Table of Contents
Conference Papers in Medicine
Volume 2013 (2013), Article ID 528909, 5 pages
http://dx.doi.org/10.1155/2013/528909
Conference Paper

Hypoxia Immunity, Metabolism, and Hyperthermia

1Centro Medico Demetra, Center for Clinical Hyperthermia and Immunity, Via Staderini, 19/B, 05100 Terni, Italy
2Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia
3Laboratoire d’Informatique, Ecole Polytechnique, 91128 Palaiseau, France
4Department of Animal Biology and CNR Institute of Molecular Genetics, Section of Histochemistry and Cytometry, University of Pavia, 27100 Pavia, Italy
5Oncology Unit, Azienda Ospedaliera Ospedale San Salvatore, 6112 Pesaro, Italy
6Integrated Health Clinic, 23242 Mavis Avenue, Fort Langley, BC, V1M 2R4, Canada

Received 14 January 2013; Accepted 3 April 2013

Academic Editors: M. Jackson, D. Lee, and A. Szasz

This Conference Paper is based on a presentation given by Gianfranco Baronzio at “Conference of the International Clinical Hyperthermia Society 2012” held from 12 October 2012 to 14 October 2012 in Budapest, Hungary.

Copyright © 2013 Gianfranco Baronzio et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hypoxia is common in solid tumors and in many other disease states such as myocardial infarction, stroke, bone fracture, and pneumonitis. Once hypoxia has developed, the undernourished and hypoxic cells trigger signals in order to obtain new blood vessels to satisfy their increasing demands and to resolve hypoxia. The principal signal activated is an ancestral oxygen sensor, the hypoxia inducible factor (HIF). After its nuclear translocation, HIF triggers a series of mediators that recruit, into the hypoxic milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells. Resident and recruited cells participate in the processes of neoangiogenesis, for resolving the hypoxia, while at the same time trigger an inflammatory reaction. The inflammatory reaction has as primary end point, the repair of the damaged area, but if an insufficient production of resolvins is produced, the inflammatory reaction becomes chronic and is unable to repair the damaged tissue. In this brief overview, we will show the differences and the similar events present in cancer, myocardial infarction, and stroke. Furthermore, the metabolic alterations produced in the tumor by hypoxia/HIF axis and the consequences on hyperthermic treatment are also discussed.

1. Introduction

The local inflammatory reaction is characterized by an initial increase in blood flow to the site of injury, by increased vascular permeability, and by an ordered influx of different effector cells, recruited from the peripheral blood and bone marrow to the site of lesion [1].

Another characteristic of the inflammatory reaction is the presence of hypoxia and its modulation of innate immunity [2].

In this overview, we will analyze the influence of the hypoxic state on inflammation and compare its interaction in diverse disease states including cancer. Interestingly, the body’s response to hypoxia in different pathological situations seems to be quite similar (see Box 1).

Box 1: In this box is illustrated the homeostatic circuit tending to eliminate hypoxia.

2. Hypoxia as a Homeostatic Response

Once hypoxia has developed, the undernourished and hypoxic cells present trigger signals, in order to obtain new blood vessels, and satisfy their ever-increasing demands. The principal signal activates an ancestral oxygen sensor, the hypoxia inducible factor (HIF). HIF is a conserved mechanism of defense present in mammals, aimed at reestablishing a supply of oxygen and nutritive substances. After its nuclear translocation, HIF triggers a series of mediators such as vascular endothelial growth factor (VEGF) and chemokines such as stromal derived growth factor-1 (SDF-1), which orchestrate a series of processes able to recruit, from bone marrow, into the hypoxic (tumour) milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells [26]. The bone-marrow-derived cells are of 4 types. (a) Circulating Endothelial Cells (CECS) [7, 8]. (b) Endothelial progenitor cells (EPCs), which are precursors of blood vessels [9, 10]. (c) Mesenchymal stem cells (MSCs) [11, 12]. (d) Immature myeloid derived cells (MDSCs) [1316].

