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 Table of Contents  
OPINION ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 4  |  Page : 170-173

Hyperthermia therapy of cancer: Need for deeper biological insights for improved therapeutic outcome


Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission10-Jan-2020
Date of Decision21-Jan-2020
Date of Acceptance21-Jan-2020
Date of Web Publication14-Feb-2020

Correspondence Address:
Dr. B N Pandey
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_2_20

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  Abstract 


Hyperthermia is the most ancient cancer treatment modality used much before even the discoveries of conventional therapeutic modalities such as radiotherapy. Since then, as a cancer therapeutic modality, hyperthermia has seen several advancements, but an upsetting decline in its recognition in last few decades. Currently, majority of the laboratories working in the research field are engaged in developing combinatorial strategies for hyperthermia along with radiation/anticancer agents. For the targeted delivery of therapeutic agents, several nano-formulations have been developed. In recent years, magnetic nanoparticle-based “nanothermotherapy” is getting the attention of researchers. Unfortunately, despite several successful clinical studies, hyperthermia could not get its due acclaim in cancer therapeutics. In the last few decades, mechanistic insights achieved using cutting-edge technologies opened several therapeutic avenues of many diseases including cancer. However, for many reasons, hyperthermia scientists could not match the pace to tap the knowledge for deeper mechanistic insights. Key questions, such as epigenetic changes, role of immune cells/abscopal effects in hyperthermia, and thermo resistance, still needs to be addressed in depth. It is noteworthy to mention that a deeper mechanistic insight shall contribute immensely in hyperthermia-based cancer therapy not only through overcoming thermoresistance but also through assisting in developing novel thermosensitizers and thermotherapy protocols.

Keywords: Heat shock proteins, hyperthermia therapy, magnetic nanoparticles, nanothermotherapy, thermo-chemo-radiotherapy, thermo resistance


How to cite this article:
Shetake NG, Pandey B N. Hyperthermia therapy of cancer: Need for deeper biological insights for improved therapeutic outcome. J Radiat Cancer Res 2019;10:170-3

How to cite this URL:
Shetake NG, Pandey B N. Hyperthermia therapy of cancer: Need for deeper biological insights for improved therapeutic outcome. J Radiat Cancer Res [serial online] 2019 [cited 2020 Apr 8];10:170-3. Available from: http://www.journalrcr.org/text.asp?2019/10/4/170/278408



Hyperthermia is a process of raising the body temperature, either locally or for the whole body for medicinal purposes. The glorious history of hyperthermia oncology began way back in 1779 by de Kizowitz in France, showing the inhibition of tumor growth by high fever caused by malaria. After surgery, this may be probably the first cancer treatment modality. However, systematic school of hyperthermia-based cancer treatment was developed in 1893 by William B. Coley, a bone surgeon in New York Memorial Cancer Hospital (now the Memorial Sloan-Kettering), who treated cancer patients using bacterial antitumor pyrogen also called “Coley toxin”.[1],[2] Later in 1898, as the first regional hyperthermia, the Swedish gynecologist, Wester Mark treated seven cervical cancer patients by running hot water through an intracavitary spiral tube, which resulted in an excellent clinical response.[3] After that by 1975, hyperthermia experienced a considerable progress and acceptance in oncologists with many advancements such as radiofrequency for hyperthermia application and techniques for whole-body hyperthermia and regional hyperthermic perfusion.[1]

An early knowledge about the systemic effects of hyperthermia in tumor control and active involvement of clinicians helped in easy acceptability of the technique in cancer therapy. The long journey of clinical hyperthermia oncology is full of many leaps, but a fall has been observed in the last two decades. The drift of oncologists from hyperthermia could be linked with many technological, clinical, and nonclinical reasons. One of the reasons is believed to be due to lack of updated mechanistic insight about the therapy. On the other hand, the technological advancements in the field of radio-/chemotherapy matched with subterranean molecular insights, which overshadowed the merits/success laurels of hyperthermia.

Mechanistic insight of hyperthermia is enriched with several early concepts of its action at cellular level. Later on, differential action of hyperthermia on tumor and normal cells got well established at tissue level. However, closure of knowledge gap in the following key areas is required for the improvement in hyperthermia therapy of cancer.


  Mechanism of Cellular Thermosensitivity under Different Hyperthermia Conditions Top


For the application of local hyperthermia therapy, contacting medium is placed on the tumor surface, which follows heat application by antennas or applicators emitting electromagnetic wave or ultrasound. In case of conventional hyperthermia therapy, tumor tissue is heated from outside at the tissue level. Despite the development of advanced strategies for uniform heating, temperature heterogeneity has been reported in the tumor mass depending on its size, composition, and magnitude of blood supply. Temperatures were inversely related to body mass, diameters, fat layer thickness, and fat percentage in Oesophageal carcinoma.[4] Even small difference in tissue temperature may be expected to have a major impact on tissue response to hyperthermia. Temperature variations as small as 2°C maintained for 30 min alter the fraction of cells killed by a factor of more than 100.[5]

