Moving the systemic evolutionary approach to cancer

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Moving the systemic evolutionary approach to cancer forward: Therapeutic implications Article  in  Medical Hypotheses · September 2018 DOI: 10.1016/j.mehy.2018.09.033

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Medical Hypotheses 121 (2018) 80–87

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

Moving the systemic evolutionary approach to cancer forward: Therapeutic implications

T



Antonio Mazzoccaa, , Giovanni Ferrarob, Giovanni Misciagnac, Stefano Faisd a

Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy Interuniversity Department of Physics, Polytechnic of Bari, Via Orabona, 4, 70126 Bari, Italy c Scientific and Ethical Committee, University Hospital Policlinico, Piazza G. Cesare, 11, 70124 Bari, Italy d Department of Oncology and Molecular Medicine (OMM), National Institute of Health, Viale Regina Elena, 299, 00161 Rome, Italy b

A R T I C LE I N FO

A B S T R A C T

Keywords: Cancer theories Endosymbiosis De-emergence Downward causation Cancer pathogenesis Paradigm shift Coherent state Protists Biomimicry Hepatocellular carcinoma

We have previously presented a new Systemic Evolutionary Theory of Cancer (SETOC) based on the failure of proper endosymbiosis in eukaryotic cells. Here, we propose that the progressive uncoupling of two endosymbiotic subsystems (information and energy) inside the cell, as a consequence of long-term injuries, gives rise to alterations (i) in tissue interactions and (ii) in cell organization. In the first case, we argue that the impairment of both the coherent state and the synergy between intercellular communications underpins the onset of tissue dysplasia, that usually evolves towards cancer development. In the second case, we suggest that the rupture of endosymbiosis drives a sort of cell regression towards a protist-like entity represented by the concept of “deemergence” postulated in our systemic evolutionary approach to carcinogenesis. This conceptual association of the cancer cell with a protist-like organism could support the development of novel cancer therapeutic approaches. To this end, we propose a paradigm shift in cancer pharmacology since: i) our knowledge of cancer pathophysiology as a complex system is insufficient, despite a vast knowledge of molecular mechanisms underlying cancer; ii) current cancer pharmacology deals only with microvariables (e.g. gene or protein targets), which do not account for the integrated pathophysiology of cancer, rather than with macrovariables (e.g. pH, membrane potential, electromagnetic fields, cell communications and so on) and mesovariables (between micro and macro), such as the interaction between various cellular components including cellular organelles. This paradigm shift should allow cancer pharmacology to move forward from molecular treatments (focusing on single targets) to modular treatments that consider cancer-related processes (i.e. inflammation, coagulation, etc.) or even to a sort of ecosystemic treatment addressing the whole functioning of the “cancer ecosystem”. Examples of ecosystems treatment may be natural plant derivatives that act synergistically or pulsed electromagnetic fields which can act on particular biological processes in cancer cells. In addition, we need different working theoretical models on which to base new anticancer pharmacological approaches. Finally, we examine what value our systemic evolutionary approach could add to cancer treatments, in particular in liver cancer as a paradigm for developing potential applications.

Introduction We have recently presented a new Systemic Evolutionary Theory of Cancer (SETOC) pathogenesis, based on the failure of the correct cellular endosymbiosis between the ancestral archaea (now the information component of the cell, chiefly the nucleus) and the ancestral prokaryote (now the energy component, the mitochondrion), which allows the virtuous cell metabolism cycle (that can properly exploit flows of energy, matter, and information) to take place by recycling waste into clean

Abbreviations:SETOC, systemic evolutionary theory of cancer ⁎ Corresponding author. E-mail address: [email protected] (A. Mazzocca). https://doi.org/10.1016/j.mehy.2018.09.033 Received 2 July 2018; Accepted 18 September 2018 0306-9877/ © 2018 Elsevier Ltd. All rights reserved.