CECs and EPCs are cells able to form new blood vessels. MDSCs concur with them to support and promote all the reactions useful to angiogenesis but are unable to form the neovessels alone. MSCs have the ability to transform into fibroblasts, to coordinate the inflammatory reaction, and also to support cells of the stroma [17]. In addition, MSCs play an important role in the repair of tissues with lesions and fractures. In the tumour, the excessive presence of IL-1 and PGE2 triggers an autocrine process that leads to tumor progression [18]. The behavior of MSCs in tumour tissue is different than that in myocardial infarction and stroke, where they cooperate to repair the lesion and reduce the inflammatory reaction. In fact, they behave differently in the primary tumour than in metastases, and usually give rise to the tumor-associated fibroblasts (CAFs) and pericytes [19] that ultimately form a favorable stroma more useful to tumor progression and with immunosuppressive activity.

When MSCs become triggered by HIF, they participate in the repair of several diseased tissues and organs such as in myocardial infaction [4], stroke [20], fractures [21], rheumatoid arthritis [22], Alzheimer’s diseases [23], Parkinson’s diseases [24], ulcerative colitis [25], and kidney disease [26].

In a certain sense, it is possible to demonstrate that the reaction of the organism to a pathogen or other danger signal is a normal law of homeostasis and is tightly regulated (see Box 1).

In fact, four to six hours after the start of the ischemic or hypoxic state, partly resident neutrophils provided by MDSCs begin to produce a series of free radicals and proteases. In both the heart and the brain, areas of ischemia show these reactions which initially seem harmful, somehow sharpening the event [11, 27]; however, after this cleaning operation they help to decrease the inflammatory reaction. In both stroke and myocardial infarction they collaborate through several known mechanisms [11, 27].

Neutrophils have a very limited life span, going rapidly into apoptosis and releasing among various other products lactoferrin. Lactoferrin has the ability to decrease the recruitment and the transmigration of neutrophils, permitting the arrival of macrophages. Macrophages not only act as scavengers but also produce abundant immunosuppressive cytokines (TGF- β ; IL-10). Macrophages also produce decoy receptors of chemokines that participate to further decrease the inflammatory reaction [26, 28]. A more recently discovered class of substances able to reduce the inflammatory response have been called resolvins [29, 30]. In summary, the termination or the partial reduction of inflammation coincides with the return of oxygenation, the coordination of leukocyte recruitment followed by macrophage recruitment, and finally the production of anti-inflammatory factors including resolvins.

3. Tumour Hypoxia

Hypoxia is common in solid tumors, and areas deprived of oxygen and nutrients can develop in many different zones of the tumor, including those with strong vascularization (Figure 1). One of the reasons for its persistence is that neoplasia grows faster and at a pace not proportional to the neoangiogenesis [3133]. This persistence creates a vortex that continues to recruit neutrophils and MDSCs from bone marrow [34]. In the tumour microenvironment, MDSCs transform into type 2 macrophages, the so-called M2 that produces an excess of molecules such as PGE2, TGF-β, and IL-10. These kinds of molecules can disorient the immune system to the point of making it ineffective [35]. Furthermore the tumour is unable to produce resolvins in an adequate concentration [3638] for at least two reasons. (a) There is no an adequate concentration of EPA and DHA in the cell membranes (principal substrates for resolvins). (b) There is an increase in COX-2 enzymes leading to overproduction of PGE2 [37, 38], which are not precursors for resolvins.

Figure 1: Zones of hypoxia adjacent to zones of necrosis. (kindly supplied by I Freitas, University of Pavia, Italy).

This is a circuit that continues to feed itself on the basis of a normal homeostatic response of the organism. Tumours follow the general pathways of several diseases in which hypoxia is implicated (i.e., myocardial infarction, stroke, etc.), but differs from them significantly in the persistence of this hypoxia and the lack of the off switch (resolvins) (Figures 2 and 3).

Figure 2: The genesis of inflammation and the circuit triggered by tumor and MDSCs are tentatively illustrated.
Figure 3: In this figure, the common response of the organism to hypoxia is illustrated together with the different responses to infarction, stroke, and cancer. It should be noted that many processes are common, but in cancer hypoxia is not completely resolved. This persistence of the hypoxic environment creates a vicious cycle that ultimately sustains the inflammation.

Another factor that seems to maintain the inflammation is the osmotic pressure. The overproduction of VEGF induced by HIF leads to increased vascular permeability, with loss in the interstitial tissue of albumin and other proteins. This loss, leads to an increased osmotic pressure that elicits the release of proinflammatory cytokines by macrophages [3941]. This factor alone would justify the use of hyperthermia for its ability to decrease the interstitial fluid pressure [42, 43].