Compared to these modalities, magnetic nanoparticles result in heat generation only when suitable magnetic field is applied across the tissue. Due to the lack of availability of sensitive thermometry, it is difficult to measure the heat generation at the nanosize dimension of the particles. However, an intense but nucleated heat generation is anticipated by these nanoparticles, which may be termed as “nanothermotherapy” [Figure 1]. Our results using mouse fibrosarcoma models showed that compared to body temperature even if the rise in temperature after magnetic hyperthermia therapy is ~2°C, magnitude of tumor regression was found to be more than 40%.[6] In both these conditions of hyperthermia application, the tumor mass will be exerted with gradient of temperature, the nucleated form in the case of magnetic nanoparticles and from the surface to the core of tumor mass for conventional hyperthermia.
Figure 1: Schematic comparison of conventional hyperthermia and magnetic nanoparticles-based nanothermotherapy

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Being amenable to various ligands, a range of nanoparticles are synthesized using different inorganic and organic substances. Depending on the size, net surface charge, and hydrophilicity of the nanoparticles, their cellular and molecular interaction at the tumor site may vary. It will also affect their interaction with cell surface molecules/receptors and thus signaling deciding the cellular fate. It may be more pertinent to understand the signaling associated with magnetic nanoparticles induced heat treatment at subcellular level.


  Development of Rationale-Based Thermosensitizers Top


The poor efficacy of hyperthermia had kept the therapy as second-line adjuvant therapy of cancer. Hence, there is a need to develop thermosensitizers based on cellular and molecular understanding of hyperthermia. Genomic and proteomic approaches contributed tremendously in understanding the molecular targets of several diseases and thus guided the development of several therapeutic agents. However, in case of hyperthermic oncology, such studies are limited. In one of the studies, three malignant breast cancer lines subjected to hyperthermic shock showed altered expression of transcripts involved in mitotic regulators, histones, and nonprotein coding RNAs.[7] Differential protein expression associated with thermoresistance has been also studied in human gastric carcinoma cell lines.[8] Bioinformatic information about drug–ligand interaction under hyperthermic conditions is required. An understanding about gene and protein networks under hyperthermia conditions may assist designing small molecules inhibitors and effective thermo sensitizers.


  Regulation and Targeting of Heat Shock Proteins Top


Heat is a pleiotropic physical agent, which affects several cellular components and associated signaling. It also affects the assembly and stability of critical macromolecular complexes including DNA replication and repair response machinery. Hyperthermia induces an increased expression of heat shock proteins, including heat shock proteins 90 (HSP90) that causes thermo resistance through the inhibition of apoptosis. HSP90 is a critical target for cancer therapy because of its involvement in folding and stabilization of various proteins. It is part of the chaperone machinery that includes other heat shock proteins (HSP70, HSP27, and HSP40). Many small molecule HSP90 inhibitors have been synthesized for cancer treatment, out of which only a few have entered clinical trials. The poor success of HSP90 inhibitors is due to their meager water solubility and difficulty in targeting the cancer cells due to HSP90 being an abundant protein. In this direction, suitable nanoparticles need to be developed to improve their solubility and targeting of these inhibitors to the cancer cells.

The regulation of HSP90 needs to be studied under different hyperthermia conditions in the tumor tissue with varying gradient and rate of heat dissipation. Typically, HSP90 is upregulated under hyperthermia conditions.[9] However, interestingly, we observed a downregulation of HSP90, when mouse fibrosarcoma tumor cells were treated with magnetic nanoparticles functionalized with oleic acid. HSP90 inhibition was further higher in tumor tissue from animals treated with magnetic hyperthermia therapy through magnetic nanoparticles. On the other hand, when cells were treated with external hyperthermia (using water bath), HSP90 was upregulated.[6] These results suggest that magnetic nanoparticle-based hyperthermia therapy may have advantage in terms of poor thermoresistance induction in cancer therapy. However, detailed mechanistic insight is required about the regulation of HSP90 and other client HSPs after different mode hyperthermia applications. HSP90 through their chaperon ability is known to affect the function of DNA repair proteins and the radio-sensitizing ability.[10] Moreover, it will be also pertinent to study the regulation of these HSPs in case of nanoparticles functionalized with different ligands.


  Epigenetic Changes After Hyperthermia Therapy Top


Hyperthermia is known to affect DNA damage and its repair through its modulation at chromatin modeling but without detailed understanding about the epigenetic changes after hyperthermia therapy. In this direction, the effect of hyperthermia on chromatin condensation and nucleoli disintegration was studied in Chinese hamster ovary cells. Exposure to heat reduced the condensation ability of interphase chromatin and disintegration of the nucleolus.[5] In another study, a nontoxic combination of hyperthermia and trifluoperazine (a calmodulin inhibitor) resulted in an accumulation of DNA damage caused by the inhibition of strand-break re-joining.[11] Higher changes at the chromatin level after external hyperthermia would be possible due to heat effect exerted at tissue level. However, chromatin may get less affected due to focused and nucleated heating in case of magnetic hyperthermia. Hence, chromatin changes under different heating conditions are warranted. Epigenetic control of gene expression through DNA methylation, histone deacetylation, and mi-RNA expression affects the pathology and therapy of cancer. It would be also of great interest to understand these changes under conventional and magnetic nanoparticle-based hyperthermia therapy conditions.


