What are the Objectives of Hyperthermia?
The broad objectives of hyperthermia include:
- Increase cyclic AMP
- Regenerate and recover mitochondria
- Eliminate immune suppressive agents produced by cancer
- Stimulate and activate the immune system
- Heal the body
Increase cyclic AMP (cAMP)
I think this is the actual first time I have written about the molecule—cAMP. Cyclic AMP is a secondary messenger within the cell that is the result of the balance between its production from the adenyl cyclase enzymes and its elimination by the phosphodiesterase enzymes. Cyclic AMP is an important means of communication within the cell. It is called a secondary messenger because of its role in the relay of signal(s) from the cell surface to internal locations throughout the cell.
Ultimately, cAMP is the breakdown byproduct of ATP. You may recognize ATP, Adenosine Triphosphate, as the primary energy molecule of the body. Adenosine Triphosphate is the primary energy end point of the glycolysis (occurs in the cell cytoplasm), Kreb’s cycle (occurs in the mitochondrial intracellular matrix), and electron transport (occurs in the inner mitochondrial membrane) energy energy pathways within the the cell. Without ATP, there is now life. These pathways dominant in healthy cell metabolism, yet dysfunction reigns as a part of the oncogenic metabolism transformation in cancer.
What is the relevance to cancer? Cancer is addicted to the communication dysfunction that is characteristic of the low cAMP environment found in cancer [i]. This communication dysfunction is like the junior High School game of Telephone where people sit in a circle and the first person whispers a secret into the ear of the second person, which then whispers it to the next, and it goes around the circle, only to end up being an entirely different secret at the end. Low cAMP levels and low cAMP activity has been shown to be present in a variety of cancer types including pancreatic cancer [ii], hepatocellular cancer [iii], colon cancer [iv], breast cancer [v], and prostate cancer [vi]. In contrast, therapies that increase cAMP, such as phosphodiesterase inhibitors, have been shown to inhibit the pro-cancer processes of angiogenesis, proliferation, mobility, invasion, and spread [vii] [viii]. Cancer is definitely a complicated process. There is no magic bullet in the cause or treatment of cancer, but cAMP sits square in the middle of the miscommunication of it all.
Regenerate and recover mitochondria
I may have caught you off guard with this one. Regenerate? Recover? Heal? But then again, we physicians are healers. These are not common objectives you would expect to hear from any conventional cancer treatment strategy, let alone any cancer treatment strategy. You sure won’t hear these words in any conventional oncology appointments. This approach to regenerate, recover, and to heal will only be found as an objective in a Holistic, Integrative cancer treatment program.
Mitochondria are the energy powerhouses of the cell. They are at the heart of normal cell function. Likewise, they are the heartbeat of oncogenic metabolism transformation. Most will better recognize this as the Warburg effect, described by Dr. Otto Warburg’s work in the 1930s [ix] [x]. The conventional medicine approach to cancer is to remove and destroy the mass of cells that have undergone the oncogenic metabolic shift. This approach is a failure to recognize that the tumor is actually a reaction to the pro-carcinogenic environment within the body. Cancer is the reaction to, the effect of, the response to, not the cause. Then it becomes the cause of chaos. It is the flashing light in the hotel hallway that alerts to the presence of a fire. Now, if there is a large tumor and large tumor burden, the surgical removal of a large tumor burden can be helpful to the overall treatment success. This approach, however, fails to recognize the oncogenic metabolic transformation connection to the heartbeat of cancer—the mitochondria. There must be a change in the internal environment and a change within the mitochondria to heal. The removal of the mass of dysfunctional cells that one can see does nothing to change the environment and the mitochondria that one does not see.
A compass setting point in history occurred in 2013-2014, and involved two men and their research teams—Thomas N. Seyfried, PhD and Tsuneo Kobayashi, MD. Independently, and unknown to each other, they were working on the same inter-connected concept of cancer, cell nucleus (DNA brain of the cell), mitochondria (energy powerhouse of the cell), and the influence of the local cell environment. Dr. Thomas Seyfried published his work in the journal Carcinogenesis, entitled Cancer as a metabolic disease: implications for novel therapeutics, in 2013 [xi]. Dr. Seyfried showed that “…tumors do not arise from nuclear genomic defects alone and that normal mitochondria can suppress tumorigenesis.” Simply stated, the environment of the cell can change the genomic abnormalities of a cancer cell nucleus to yield normal cell offspring.
