Photon emission in tumor biology

Photon emission from mammalian cells has been subject of study for many years. Growing research activity is directed on the photon emission within the field of tumor biology. These studies, applying high-sensitivity photon counting methods, have paid attention to several aspects, including photon emission from serum of tumor-bearing animals, photon emission of tumors and of isolated tumor cells. In addition, research activity is increased with respect to the photon emission by white light from cultured tumor cells. In this review we report on the different aspects of spontaneous and induced photon emission of tumor cells as compared to normal cells. Throughout these studies the question of a functional biological role of this spontaneous and light-induced photon emission has been raised and some different points of view will be discussed.     

Regulatory aspects of low intensity photon emission

Photon emission from unicellular and multicellular organisms has been a subject of study for many decennia. In contrast to the well-known phenomenon of bioluminescence originating in luciferin-luciferase reactions, low intensity emission in the visible region of the electromagnetic spectrum has been found in almost every species studied so far. At present, the nomenclature of this phenomenon has not crystallized and it is referred to by a variety of names, such as mitogenetic radiation 29, dark luminescence 7, low-level chemiluminescence 20,36, and biophotons 57. Particular attention has been focussed on the relationship between photon emission and the regulation of various aspects of cellular metabolism, although in many cases quantitative data are still lacking. Throughout the history of this field of research the question of a functional biological role of the low intensity emission has been repeatedly raised; this is reflected, for instance, in the heterogeneity of the terms used to describe it. The discussion concerns the possible participation of photons of low intensity in intra- and intercellular communication. This paper reviews literature on the metabolic regulation of low intensity emission, as well as the regulation of photon emission initiated by external light. Furthermore, recent data are discussed with respect to a possible biocommunicative function of low intensity photon emission.     

Regulatory aspects of low intensity photon emission

Summary Photon emission from unicellular and multicellular organisms has been a subject of study for many decennia. In contrast to the well-known phenomenon of bioluminescence originating in luciferin-luciferase reactions, low intensity emission in the visible region of the electromagnetic spectrum has been found in almost every species studied so far. At present, the nomenclature of this phenomenon has not crystallized and it is referred to by a variety of names, such as mitogenetic radiation²⁹, dark luminescence⁷, low-level chemiluminescence^{20, 36}, and biophotons⁵⁷. Particular attention has been focussed on the relationship between photon emission and the regulation of various aspects of cellular metabolism, although in many cases quantitative data are still lacking. Throughout the history of this field of research the question of a functional biological role of the low intensity emission has been repeatedly raised; this is reflected, for instance, in the heterogeneity of the terms used to describe it. The discussion concerns the possible participation of photons of low intensity in intra- and intercellular communication. This paper reviews literature on the metabolic regulation of low intensity emission, as well as the regulation of photon emission initiated by external light. Furthermore, recent data are discussed with respect to a possible biocommunicative function of low intensity photon emission.     

Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Natural killer (NK) cells have originally been identified by their spontaneous cytolytic potential against tumor cells, which, however, might result from pre-activation due to prior pathogen exposure. Resting NK cells, on the contrary, require activation by bystander antigen-presenting cells to reach their full functional competence. In this review, we will summarize studies on how dendritic cells (DCs), the most potent type of antigen-presenting cell, communicate with human NK cells to activate them in secondary lymphoid organs and to integrate signals from activated NK cells at sites of inflammation for their own maturation. Furthermore, we will review aspects of the immunological synapse, which mediates this cross-talk. These studies provide the mechanistic understanding of how mature DCs can activate NK cells and survive to go on for the activation of adaptive immunity. This feature of DCs, to activate different waves of immune responses, could be harnessed for immunotherapies, including vaccinations.     

Super-high sensitivity systems for detection and spectral analysis of ultraweak photon emission from biological cells and tissues

In this paper we summarize and discuss the modern technology and systems, studied and established by our research group, for performing the detection and special analysis incorporated with the super-high sensitivity photon counting method for the study of ultraweak photon emission; for example, extra-weak bioluminescence and chemiluminescence from living cells and tissues, closely related to biochemical and biophysical processes and activities. An excellent sensitivity of the basic photon counting system, making it possible to achieve count rates in the very low range of one photoelectron per second to one per minute, allowed us to carry out in vivo as well as in vitro measurements, and analyses of ultraweak bioluminescence and chemiluminescence. Recent results concerning ultraweak photon emission from blood samples and organ homogenates of rats are presented and reviewed as one of the interesting and valuable applications of our modern technology for studying ultraweak cell and tissue radiation.     