  Action of Immune Cells in Heat-Killed Tumor Cells and Abscopal Effects Top


In vivo examination showed that natural killer cells, dendritic cells, and phagocytes are activated in the tumors treated with hyperthermia. The active contribution of immune cells would result in not only killing of tumor cells at the site of heat but also likely to control distant tumors through abscopal effects. Such effects can treat micrometastatic tumors, which otherwise are difficult to treat using local hyperthermia. In carcinosarcoma-bearing rats, magnetic hyperthermia at a higher temperature (50°C–55°C) showed improved antitumor abscopal effect through stimulation of endogenous immune response in terms of increased number of CD4- and CD8-positive T-cells in tumor tissue and higher levels of interferon gamma and interleukin-2 in serum of these mice.[12] A recent study showed enhancement of abscopal effect of radiation and immune checkpoint inhibitor therapies along with magnetic nanoparticle hyperthermia in metastatic breast cancer mouse model.[13] Compared to conventional hyperthermia, in case of magnetic hyperthermia, nucleated intense heating will result in nonapoptotic mode of cell death (like necrosis) attracting immune cells and hence higher magnitude of abscopal effect. However, the hypothesis needs to be further evaluated with detailed mechanistic insight and translation at the clinical level.

In summary, several gaps exist in understanding the cellular and molecular mechanism of different conditions of hyperthermia, which impede the success of hyperthermia therapy of cancer. In this direction, there is an urgent need to tap fast-expanding biological knowledge and cutting-edge technologies to understand the mechanism of thermo resistance and develop thermo-sensitizing agents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Roussakow S. The history of hyperthermia rise and decline. In: Conference Papers in Medicine. Vol. 428027. Hungary: Hindawi Publishing Corporation; 2013. p. 1-40. Article ID 428027.  Back to cited text no. 1
    
2.
Gas P. Essential facts on the history of hyperthermia and their connections with electromedicine. Prz Elektrotechniczny 2011;87:37-40.  Back to cited text no. 2
    
3.
Hegyi G, Szigeti GP, Szász A. Hyperthermia versus oncothermia: Cellular effects in complementary cancer therapy. Evid Based Complement Alternat Med 2013;2013:672873.  Back to cited text no. 3
    
4.
van Haaren PM, Hulshof MC, Kok HP, Oldenborg S, Geijsen ED, van Lanschot JJ, et al. Relation between body size and temperatures during locoregional hyperthermia of oesophageal cancer patients. Int J Hyperthermia 2008;24:663-74.  Back to cited text no. 4
    
5.
Gerweck LE. Hyperthermia in cancer therapy: The biological basis and unresolved questions. Cancer Res 1985;45:3408-14.  Back to cited text no. 5
    
6.
Shetake NG, Kumar A, Gaikwad S, Ray P, Desai S, Ningthoujam RS, et al. Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation. Int J Hyperthermia 2015;31:909-19.  Back to cited text no. 6
    
7.
Amaya C, Kurisetty V, Stiles J, Nyakeriga AM, Arumugam A, Lakshmanaswamy R, et al. A genomics approach to identify susceptibilities of breast cancer cells to “fever-range” hyperthermia. BMC Cancer 2014;14:81.  Back to cited text no. 7
    
8.
Sinha P, PolanD J, Schnölzer M, Celis JE, Lage H. Characterization of the differential protein expression associated with thermoresistance in human gastric carcinoma cell lines. Electrophoresis 2001;22:2990-3000.  Back to cited text no. 8
    
9.
Sauvage F, Messaoudi S, Fattal E, Barratt G, Vergnaud-Gauduchon J. Heat shock proteins and cancer: How can nanomedicine be harnessed? J Control Release 2017;248:133-43.  Back to cited text no. 9
    
10.
Shetake NG, Kumar A, Pandey BN. Iron-oxide nanoparticles target intracellular hsp90 to induce tumor radio-sensitization. Biochim Biophys Acta Gen Subj 2019;1863:857-69.  Back to cited text no. 10
    
11.
Smith PJ, Mircheva J, Bleehen NM. Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: II. DNA damage, repair and chromatin changes. Br J Cancer 1986;53:105-14.  Back to cited text no. 11
    
12.
Wang H, Zhang L, Shi Y, Javidiparsijani S, Wang G, Li X, et al. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on walker-256 carcinosarcomas in rats. Oncol Lett 2014;7:764-70.  Back to cited text no. 12
    
13.
Oei AL, Korangath P, Mulka K, Helenius M, Coulter JB, Stewart J, et al. Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer. Int J Hyperthermia 2019;36:47-63.  Back to cited text no. 13
    


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