Dr. Kobayashi’s simultaneous work, Elucidation of the core reason for carcinogenesis and prevention of cancer recurrence, looked specifically at cancer as a disease of mitochondrial dysfunction that causes oncogenic metabolic transformation instead of the DNA multiple hit theory for the purpose of prevention of cancer recurrence. These two men were joined by common thought and dual purpose, yet were separated by approximately 7,000 miles. Independently, they came to the same conclusion—Cancer is a reversible metabolic disease. You did read that correct. Metabolically speaking, and according to this research, cancer cells can heal.
The readily used word remission in cancer, just means that the cancer is no longer visible to our current technologic ability to detect it. That is great, but we must work beyond what we see to what is unseen. After all, this is a metabolic process. It is only the Holistic, Integrative cancer treatment that recognizes the impact of the metabolically unseen and the connection between mitochondria and the oncogenic metabolism transformation of cancer. In contrast to the conventional medicine approach, the Holistic cancer approach is to restore, recovery, regenerate, and to heal the mitochondria and the corresponding surrounding environment. It is only through this approach can one change the mitochondria heartbeat of the cell, change the environment surround the cell, all to change from oncogenic metabolism and restore healthy metabolism—Restore, Regenerate, Recover, Heal.
Eliminate immune suppressive agents produced by cancer
Cancer is the great disruptor. There is no better example of this than cancer’s impact on the immune system. Cancer manipulates the environment around the cancer, in what is called the tumor microenvironment (TME). The tumor microenvironment is where the tumor and the body interface and interact. It should come as no surprise, that the immune system is front and center in the tumor microenvironment. At hand is not the mere presence of the immune system in the tumor microenvironment, but also the manipulation of the responding immune system by cancer in the tumor microenvironment.
Cancer suppresses the immune system in the tumor microenvironment via a variety of mechanisms:
- oncogenic metabolism
- oncogenic mutations
- oncogenic signaling
- growth factors
Oncogenic metabolism includes the well known examples of hypoxia (low oxygen) [xii] [xiii], chronic inflammation (NF-kappaB activation) [xiv] [xv], acid pH (elevated lactic acid) [xvi] [xvii] [xviii] that are characteristic of the Warburg effects [xix] in the carcinogenic environment. Oncogenic mutations, that occur as a result of the metabolic oncogenic transformation, help to contribute to tumor microenvironment immunosuppression include the likes of BRAF [xx], Ras [xxi], KRAS [xxii], and c-MYC [xxiii]. Of course, there are many more. Oncogenic signaling includes the like of so many pathways including an increase in mitogen-activated protein kinase (MAPK), Phosphoinositide 3 kinase (PI3k)-Akt, mechanistic target of rapamycin (mTOR), protein kinase C (PKC), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) activity [xxiv] [xxv] [xxvi] [xxvii] [xxviii]. Growth factors that contribute to immunosuppression in the tumor microenvironment include epidermal growth factor receptor (EGFR) [xxix], vascular endothelial growth factor (VEGF) [xxx] [xxxi], platelet-derived growth factor (PDGF) [xxxii], and hypoxia-Inducible factor 1alpha (HIF-1alpha) [xxxiii]. Metabolites that contribute to immunosuppression include lactic acid (above), adenosine, and the disordered tryptophan metabolites kyneurinate and quinolinate (via increased indoleamine 2,3 dioxygenase) [xxxiv]. Finally, cytokines and chemokines that suppress immune activity within the tumor microenvironment include TGF-beta, T regulator cells, interleukin 6, and interleukin 10 [xxxv] [xxxvi] [xxxvii] [xxxviii] [xxxix] [xl].
It is important to recognize that these different lines of immunosuppression attack are not independent, but are in fact intimately intertwined. It is almost as cancer coordinates its attack on the body’s defenses. Cancer weaves an intricate web of immunosuppression. From the targeting of the lactic acid and hypoxic environment in cancer that is the result of aerobic glycolysis (Warburg effect) in oncogenic metabolism, to the inhibition of VEGF growth factor critical to angiogenesis in cancer, to the inhibition of T regulator cells and TGF-beta and other cytokines and chemokines, hyperthermia alone or in combination with other anti-cancer therapies directly counters this broad web of immunosuppression [xli] [xlii] [xliii] [xliv] [xlv].