energy production [1]. Accordingly, the acronym SETOC could also mean “Systemic Endosymbiotic Theory of Cancer”. In the proposed theory, we have emphasized the importance of the regular energy budget needed to control the cell systems, ensuring the proper functioning of the differentiated eukaryotic cell as a complex adaptive system able to cope with and resist, within certain limits, perturbations (i.e. stress, injuries, damage, etc.) of a certain amplitude. In our view, the effect of prolonged injuries, causing tissue damage and inflammation, for example, as well as impairing the perturbation damping

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Fig. 1. A schematic model illustrating our proposed systemic evolutionary theory of cancer (SETOC). The condition of eukaryotic cells is maintained by a complex adaptive dynamic system that “emerges” from the endosymbiosis between the ancestral archea (now the nucleus and the cytoplasm) and the ancestral prokaryote (now the mitochondrion). In this model, we propose that the progressive uncoupling of these endosymbiotic subsystems inside the cell, as a consequence of long-term injuries, gives rise to alterations at cellular and tissue level, leading to dysplasia, and over time to cancer. We also propose that the failure of endosymbiosis drives the “de-emergence” of the eukaryotic cell and the reappearance of two endosymbiotic subsystems with autonomous and uncoordinated behaviors, characteristic of transformed cells. This would result in a sort of cell regression, reverting the eukaryotic cell phenotypically closer to a protist. Dysplasia would represent a partial de-emergence of eukaryotic cells within a tissue.

prokaryote (mitochondria) produce energy mostly by catabolizing glutamine and supplying amino acids to the TCA cycle to produce ATP [8]. In cancer cells, the cycle producing energy (ATP) from metabolites and then clean energy no longer occurs. In fact, the nucleus/cytoplasm subsystem generates lactic acid whereas the mitochondria subsystem produces amino-groups. Both catabolites are difficult to eliminate from cells and tissues and from the body, and can be utilized, in a non-finalistic way, as substrates for building cancer cells [8]. In addition to the above energy problems (i.e. abnormalities in energy metabolism), failure of endosymbiosis can result in abnormal or defective cell division and chromosome abnormalities in terms of number (i.e. aneuploidy) or structure (i.e. deletions, duplications, translocations, etc.). Like the two integrated and coupled ancestral subsystems, the two altered processes, namely energy problems and defects in cell division, are obviously linked like two sides of the same coin.

function, leading to the failure of the proper endosymbiosis and consequent decrease of the optimal energy budget, are all potential factors underlying tumor initiation and development (Fig. 1). A body of scientific evidence supports the idea that eukaryotic cells evolved from endosymbiosis between anaerobic archaea and aerobic prokaryotes, with the first engulfing the latter, likely more than two billion years ago [2–4]. According to the endosymbiotic theory of the origin of eukaryotic cells, the anaerobic archaea turned into the nucleus and the cytoplasm of future eukaryotes, whereas the aerobic bacteria generated mitochondria. The archaea (nucleus and cytoplasm) retained most of the information of eukaryotic cells but little capacity to produce energy. By contrast, the aerobic bacteria (mitochondria) kept most of the energy generation capacity and retained very little information (mitochondrial genome). We have previously suggested that mitochondria work in series with both the nucleus and the cytoplasm and in parallel with each other, thus maximally protecting the energetic component of eukaryotic cells [1]. From an energy point of view, eukaryotes can be viewed as a circular system [5]. In fact, products of the anaerobic subsystem (i.e. the nucleus and cytoplasm), mainly pyruvate from anaerobic glycolysis, are further catabolized by the aerobic mitochondria into CO2 and H2O, that are easily eliminated from the cell and from the body [6]. Our hypothesis about cancer pathogenesis may be considered to some extent as an extension or a continuation of Warburg’s hypothesis on the origin of cancer. The German cellular physiologist Otto Warburg hypothesized that multiple factors, mostly acting together, cause cancer, but the final mechanism generating cancer was damage to the mitochondria [7]. We wish to extend the Warburg hypothesis, and propose that the final mechanism is the loss of the balanced endosymbiosis which originated the eukaryotic cell from two different energy systems, one aerobic and the other anaerobic. As mentioned above, the causes of cancer are multiple and of different natures (i.e. physical, chemical and biological). A local alteration in tissue architecture due to these causes, leading to chronic inflammation or other damaging processes, is an explanatory example. The interruption of endosymbiosis caused by prolonged exposure to harmful agents generates cells that lose the characteristics of current eukaryotic cells in favor of elements displaying ancestral-like characteristics, in which anaerobic archaea (nucleus & cytoplasm) generally produce energy by catabolizing glucose at high rates (e.g. activity evidenced by PET = positron emission tomography) and eliminating lactic acid, whereas the de-emerging ancestral