Super-high sensitivity systems for detection and spectral analysis of ultraweak photon emission from biological cell cells and tissues

Summary In this paper we summarize and discuss the modern technology and systems, studied and established by our research group, for performing the detection and special analysis incorporated with the super-high senstivity photon counting method for the study of ultraweak photon emission; for example, extra-weak bioluminescence and chemiluminescence from living cells and tissues, closely related to biochemical and biophysical processes and activities. An excellent sensitivity of the basic photon counting system, making it possible to achieve count rates in the very low range of one photoelectron per second to one per minute, allowed us to carry out in vivo as well as in vitro measurements, and analyses of ultraweak bioluminescence and chemiluminescence. Recent results concerning ultraweak photon emission from blood samples and organ homogenates of rats are presented and reviewed as one of the interesting and valuable applications of our modern technology for studying ultraweak cell and tissue radiation.     

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002     

Myosin regulation in the migration of tumor cells and leukocytes within a three-dimensional collagen matrix

The migration of cells is a complex regulatory process which results in the generation of motor forces through the reorganization of the cytoskeleton. Here we present a comparative study of the expression and involvement of myosin in the regulation of the physiological migration of leukocytes and the pathological migration of tumor cells. We show that the involvement of myosin in the migration is distinct in these two cell types. In leukocytes, the activity of non-muscle myosin II is essential for both the spontaneous (matrix-induced) migration and the migration induced by ligands to G protein-coupled receptors, i.e. chemokines and neurotransmitters. In contrast, spontaneous tumor cell migration is largely independent of non-muscle myosin II activity, whereas the norepinephrine-induced migration is completely inhibited by either direct inhibition of non-muscle myosin II or of the kinases phosphorylating the myosin light chain, namely ROCK or the calcium/calmodulin-dependent myosin light-chain kinase.Received 31 August 2004; accepted 26 October 2004     

The effect of stress factors on the spontaneous photon emission from microorganisms

The results of recent work on the photon emission from three yeasts and a bacterium is presented. Both visible region and ultraviolet photon emission is observed; however, no luminescence is observed in the absence of oxygen. The visible region emission is attributed to excited carbonyl groups and excited singlet oxygen dimers formed during the decomposition of lipid hydroperoxides. Possible sources of the ultraviolet photon emission are also examined. The use of microorganisms in the study of ultraweak photon emission and its relation to oxidative, temperature and chemical stress is reviewed and the applications and (or) functions of this photon emission are also discussed.     

The effect of stress factors on the spontaneous photon emission from microorganisms.

The results of recent work on the photon emission from three yeasts and a bacterium is presented. Both visible region and ultraviolet photon emission is observed; however, no luminescence is observed in the absence of oxygen. The visible region emission is attributed to excited carbonyl groups and excited singlet oxygen dimers formed during the decomposition of lipid hydroperoxides. Possible sources of the ultraviolet photon emission are also examined. The use of microorganisms in the study of ultraweak photon emission and its relation to oxidative, temperature and chemical stress is reviewed and the applications and (or) functions of this photon emission are also discussed.     

Biophoton emission fromDaphnia magna: A possible factor in the self-regulation of swarming

Summary The formation of swarms by planktonic organisms was first described almost 100 years ago, but the mechanisms governing the development of patterns in population size and density are still not understood. In this study, we investigated one biophysical factor that may play an important role in swarm-formation. Spontaneous ultraweak photon emission in the visible range has been well documented for living cells, tissues and individuals in the plant and animal kingdom, including humans. We demonstrate here that the intensity of light emitted by the planktonic crustaceanDaphnia magna is a function of population density in relation to body size. The effects are discussed on the basis of the theory of Dicke^1,2, and it is suggested that biophoton emission may be a basic factor in the self-regulation of swarm density.     

Immunogenicity of necrotic cell death

The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity.     

‘Heated’ Debates in Apoptosis

Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles, making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research. Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007     

Administration of the antitumor drug mitoguazone protects normal thymocytes against spontaneous and etoposide-induced apoptosis

The suggestion has been made that polyamines may be involved in the control of cell death, since exceedingly high or low levels induce apoptosis in different cell systems. For a deeper insight into the relationship between apoptosis and polyamine metabolism, we investigated in vitro the effect on rat thymocytes of mitoguazone (MGBG, which inhibits S-adenosylmethionine decarboxylase, i.e. a key enzyme in the polyamine biosynthetic pathway). Thymocytes were selected as an especially suitable model system, since they undergo spontaneous apoptosis in vivo and can be easily induced to apoptose in vitro by etoposide, used here as an apoptogenic agent. MGBG protected thymocytes from both spontaneous and drug-induced apoptosis, and this protective effect was associated with a decrease in polyamine oxidase activity and total polyamine levels.Received 7 July 2004; received after revision 2 September 2004; accepted 9 September 2004     

The contribution of neuronal–glial–endothelial–epithelial interactions to colon carcinogenesis

Several different cell types constitute the intestinal wall and interact in different manners to maintain tissue homeostasis. Elegant reports have explored these physiological cellular interactions revealing that glial cells and neurons not only modulate peristalsis and mechanical stimulus in the intestines but also control epithelial proliferation and sub-epithelial angiogenesis. Although colon carcinoma arises from epithelial cells, different sub-epithelial cell phenotypes are known to support the manifestation and development of tumors from their early steps on. Therefore, new perspectives in cancer research have been proposed, in which neurons and glial cells not only lead to higher cancer cell proliferation at the tumor invasion front but also further enhance angiogenesis and neurogenesis in tumors. Transformation of physiological neural activity into a pro-cancer event is thus discussed for colon carcinogenesis herein.     