Stimulate and activate the immune system
Though this may appear to be similar to the previous point, it is quite different. They are connected, but they are unique. The immune system is the God created system that protects the body against enemies, foreign and domestic. The immune system is designed to identify, target and eliminate cancer. No need to recreate the wheel here. The immune system is present, but dysfunctional at the hands of the cancer in the tumor microenvironment. The goal here is to activate and stimulate the immune system back to doing its job. Hyperthermia counters the immunosuppression, briefly highlighted above, and directly stimulates the innate and adaptive immune system to target and attack cancer [xlvi].
Heal the body
Did I catch you off guard again. Is this not the ultimate goal of any cancer treatment program! Conventional, alternative, Holistic, whatever… Don’t get me wrong, remissions are great. Five year survivals are awesome. But, these are just words and phrases. As good as they may make us feel, they do nothing to impact and impart healing. Healing, is the process of restoring wellness; and wellness is to restore the whole.
Question: how can any treatment that detracts from the whole be said to be a part of healing?
Despite intense statistical marketing, remissions and five year survivals do not equate too healing. How many patients are told they are in remission, only to recur 3 or 6 months later? A lot, I assure you.
Question: in that scenario, was there ever really a remission?
The answer is an obvious no. How many patients that achieve 5 year survival to then only present with a later recurrence or a new secondary cancer secondary to treatment were cured? Even the term ‘cure’ does not equate too healing. Just as a physician cannot cure aging, a physician cannot cure cancer, no matter the approach to treatment. A cure is absolute. Only God has the absolute power to cure. It is only the result of our pride that we physicians think that as gods, we can cure anything. It is only through the process of healing that the environment of the body changes so as to make the environment no longer cohabit-able to cancer. Beyond that, healing makes sure cancer never comes back. Healing can not be defined by a six month cycle of treatment, but, instead, is a continual, daily process that never ends.
There is no magic bullet in the treatment of cancer. There is no perfect therapy in cancer treatment. It is the combination and sequencing of therapies that promote healing to heal the internal cell environment, and target the mitochondrial heart of cancer, that is the key. Moving forward, the real hyperthermia benefits will stand tall and stand out.
[i] McEwan DG, Brunton VG, Baillie GS, Leslie NR, Houslay MD, Frame MC. Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res. 2007 Jun 1;67(11):5248-57. doi: 10.1158/0008-5472.CAN-07-0097.
[ii] Zimmerman NP, Roy I, Hauser AD, Wilson JM, Williams CL, Dwinell MB. Cyclic AMP regulates the migration and invasion potential of human pancreatic cancer cells. Mol Carcinog. 2015;54(3):203-215. doi:10.1002/mc.22091
[iii] Massimi M, Ragusa F, Cardarelli S, Giorgi M. Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma. Cells. 2019; 8(12):1511. https://doi.org/10.3390/cells8121511
[iv] McEwan DG, Brunton VG, Baillie GS, Leslie NR, Houslay MD, Frame MC. Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4–Regulated Compartment via Effects on Phosphoinositide 3-Kinase. Cancer Res. June 2007;67 (11) 5248-5257; DOI: 10.1158/0008-5472.CAN-07-0097
[v] Dong H, Claffey KP, Brocke S, Epstein PM. Inhibition of breast cancer cell migration by activation of cAMP signaling. Breast Cancer Res Treat. 2015 Jul;152(1):17-28. doi: 10.1007/s10549-015-3445-9. Epub 2015 May 29. PMID: 26022351.
[vi] Powers GL, Hammer KD, Domenech M, et al. Phosphodiesterase 4D inhibitors limit prostate cancer growth potential. Mol Cancer Res. 2015;13(1):149-160. doi:10.1158/1541-7786.MCR-14-0110
[vii] Peng T, Gong J, Jin Y, Zhou Y, Tong R, Wei X, Bai L, Shi J. Inhibitors of phosphodiesterase as cancer therapeutics. European Journal of Medicinal Chemistry. April 2018;150:742-756.