Impairment of endosymbiosis and its consequences From the biological behavior standpoint, we propose that the progressive uncoupling of two endosymbiotic subsystems (information and energy) inside the cell eventually gives rise to (i) altered interactions within tissues and (ii) alterations in cell structure (Fig. 1). Altered interactions within tissues Tissue damage can be caused by a large variety of injuries and the consequent effects may vary case-by-case, depending on the type of tissue and the harmful factor. Here, we postulate that the loss of endosymbiosis in cells forming a tissue could be the “turning point” generating instability of the integrated structures forming the basis of tissue organization. In physiological conditions, the virtuous feedback systems which guarantee the proper functioning of healthy tissues are based on a continuous intercorrelation between the “tissue field” (a coupling mechanism between mechanical vibrations of polar molecules and electromagnetic fields) and the chemical reactions. This results in a continuous balance, intended to maintain an organizational and nonlinear dynamic state far from thermodynamic equilibrium, but capable of generating a sort of overall “coherent state of tissue”. This coherent state, in turn, fosters the synergy and virtuous cooperation of the cells that form a tissue, according to several theoretical explanations 81

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whereby cancer constitutes a regression to a unicellular organism, a sort of protist-like entity [48–57]. Also, there is evidence supporting the concept of cancer as an atavistic phenomenon at cellular level leading to cell regression [58–62], that is in line with the concept of “deemergence” postulated in our systemic evolutionary approach to carcinogenesis [1]. In this sense, cancer cells would resemble protists or metabolic entities resembling fungi or fungus-like organisms (i.e. yeasts and molds) [63]. Alternatively, it can be speculated that cancer cells could be more similar to protozoa (i.e. amoeba) when considering, for example, the phenomenon of cell cannibalism [64–65]. This conceptual association of the cancer cell with a protist-like organism (i.e. saccharomyces or amoeba) could be useful to lay the basis for new anticancer therapeutic approaches. All together, these assumptions are in line with the idea that, like a protist, a malignant cell can adapt or survive in hostile microenvironment conditions [66–70]. This view may explain different aspects of the cancer cell behavior, so fitting the right pieces of a puzzle in their right places. Firstly, the Warburg effect which induces an acidic microenvironment, and a deranged metabolism according to which cells ferment sugar with lactate production even in the presence of oxygen. Secondly, the surviving cells display active proton exchangers, avoiding intracellular acidification but further contributing to the acidification of the extracellular microenvironment [71]. We know, in fact, that the mean pH of cancers is 6.5, but some cancers can live at a pH of 5.0 [72]. However, it has recently been shown that within the tumor population some cells can use lactate produced by other cells as fuel [73]. Moreover, the malignant phenotype of tumor cells can be enhanced by hypoxia and by a low blood flow and nutrient supply, further contributing to select cells able to survive in hostile conditions that would be lethal for normal cells. Due to mitochondrial insufficiency, tumor cells have adapted a fermentative metabolism by replacing respiration with fermentation and can therefore survive under hypoxic conditions. Cell cannibalism is one of these advantages, enabling cancer cells to feed upon other cells (like amoebas do) [64]. It is also known that hypoxia can select cells with very active carbonic anhydrases [74]. All these “advantages” very closely recall cells with primeval properties or embryonic cells. This is supported by elevated expression levels of retroelements in malignant cells, that are not expressed in adult organisms whereas they are fully expressed during embryonic life [75]. Another mechanism contributing to malignant cells survival in a hostile environment is mediated by extracellular vesicles (EVs). For example, cancer cells release elevated levels of EVs both in vivo and in vitro when cultured in acidic conditions [76–77]. EVs are believed to be involved in physiological communication between cells, organs and compartments [78], but in tumor cells they can be implicated in eliminating unwanted materials and in mediating drug resistance [79]. Moreover, a large amount of tumor-derived EVs is released in the blood flow [80,77] and this may favor the metastatic dissemination of tumor cells [81].