Tumour vasculature is not necessarily derived from endothelial cell sprouting; instead, cancer tissue can acquire its vasculature by alternative mechanisms, such as vasculogenic mimicry (VM). VM is the hypoxia-adaptation mechanism of tumour vascularisation. Hypoxia-induced VM plays an important role in tumour progression [44, 45].

4. Hypoxia Metabolism

HIF not only plays an important role in inflammation but also determines the metabolic conversion in tumours to anaerobic glycolysis, the so-called Warburg effect. This increased consumption of glucose and its incomplete and inefficient metabolism is due at least to two factors: (a) an increase in membrane receptors for glucose (Glut-1 membrane protein), (b) Blocking of pyruvate dehydrogenase and suppression of pyruvate conversion to acetyl CoA [4648].

5. Hyperthermia and Immunity

Can hyperthermia be used to modify this destructive and cancer-promoting circuit of hypoxia, inflammation, and then hypoxia? Is it possible that hyperthermia can affect HIF expression and, beyond that, immunity against malignancy?

This association between hyperthermia and tumor hypoxia and pH response has been known since 1990, in large part because of the work of Koutcher and Gerweck on glioblastoma and other tumours [49, 50]. What is more is that hyperthermia’s activity as a radiation sensitizer is well known [5155]. Hyperthermia, in almost every way it has been applied, consistently seems to affect immunity through several known mechanisms [5658]. Hyperthermia enhances the antigenic presentation to effector cells, recruiting macrophages, natural killer cells, regulatory cells, and neutrophils to the tumour area [5658]. The association with radiotherapy and the favorable changes to the tumour microenvironment by hyperthermia, as outlined by Muthana et al. can affect regulatory cell behavior and macrophage activity [59]. In fact, the concurrent use of hyperthermia with radiotherapy can decrease the recruitment of regulatory cells, compared to hyperthermia alone, and also the behaviour of macrophages seems to be affected by this association, ultimately decreasing their M2 types [60]. The macrophage programming in the tumour microenvironment is a hallmark of cancer, with its autosustaining abilities regarding inflammation [58]. The increase of heat shock protein (HSP) induced by hyperthermia [61], particularly HSP 70, has been found to act as a recognition structure for natural killer (NK) cells, increasing their activity [62, 63]. In vivo hyperthermia triggers innate and adaptive immunity aiding in tumour eradication [64, 65].

6. Conclusions

The explanation of these specific components of tumour biology in this way is not meant as an oversimplification but is meant as an effort to show that tumour biology is not all chaotic, but that they follow some normal routes of repair. Tumours exploit some of the weaknesses of the body and profit from normal attempts of the body to repair and recover organ integrity and functionality. In the works of Lowe and Storkus, by minimizing exposure to risk factors that contribute to chronic inflammation and reconditioning the patient into a state of acute inflammation, we could have a significant decrease in cancer incidence and improvements to life prolongation [66]. Hyperthermia in this context can have a significant role as an inducer of acute inflammation [64, 65].