[viii] Ashour AE. Phosphodiesterase-5 inhibitors in the management of cancer. Asian Journal of Biomedical and Pharmaceutical Sciences. 2013;3(20):1-5.
[ix] Warburg O . (1931) The Metabolism of Tumours. Richard R. Smith , New York
[x] Seyfried TN, Yu G, Maroon JC et al. Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab (Lond). 2017;14(19). https://doi.org/10.1186/s12986-017-0178-2
[xii] Mo Z, Liu D, Rong D, Zhang S. Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma. Front Immunol. Feb 2021. https://doi.org/10.3389/fimmu.2021.611058.
[xiii] Nejad EA, Najafgholian S, Rostami A et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 2021; 21(62). https://doi.org/10.1186/s12935-020-01719-5
[xiv] Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med. Jun 2008;205(6):1261-8. doi: 10.1084/jem.20080108.
[xv] Xie Y, Shen S, Verma IM. NF-κB, an Active Player in Human Cancers. Cancer Immunol Res Sept 2014;2(9):823-830; DOI: 10.1158/2326-6066.CIR-14-0112
[xvi] Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J, Wang Y. Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity. Int J Mol Sci. Nov 2020;21(21):8363. doi: 10.3390/ijms21218363.
[xvii] Choi SY, Collins CC, Gout PW, Wang Y. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol. Aug 2013;230(4):350-5. doi: 10.1002/path.4218.
[xviii] Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, Tuccitto A, Tagliabue E, Castelli C, Rivoltini L. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. Apr 2017;43:74-89. doi: 10.1016/j.semcancer.2017.03.001.
[xix] Ganapathy-Kanniappan S. Linking tumor glycolysis and immune evasion in cancer: Emerging concepts and therapeutic opportunities. Biochim Biophys Acta Rev Cancer. Aug 2017;1868(1):212-220. doi: 10.1016/j.bbcan.2017.04.002.
[xx] Colombino M, Paliogiannis P, Cossu A, et al. BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas. J Clin Med. 2019;8(10):1577. Published 2019 Oct 1. doi:10.3390/jcm8101577
[xxi] Tuccitto A, Shahaj E, Vergani E, Ferro S, Huber V, Rodolfo M, Castelli C, Rivoltini L, Vallacchi V. Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy. Virchows Arch. Apr 2019;474(4):407-420. doi: 10.1007/s00428-018-2477-z.
[xxii] Hamarsheh S, Groß O, Brummer T et al. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020; 11:5439. https://doi.org/10.1038/s41467-020-19288-6
[xxiii] Meng X, Carlson NR, Dong J, Zhang Y. Oncogenic c-Myc-induced lymphomagenesis is inhibited non-redundantly by the p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways. Oncogene. 2015;34(46):5709-5717. doi:10.1038/onc.2015.39
[xxiv] Khalili JS, Hwu P, Lizée G. Forging a link between oncogenic signaling and immunosuppression in melanoma. Oncoimmunology. 2013;2(2):e22745. doi:10.4161/onci.22745
[xxv] Marmor MD, Skaria KB, Yarden Y: Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys. 2004;58:903-913.
[xxvi] Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. Oct 2016;82(4):943-56. doi: 10.1111/bcp.13021.
[xxvii] Chen B, Gao A, Tu B, Wang Y, Yu X, Wang Y, Xiu Y, Wang B, Wan Y, Huang Y. Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery. Biomaterials. Oct 2020;255:120187. doi: 10.1016/j.biomaterials.2020.120187
[xxviii] Owen KL, Brockwell NK, Parker BS. JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression. Cancers (Basel). 2019;11(12):2002. doi:10.3390/cancers11122002
[xxix] Concha-Benavente F, Ferris RL. Oncogenic growth factor signaling mediating tumor escape from cellular immunity. Current Opinion in Immunology. Apr 2017;45:52-59.
[xxx] Tamura R, Tanaka T, Akasaki Y, Murayama Y, Yoshida K, Sasaki H. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med Oncol. Nov 2019;37(1):2. doi: 10.1007/s12032-019-1329-2.