proposed by physicists over the last two decades [9–31], as well as recent experimental findings in the field of photosynthetic light harvesting [32–34]. We argue that for various reasons (i.e. lowering energy and information flux, aberrant ions or signaling pathways, etc.), the impairment of the coherent state or of the correct “synergetic” cellular relationships [35] could explain the onset of the tissue dysplasia that usually evolves towards cancer development. It might be thought that phylogenetic and ontogenetic regression to the protist-like state is conceptually simpler, but this would be related only to biological behavior (e.g. unrestricted aggressiveness and proliferation at the host's expense). From the living tissue standpoint, the increase in complexity could be due to alterations of fundamental “biocommunication” aspects caused by the loss of coherent fields (i.e. protists-like generated disorders, see below). Malfunctions and the disruption of intracellular symbiosis may also result in a curtailment of the energy needed to maintain the coherent state, because the more severe the exclusion of cells from synergy and co-operation mechanisms the greater the impairment of the contribution to the emergence of multicellular tissue order. The immediate consequence of this failure is the mesoscopic appearance of an inflammatory state of tissue (see the hepatocarcinogenesis paradigm [1]) and eventually of a state of dysplasia (we believe that dysplasia is the classic example of partial de-emergence of a tissue). Also, the interruption of coherence, synergy and co-operation causes a disruption of the electrodynamic field of tissue that is critical to the correct intercellular communication network. Malignant tissues have higher permissiveness and conductivity compared to healthy tissues. For example, the potentials of plasma membranes and mitochondrial membranes are both hyperpolarized in tumor cells compared with normal cells [36]. Analyses of electric field distribution show that malignant tissues have a reduced field strength, indicating a greater susceptibility to external influences including electrical pulses [37]. In support of these observations, an interesting study has been conducted on a greater adsorption of gold nanoparticles by cancer tissues [38]. Alteration in cell structure: Can a cancer cell resemble a protist? What might cause the presence of a protist-like behavior in cells within a cancerous tissue as a consequence of endosymbiosis disruption? An alternative model, proposed in an attempt to explain the origin of cancer cells, envisages tumor cells as cells which have undergone a switch towards a relatively simple level of organization. For example, the idea that tumors could be related to fungi or fungus-like organisms has been postulated in recent years. Some authors have even proposed that certain fungi could drive normal cells toward a transformation into cancerous cells as a consequence of infection. In any case, the idea that a cancer cell may be something similar to a protist or to one of the simplest forms of cellular life, especially metabolically, is intellectually stimulating. There is scientific evidence that evolution of eukaryotic cells occurs not only due to random genetic variations causing phenotypic selection, as postulated by the neo-darwinism view [39], but also to other mechanisms [40,41] including epigenetic variations [42], gene transposition [43], horizontal transfer of genetic information from other living structures [44], symbiogenesis [3] and duplication of DNA [45]. Of course, all these genetic evolutionary modalities are matched to phenotype selections. Furthermore, there is a lot of noncoding DNA in chromosomes (dark DNA), that is perhaps a byproduct of genetic evolution that could be reused by the cell if needed. The eukaryotic cell seems rather like a Russian matryoshka, with one part inside the other, the oldest phylogenetic parts on the inside, the most recent outside, in which it is the environment that determines the working part by topdown (downward) causation [46]. The idea that random genomic variations or mutations can change a normal cell into a cancer cell seems rather improbable, given the fact that casual genetic variations are evolutionarily negative unless the cell environment changes [47]. Many cancer researchers have hypothesized that the cancer cell is a product of atavistic phenomena caused by changes in the cell environment,

