higher than those in the control group (P < 0.05)."

Deng CN, Zhang Y, Xu L, Zhao LN, Linghu Y, Yu YN - "Change and relationship between Gli1 and β-catenin on rats' bone formation with chronic fluorosis" Chin J of Pathology 49(2):168-173 (2020) doi: 10.3760/cma.j.issn.0529-5807.2020.02.012
https://pubmed.ncbi.nlm.nih.gov/32074731/

Nowak M, Skórka-Majewicz M, Żwierełło W - "Changes in gene expression of metalloproteinases-2 and -9 and their inhibitors TIMP2 and TIMP3 in human glioma cells exposed to low levels of fluoride" Med Sci Forum 3(1):14 (2021)
The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, Session Poster
https://doi.org/10.3390/IECC2021-09229
https://www.mdpi.com/2673-9992/3/1/14
"The obtained results may suggest that even low concentrations of fluorine compounds may have an undesirable influence promoting the invasive potential of human glioblastoma cells."

PFAS

Xie MY, Sun XF, Wu CC, Huang GL, Wang P, Lin ZY, Liu YW, Liu LY, Zeng EY - "Glioma is associated with exposure to legacy and alternative per- and polyfluoroalkyl substances" J Hazard Mater 441:129819 (2023) doi: 10.1016/j.jhazmat.2022.129819
https://www.sciencedirect.com/science/a ... 9422016120
"Our findings suggested that exposure to PFASs might increase the probability to develop glioma. This is the first case study demonstrating associations between PFASs exposure and brain cancer."

Merritt RL, Foran CM - "Influence of persistent contaminants and steroid hormones on glioblastoma cell growth" J Toxicol Environ Health A 70(1):19-27 (2007) doi: 10.1080/15287390600748807
https://www.tandfonline.com/doi/abs/10. ... 0600748807
"Perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS), and testosterone stimulated proliferation in the T98G cells at 500, 1000, and 1000 nM, respectively."
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