Resistance of in vivo-selected spontaneously transformed cells and Rous sarcoma virus-transformed cells to macrophage-mediated cytotoxicity.

The cytotoxic activity (CTA) of activated peritoneal macrophages (MP) on variant lines of Syrian hamster embryo (HE) cells of differing malignant characteristics was studied. The target cells were a line of low-malignant cells resulting from spontaneous transformation of HE cells in vitro (STHE strain), and malignant variants selected from them in vivo (STHE-LM-4, STHE-LM-8, and STHE-75/18 strains). In addition, we used cells of the HET-SR-1 strain; these are HE cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain, RSV-SR), or the TU-SR strain induced by RSV-SR in vivo. Thioglycollate-elicited peritoneal MP from Syrian hamsters were activated in vitro with bacterial levan, LPS or MDP and used as effector cells. MP-mediated cytolysis was determined by means of a 42-h radioactivity release assay with 3H-thymidine-labeled target cells. We found that only the parental STHE cells were susceptible towards fully-activated MP-mediated CTA. All three of the in vivo-selected malignant variants of the STHE cell sublines, as well as the tumorigenic RSV-SR transformants, were resistant to cytolysis by activated MP. Non-activated thioglycollate-elicited MP did not lyse any of the tumor cells studied.     

Resistance of in vivo-selected spontaneously transformed cells and Rous sarcoma virus-transformed cells to macrophage-mediated cytotoxicity

The cytotoxic activity (CTA) of activated peritoneal macrophages (MP) on variant lines of Syrian hamster embryo (HE) cells of differing malignant characteristics was studied. The target cells were a line of low-malignant cells resulting from spontaneous transformation of HE cells in vitro (STHE strain), and malignant variants selected from them in vivo (STHE-LM-4, STHE-LM-8, and STHE-75/18 strains). In addition, we used cells of the HET-SR-1 strain; these are HE cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain, RSV-SR), or the TU-SR strain induced by RSV-SR in vivo. Thioglycollate-elicited peritoneal MP from Syrian hamsters were activated in vitro with bacterial levan, LPS or MDP and used as effector cells. MP-mediated cytolysis was determined by means of a 42-h radioactivity release assay with³H-thymidine-labeled target cells. We found that only the parental STHE cells were susceptible towards fully-activated MP-mediated CTA. All three of the in vivo-selected malignant variants of the STHE cell sublines, as well as the tumorigenic RSV-SR transformants, were resistant to cytolysis by activated MP. Non-activated thioglycollate-elicited MP did not lyse any of the tumor cells studied.     

Physiological functions of D-amino acid oxidases: from yeast to humans

D-Amino acid oxidase (DAAO) is a FAD-containing flavoenzyme that catalyzes the oxidative deamination of D-isomers of neutral and polar amino acids. This enzymatic activity has been identified in most eukaryotic organisms, the only exception being plants. In the various organisms in which it does occur, DAAO fulfills distinct physiological functions: from a catabolic role in yeast cells, which allows them to grow on D-amino acids as carbon and energy sources, to a regulatory role in the human brain, where it controls the levels of the neuromodulator D-serine. Since 1935, DAAO has been the object of an astonishing number of investigations and has become a model for the dehydrogenase-oxidase class of flavoproteins. Structural and functional studies have suggested that specific physiological functions are implemented through the use of different structural elements that control access to the active site and substrate/product exchange. Current research is attempting to delineate the regulation of DAAO functions in the contest of complex biochemical and physiological networks.     

Photobiochemistry without light

Efficient excited state formation - much higher than that hitherto expected - may occur in organelles and in intact cells. Excited triplet states can be enzymatically generated in high yields by different routes. An example is the oxidation of isobutanal to acetone and formic acid, catalyzed by horseradish peroxidase. Other enzymatic systems that generate triplet carbonyls are linear aliphatic aldehydes when oxidized by peroxidase/O2, or the indole-3-acetic acid/peroxidase/O2-reaction. The latter is widespread in plants. This new field - photobiochemistry without light - has led to a growing awareness of the idea that cells may utilize excited states to trigger photochemical processes even in the dark. Such phenomena are of considerable importance, also for the understanding of weak photon emission from biological systems.