References

  1. http://www.copewithcytokines.de/cope.cgi.
  2. A. Sica, G. Melillo, and L. Varesio, “Hypoxia: a double-edged sword of immunity,” Journal of Molecular Medicine, vol. 89, no. 7, pp. 657–665, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. K. Korybalska, M. Pyda, E. Kawka, S. Grajek, A. Bręborowicz, and J. Witowski, “Interpretation of elevated serum VEGF oncentrations in patients with myocardial infarction,” Cytokine, vol. 54, no. 1, pp. 74–78, 2011. View at Google Scholar
  4. N. G. Frangogiannis, “Regulation of the inflammatory response in cardiac repair,” Circulation Research, vol. 110, no. 1, pp. 159–173, 2012. View at Google Scholar
  5. F. Jin, U. Brockmeier, F. Otterbach, and E. Metzen, “New insight into the SDF-1/CXCR4Axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumorcell CXCR4 are required for tumor cell intravasation,” Molecular Cancer Research, vol. 10, no. 8, pp. 1021–1031, 2012. View at Google Scholar
  6. X. Liu, B. Duan, Z. Cheng et al., “SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine ecretion,” Protein-Cell, vol. 2, no. 10, pp. 845–854, 2011. View at Google Scholar
  7. S. Prokoph, E. Chavakis, K. R. Levental et al., “Sustained delivery of SDF-1α from eparin-based hydrogels to attract circulating pro-angiogenic cells,” Biomaterials, vol. 33, no. 19, pp. 4792–4800, 2012. View at Google Scholar
  8. S. Damani, A. Bacconi, O. Libiger et al., “Characterization of circulating endothelial cells in acute myocardial infarction,” Science Translational Medicine, vol. 4, no. 126, Article ID 126ra33, 2012. View at Google Scholar
  9. T. Yamashita and K. Abe, “Mechanisms of endogenous endothelial repair in stroke,” Current Pharmaceutical Design, vol. 18, no. 25, pp. 3649–3652, 2012. View at Google Scholar
  10. A. Woywodt, S. Gerdes, B. Ahl, U. Erdbruegger, M. Haubitz, and K. Weissenborn, “Circulating endothelial cells and stroke: influence of stroke subtypes andchanges during the course of disease,” Journal of Stroke and Cerebrovascular Diseases, vol. 21, no. 6, pp. 452–458, 2012. View at Google Scholar
  11. N. G. Frangogiannis, “The immune system and cardiac repair,” Pharmacological Research, vol. 58, no. 2, pp. 88–111, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. W. Wojakowski, U. Landmesser, R. Bachowski, T. Jadczyk, and M. Tendera, “Mobilization of stem and progenitor cells in cardiovascular diseases,” Leukemia, vol. 26, no. 1, pp. 23–33, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. K. P. Doyle and M. S. Buckwalter, “The double-edged sword of inflammation after stroke:what sharpens each edge?” Annals of Neurology, vol. 71, no. 6, pp. 729–731, 2012. View at Google Scholar
  14. D. Kretzschmar, S. Betge, A. Windisch et al., “Recruitment of circulating dendritic cell precursors into the infracted myocardium and pro-inflammatory response in acute myocardial infarction,” Clinical Science, vol. 123, no. 6, pp. 387–398, 2012. View at Google Scholar
  15. S. Frantz and U. Hofmann, “Monocytes on the scar's edge,” American College of Cardiology, vol. 59, no. 2, pp. 164–165, 2012. View at Google Scholar
  16. D. I. Gabrilovich, S. Ostrand-Rosenberg, and V. Bronte, “Coordinated regulation of myeloid cells by tumours,” Nature Reviews Immunology, vol. 12, no. 4, pp. 253–268, 2012. View at Google Scholar
  17. G. Lazennec, “Les cellules souches mésenchymateuses,” Medicine Sciences, vol. 27, pp. 285–288, 2011. View at Google Scholar
  18. H. J. Li, F. Reinhardt, H. R. Herschman, and R. A. Weinberg, “Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling,” Cancer Discovery, vol. 2, no. 9, pp. 840–855, 2012. View at Publisher · View at Google Scholar
  19. S. P. Kerkar and N. P. Restifo, “Cellular constituents of immune escape within the tumor microenvironment,” Cancer Research, vol. 72, no. 13, pp. 3125–3130, 2012. View at Google Scholar
  20. E. Mezey, K. J. Chandross, G. Harta, R. A. Maki, and S. R. McKercher, “Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow,” Science, vol. 290, no. 5497, pp. 1779–1782, 2000. View at Publisher · View at Google Scholar · View at Scopus
  21. K. Murata, T. Kitaori, S. Oishi et al., “Stromalcell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy,” PLoS ONE, vol. 7, no. 5, Article ID e37163, 2012. View at Google Scholar
  22. S. Konisti, S. Kiriakidis, and E. M. Paleolog, “Hypoxia—a key regulator of angiogenesis and inflammation in rheumatoid arthritis,” Nature Reviews Rheumatology, vol. 8, no. 3, pp. 153–162, 2012. View at Google Scholar