Existing anticancer therapies A number of anticancer therapies have turned out quite ineffective [82,83] and cause serious complications [84–86]. Most of these therapies are based on consolidated cancer theories, such as the somatic mutation theory (SMT) of cancer and its variants [87]. However, since the discovery of hundreds of oncogenes and tumor suppressor genes, the SMT has recently lost its initial appeal and is now stalling [88,89,47]. The traditional antineoplastic treatments with alkylating agents, antimetabolites, antimitotics are generally directed against the increased proliferative rate of cancer cells compared to normal cells. However, since several normal cells within tissues undergo proliferation, these therapies elicit important side effects, as well as often yielding scarce results [82]. Recently, the most specific anticancer treatments based on signal transduction inhibitors (i.e. kinase inhibitors), immunotherapies (i.e. antibody-drug conjugates, bispecific monoclonal antibodies, etc.) have not proven very effective in the long 82

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macrovariables in cancer are the pH, membrane potential, electromagnetic fields (including quantum mechanics of the cancer system), bioenergetics systems as well as cellular and extracellular matrix communications, cell movement, and so on. In addition, another noteworthy concept is that of “mesovariables”, lying between micro and macro, such as interactions between the various cellular components or cellular organelles (essential to determining the physiological and pathological life of the cell). These interactions were determined during evolution (phylogenetic aspects). In this regard, our systemic-evolutionary theory about the cancer pathogenesis encounters a fundamental support, since it is based on the functional coupling of evolutionarily conserved components or subsystems such as the nuclear-information subsystem (the ancestral archaea) and the mitochondrial bioenergetic subsystem (ancestral prokaryotes). According to the proposed theory, these two components or subsystems are perfectly integrated in the cell under normal conditions and require a certain, constant amount of energy to function properly. Conversely, as a result of prolonged injury or organ damage (e.g. chronic inflammation, fibrosis, etc.) that causes a reduction of cellular energy (e.g. reduced oxygen supply and nutrients), the two subsystems could undergo a gradual process of decoupling and, over time, reach a state of dedifferentiation/a preneoplastic or dysplastic or frankly neoplastic state. Therefore, a focus on the mechanisms governing the so-called “mesovariable” (like in the aforementioned example) as a target for pharmacological interventions in cancer could be a step forward toward the beginning of a new era in cancer pharmacology. The reductionist, or gene-centric, view has led modern pharmacology to base cancer therapies predominantly upon microvariables such as gene products and signaling molecules. Macrovariables, instead, can be understood as variables governing the functioning of many other variables, where the pH, electric potential of the cellular or mitochondrial membrane, the Warburg effect and the glutamine metabolism are just some examples of cancer cell macrovariables. Therefore, it is time to bring about a paradigm shift in cancer pharmacology and treatment. The new approach should range from molecular treatment focused on single molecular targets (i.e. receptors, enzymes, etc.) to modular treatment that considers cancer-related processes (i.e. inflammation, coagulation, etc.), or even to a sort of ecosystemic treatment addressing the whole functioning of the “cancer ecosystem” [96]. Examples of ecosystemic treatments could be natural plant derivatives, which act using multiple substances at the same time, or pulsed electromagnetic fields selectively acting on determined features of cancer cells, and whose potential benefits include a lack of toxicity for normal cells and the combination with other therapies. We need different working theoretical models on which to base the new anticancer pharmacological approach.