[xxxi] Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, Taieb J. Immunomodulatory Activity of VEGF in Cancer. Int Rev Cell Mol Biol. 2017;330:295-342. doi: 10.1016/bs.ircmb.2016.09.007
[xxxii] Han C, Liu T, Yin R. Biomarkers for cancer-associated fibroblasts. Biomark Res. Nov 2020;8(1):64. doi: 10.1186/s40364-020-00245-w.
[xxxiii] Rankin EB, Nam JM, Giaccia AJ. Hypoxia: Signaling the Metastatic Cascade. Trends in Cancer. June 2016;2(6):295-304. https://doi.org/10.1016/j.trecan.2016.05.006.
[xxxiv] Tanizaki Y, Kobayashi A, Toujima S, et al. Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. Cancer Sci. 2014;105(8):966-973. doi:10.1111/cas.12445
[xxxv] Dahmani A, Delisle JS. TGF-β in T Cell Biology: Implications for Cancer Immunotherapy. Cancers (Basel). Jun 2018;10(6):194. doi: 10.3390/cancers10060194.
[xxxvi] Imamura T, Hikita A, Inoue Y. The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer. Apr 2012;19(2):118-24. doi: 10.1007/s12282-011-0321-2.
[xxxvii] Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression – implications for anticancer therapy. Nat Rev Clin Oncol. Jun 2019;16(6):356-371. doi: 10.1038/s41571-019-0175-7.
[xxxviii] Najafi M, Farhood B, Mortezaee K. Contribution of regulatory T cells to cancer: A review. J Cell Physiol. Jun 2019;234(6):7983-7993. doi: 10.1002/jcp.27553.
[xxxix] Shimizu K, Iyoda T, Okada M, Yamasaki S, Fujii S. Immune suppression and reversal of the suppressive tumor microenvironment. International Immunology. Oct 2018;30(10):445–455. https://doi.org/10.1093/intimm/dxy042
[xl] Zhang Y, Rajput A, Jin N, Wang J. Mechanisms of Immunosuppression in Colorectal Cancer. Cancers. 2020; 12(12):3850. https://doi.org/10.3390/cancers12123850
[xli] Sardari, Dariush & Verga, Nicolae. 2011. Cancer Treatment with Hyperthermia. 10.5772/24049.
[xlii] Krenacs T, Meggyeshazi N, Forika G, et al. Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models. Int J Mol Sci. 2020;21(17):6270. Published 2020 Aug 29. doi:10.3390/ijms21176270
[xliii] Sawaji Y, Sato T, Takeuchi A, Hirata M, Ito A. Anti-angiogenic action of hyperthermia by suppressing gene expression and production of tumour-derived vascular endothelial growth factor in vivo and in vitro. Br J Cancer. 2002;86(10):1597-1603. doi:10.1038/sj.bjc.6600268
[xliv] Overgaard J, Bichel P. The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitro. Radiology. May 1977;123(2):511-4. doi: 10.1148/123.2.511.
[xlv] Krenacs T, Meggyeshazi N, Forika G, et al. Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models. Int J Mol Sci. 2020;21(17):6270. doi:10.3390/ijms21176270
[xlvi] Baronzio GF, Seta RD, D’Amico M, et al. Effects of Local and Whole Body Hyperthermia on Immunity. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6083/
Find more articles like, “Immunotherapy Series – What are the Objectives of Hyperthermia?”, visit our blog.
Dr. Nathan Goodyear is dedicated to disease prevention, disease resolution, and the Wellness Lifestyle through a solution-based, Integrative Medicine approach founded in science. Dr. Goodyear received his Bachelor of Arts from Louisiana Tech University and his Doctor of Medicine from LSU Health Sciences Center.
He is Board Certified in Obstetrics and Gynecology and served as the Chief Resident in Obstetrics and Gynecology at the University of Tennessee. Dr. Goodyear has practiced Integrative Medicine since 2006. Dr. Goodyear is a Fellow in Functional and Regenerative Medicine and served on the board of the American Functional Medicine Association. Dr Goodyear is licensed by the Arizona Homeopathic and Integrative Medical Board in the State of Arizona. Dr. Goodyear is a published author, Man Boob Nation–an Integrative medicine approach to low Testosterone published in 2014, and Total Testosterone Transformation published in 2017