  23. A. Mildner, B. Schlevogt, K. Kierdorf et al., “Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease,” Journal of Neuroscience, vol. 31, no. 31, pp. 11159–11171, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. X. G. Luo, J. J. Zhang, C. D. Zhang et al., “Altered regulation of CD200 receptor in monocyte-derived macrophages from individuals with Parkinson's disease,” Neurochemical Research, vol. 35, no. 4, pp. 540–547, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. L. A. Haile, R. von Wasielewski, J. Gamrekelashvili et al., “Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway,” Gastroenterology, vol. 135, no. 3, pp. 871.e5–881.e5, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. V. Ninichuk and H. J. Anders, “Bone marrow-derived progenitor cells and renal fibrosis,” Frontiers in Bioscience, vol. 13, no. 13, pp. 5163–5173, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. N. G. Frangogiannis, “Regulation of the inflammatory response in cardiac repair,” Circulation Research, vol. 110, no. 1, pp. 159–173, 2012. View at Google Scholar
  28. R. R. Ji, Z. Z. Xu, G. Strichartz, and C. N. Serhan, “Emerging roles of resolvins in the resolution of inflammation and pain,” Trends in Neurosciences, vol. 34, no. 11, pp. 599–609, 2011. View at Google Scholar
  29. W. J. Janssen and P. M. Henson, “Cellular regulation of the inflammatory response,” Toxicologic Pathology, vol. 40, no. 2, pp. 166–173, 2012. View at Google Scholar
  30. C. N. Serhan, “Petasis NAResolvins and protectins in inflammation resolution,” Chemical Reviews, vol. 111, no. 10, pp. 5922–5943, 2011. View at Google Scholar
  31. C. N. Serhan, “Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?” American Journal of Pathology, vol. 177, no. 4, pp. 1576–1591, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Bayer and P. Vaupel, “Acute versus chronic hypoxia in tumors: controversial data concerning time frames and biological consequences,” Strahlentherapie und Onkologie, vol. 188, no. 7, pp. 616–627, 2012. View at Google Scholar
  33. P. W. Vaupel and D. K. Kelleher, “Pathophysiological and vascular characteristics of tumours and their importance for hyperthermia: heterogeneity is the key issue,” International Journal of Hyperthermia, vol. 26, no. 3, pp. 211–223, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. C. A. Corzo, T. Condamine, L. Lu et al., “HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment,” Journal of Experimental Medicine, vol. 207, no. 11, pp. 2439–2453, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Ostrand-Rosenberg, P. Sinha, D. W. Beury, and V. K. Clements, “Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression,” Seminars in Cancer Biology, vol. 22, no. 4, pp. 275–281, 2012. View at Google Scholar
  36. F. Zhang and G. Du, “Dysregulated lipid metabolism in cancer,” World Journal of Biological Chemistry, vol. 3, no. 8, pp. 167–174, 2012. View at Google Scholar
  37. N. B. Janakiram and C. V. Rao, “Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer,” Current Molecular Medicine, vol. 9, no. 5, pp. 565–579, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. N. B. Janakiram, A. Mohammed, and C. V. Rao, “Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer,” Cancer and Metastasis Reviews, vol. 30, no. 3-4, pp. 507–523, 2011. View at Google Scholar
  39. G. Sethi, M. K. Shanmugam, L. Ramachandran, A. P. Kumar, and V. Tergaonkar, “Multifaceted link between cancer and inflammation,” Bioscience Reports, vol. 32, no. 1, pp. 1–15, 2012. View at Google Scholar
  40. L. Schwartz, A. Guais, M. Pooya, and M. Abolhassani, “Is inflammation a consequence of extracellular hyperosmolarity?” Journal of Inflammation, vol. 6, article 21, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. G. Baronzio, L. Schwartz, M. Kiselevsky et al., “Tumor interstitial fluid as modulator of cancer inflammation, thrombosis, immunity and angiogenesis,” Anticancer Research, vol. 32, no. 2, pp. 405–414, 2012. View at Google Scholar
  42. A. Sen, M. L. Capitano, J. A. Spernyak et al., “Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models,” Cancer Research, vol. 71, no. 11, pp. 3872–3880, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Leunig, A. E. Goetz, M. Dellian et al., “Interstitial fluid pressure in solid tumors following hyperthermia: possible correlation with therapeutic response,” Cancer Research, vol. 52, no. 2, pp. 487–490, 1992. View at Google Scholar · View at Scopus
  44. B. Döme, M. J. C. Hendrix, S. Paku, J. Tóvári, and J. Tímár, “Alternative vascularization mechanisms in cancer,” The American Journal of Pathology, vol. 170, no. 1, pp. 1–15, 2007. View at Google Scholar