run, apart from their many side effects [83]. Furthermore, these therapies are still based on the genetic theory of cancer, whose underlying paradigm, as pointed out above, is now being queried. Cancer treatment with hormones or with hormone-related drugs (i.e. selective estrogen receptor modulators including tamoxifen, anti-androgens, anti angiogenesis agents) is used in a restricted number of cancers and is scarcely effective in the long term [83]. Drugs directed against some characteristics of the neoplastic environment, including the acidic pH and proton pump inhibitors, have been proposed to change the approach [90,91]. Proton exchanger inhibitors, alone or in combination, have shown encouraging effects against cancer cells [71,92]. Clinical trials supporting these pre-clinical studies have shown that proton exchanger inhibitors may at least be implemented with current anti-tumor therapies [93]. Immunomodulatory drugs [94] and ketogenic diets (diets with a very low carbohydrates content) seem to be therapeutic interventions moving in another direction [95]. However, new forms of intervention are needed and these could be based on more convincing theories of cancer. In this context, our systemic-evolutionary theory of cancer pathogenesis could suggest new therapeutic strategies.

What value could the systemic evolutionary approach add to cancer treatment? One of the fields in which the paradigm shift might be largely applied is cancer pharmacology. Generally speaking, in pharmacology, while many things appear linear, fairly clear and effective, others seem to be incongruous. Cancer pharmacology belongs to the latter category. Here is an example to better clarify the concept. It is well known that antihypertensive pharmacology is quite effective and based on a variety of drugs belonging to different classes, but all quite effective. Antihypertensive pharmacology is based on an excellent knowledge of the physiology of organ systems (e.g. the cardiovascular and renal systems) and acts effectively on these systems at different levels (i.e. on macro and micro variables). By contrast, this does not happen in cancer pharmacology. Firstly, the knowledge about the cancer pathophysiology as a complex system is insufficient, despite a vast knowledge of molecular mechanisms underlying cancer cell (reductionist approach). In addition, cancer pharmacology deals only with microvariables, and so does not meet the overall physiological integration of cancer biology (Fig. 2). Faced with this limitation, it is obvious that the only targets for cancer pharmacology are the molecular determinants, so this is what the entire modern antineoplastic pharmacology is based on. However, the fact that only microvariables (and not macrovariables, like hypertension in the example) are taken into consideration poses serious limits to the pharmacological treatment of tumors. Examples of

Fig. 2. Comparison between two pharmacological approaches underpinning hypertension and cancer, based on different paradigms. Hypertension pharmacology is based on an excellent knowledge of the physiology of organ systems (e.g. the cardiovascular and renal systems) and acts effectively on these systems at different levels (macro and micro variables). By contrast, this does not occur in cancer pharmacology. A paradigm shift in cancer pharmacology is therefore needed, since the knowledge of cancer pathophysiology as a complex system is insufficient, despite a vast knowledge of molecular mechanisms underlying cancer (reductionistic approach). Current cancer pharmacology deals only with microvariables (e.g. gene or protein targets) rather than macrovariables which, instead, take into account the integrated pathophysiology of cancer (e.g. pH, membrane potential, electromagnetic fields, bioenergetics systems, cell communications and so on). Our proposed systemic evolutionary theory based on an integrated view of cancer pathogenesis could largely support this necessary paradigm shift. 83

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Fig. 3. A scheme illustrating the parallelism between (A) plant defense mechanisms (i.e. secondary metabolites) against external aggressors and (B) the biomimicry approach, potentially useful in the pharmacological treatment of cancer. In particular, assuming that cancer cells display a protist-like phenotype, the biomimicry in plant defense strategy, encompassing the use of blends of compounds directed against external aggressors including protists (i.e. fungi, molds), may result conceptually correct and be translated into cancer research. Assuming cancer to be the final result of endosymbiosis gone awry, leading to the regression towards a protist-like entity, a similar strategy employing secondary metabolites of plants may improve anticancer therapeutic interventions.