  45. R. E. Seftor, A. R. Hess, E. A. Seftor et al., “Tumor cell vasculogenic mimicry: from controversy to therapeutic promise,” The American Journal of Pathology, vol. 181, no. 4, pp. 1115–1125, 2012. View at Google Scholar
  46. M. C. Brahimi-Horn, G. Bellot, and J. Pouysségur, “Hypoxia and energetic tumour metabolism,” Current Opinion in Genetics & Development, vol. 21, no. 1, pp. 67–72, 2011. View at Google Scholar
  47. J. W. Kim, P. Gao, and C. V. Dang, “Effects of hypoxia on tumor metabolism,” Cancer and Metastasis Reviews, vol. 26, no. 2, pp. 291–298, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Dhup, R. K. Dadhich, P. E. Porporato, and P. Sonveaux, “Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis,” Current Pharmaceutical Design, vol. 18, no. 10, pp. 1319–1330, 2012. View at Google Scholar
  49. J. A. Koutcher, D. Barnett, A. B. Kornblith, D. Cowburn, T. J. Brady, and L. E. Gerweck, “Relationship of changes in pH and energy status to hypoxic cell fraction and hyperthermia sensitivity,” International Journal of Radiation Oncology Biology Physics, vol. 18, no. 6, pp. 1429–1435, 1990. View at Google Scholar · View at Scopus
  50. L. E. Gerweck and K. Seetharaman, “Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer,” Cancer Research, vol. 56, no. 6, pp. 1194–1198, 1996. View at Google Scholar · View at Scopus
  51. C. W. Song, H. Park, and R. J. Griffin, “Improvement of tumor oxygenation by mild hyperthermia,” Radiation Research, vol. 155, no. 4, pp. 515–528, 2001. View at Google Scholar · View at Scopus
  52. M. R. Horsman and J. Overgaard, “Hyperthermia: a potent enhancer of radiotherapy,” Clinical Oncology, vol. 19, no. 6, pp. 418–426, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. P. Pontiggia, J. R. McLaren, G. F. Baronzio, and I. Freitas, “The biological responses to heat,” Advances in Experimental Medicine and Biology, vol. 267, pp. 271–291, 1990. View at Google Scholar · View at Scopus
  54. H. I. Bicher, “The physiological effects of hyperthermia,” Radiology, vol. 137, no. 2, pp. 511–513, 1980. View at Google Scholar · View at Scopus
  55. B. Hildebrandt and P. Wust, “The biologic rationale of hyperthermia,” Cancer Treatment and Research, vol. 134, pp. 171–184, 2007. View at Google Scholar · View at Scopus
  56. K. Yona, Tumor Ablation, Springer, 2012.
  57. C. T. Lee, T. MacE, and E. A. Repasky, “Hypoxia-driven immunosuppression: a new reason to use thermal therapy in the treatment of cancer?” International Journal of Hyperthermia, vol. 26, no. 3, pp. 232–246, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. J. J. Skitzki, E. A. Repasky, and S. S. Evans, “Hyperthermia as an immunotherapy strategy for cancer,” Current Opinion in Investigational Drugs, vol. 10, no. 6, pp. 550–558, 2009. View at Google Scholar · View at Scopus
  59. M. Muthana, G. Multhoff, and A. G. Pockley, “Tumour infiltrating host cells and their significance for hyperthermia,” International Journal of Hyperthermia, vol. 26, no. 3, pp. 247–255, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. B. Ruffell, N. I. Affara, and L. M. Coussens, “Differential macrophage programming in the tumor microenvironment,” Trends in Immunology, vol. 33, no. 3, pp. 119–126, 2012. View at Google Scholar
  61. T. Torigoe, Y. Tamura, and N. Sato, “Heat shock proteins and immunity: application of hyperthermia for immunomodulation,” International Journal of Hyperthermia, vol. 25, no. 8, pp. 610–616, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. G. Multhoff, “Activation of natural killer cells by heat shock protein 70,” International Journal of Hyperthermia, vol. 18, no. 6, pp. 576–585, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Multhoff, “Activation of natural killer cells by heat shock protein 70,” International Journal of Hyperthermia, vol. 25, no. 3, pp. 169–175, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. B. Frey, E. M. Weiss, Y. Rubner et al., “Old and new facts about hyperthermia-induced modulations of the immune system,” International Journal of Hyperthermia, vol. 28, no. 6, pp. 528–542, 2012. View at Google Scholar
  65. G. Baronzio, A. Gramaglia, and G. Fiorentini, “Hyperthermia and immunity. A brief overview,” In Vivo, vol. 20, no. 6 A, pp. 689–696, 2006. View at Google Scholar · View at Scopus
  66. D. B. Lowe and W. J. Storkus, “Chronic inflammation and immunologic-based constraints in malignant disease,” Immunotherapy, vol. 3, no. 10, pp. 1265–1274, 2011. View at Google Scholar