Therapeutic approaches with secondary metabolites of plants against the protist-like cancer phenotype

proposed against cancer. One of the most debated plant-derived anticancer compounds is amygdalin, a cyanogenic glycoside belonging to a large group of plant secondary metabolites, reported to inhibit cancer cell growth based on different metabolic/enzymatic features between cancer and normal cells. In particular, the underlying rationale would lie in the abundance in cancer cells of beta-glucuronidase and in the shortage of rhodanese, a mitochondrial enzyme that detoxifies cyanide, that could make amygdalin harmful for cancer cells and more tolerable for normal cells [104]. Another interesting example is salvestrols, a group of substances classified as plant secondary metabolites, that kill cancer cells using the enzyme CYP1B1 expressed in cancer cells, as well as in fungi, but absent in normal cells [105]. However, salvestrols are produced only when plants and fruits are grown organically, without chemical manure and pesticides, and are present only when fruits are harvested mature, just the opposite of what is done in the modern industrial agriculture [106]. This may explain the observations of recent epidemiological studies showing a less protective effect of fruits and vegetables against cancer in comparison with older studies [107]. Industrial agriculture, using pesticides and chemical manure, and harvesting unripe fruit and vegetables, impedes or limits the production of plant secondary metabolites produced against microorganisms, including fungi, that could potentially be protective against cancer. Furthermore, in refined foods, very few plant secondary metabolites are ingested. A return to pre-industrial agriculture and to whole plant foods should be mandatory in order to promote preventive or even curative effects on cancer. Other examples of plant secondary metabolites tested against cancer include essential oils [108] especially cannabis oil [109], the products of the antimalarial plant Artemisia Annua [110], iscador [111,112], Edgar Cayce and Harry Hoxsey's herbal cancer formulas [113], aloe derivatives [114], Rene Caisse’s Essiac herbal tea [115], and many herbs in Chinese medicine [116]. All these treatments are currently components of alternative and complementary oncology approaches that essentially consist of administering many plant secondary

The conceptual association of neoplastic cells with fungi may be instrumental to suggest new therapeutic approaches for cancer, adopting the same proof-of-principle used for antibiotics, the most successful therapeutics in modern medicine. Penicillin, the first antibiotic, was serendipitously discovered by Sir Alexander Fleming and like many antibiotics, is a product of fungi used against bacteria [97]. Over the last years, antibiotics have been explored for use against cancer cells [98]. Interestingly, some antibiotics have been studied for their effects against the mitochondrial biogenesis necessary for the reproduction of cancer stem cells and for their similarities between mitochondria and bacteria [99]. Are there substances in nature produced against protists, in the same way as protists (i.e. fungi or molds) produce antibiotics against bacteria? Is there anything in nature produced against fungi, in the same way as fungi produce antibiotics against bacteria, which by analogy could be used against cancer cells? Indeed, we could search for therapeutics against cancer cells using biomimicry against fungi, by screening substances that are already used in nature against fungi (Fig. 3). However, these substances should be used against cancer in the same way that plants use their secondary metabolites, including antifungal compounds, against biogenic stressors (i.e. bacteria, protists mainly fungi, arthropods and so on), in other words to exploit multiple compounds acting in synergy in the same defense act [100]. Focused on a single key molecular target, the primary strategy of reductionist drug development ignores the complexity of cancer cells. Targeting multiple components of cancer as a complex system may therefore be necessary to provide effective treatment [101]. Indeed, the tumor microenvironment and inflammation have been added in the new version of “hallmarks of cancer” [102] as targets for cancer treatment [103]. Over the past few years, many secondary metabolites of plants, including phytoanticypins and phytoalexins, have been 84

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to treat liver cancer, due to the limitations posed by the compromised underlying hepatic tissue. Hence, there is a need to find effective therapeutics against liver cancer that also have low toxicity. One strategy could be to employ the biomimicry of plant defense mechanisms. To defend themselves from aggressors (i.e. fungi, molds, and bacteria) plants release a mixture of active compounds (e.g. secondary metabolites) at low dosage. According to the biomimicry view (imitating what plants do with their aggressors), hepatic cancer could be seen as an aggressor to be treated with a cocktail of compounds at low dosage to inhibit cancer growth and at the same time preserve the residual liver function. In addition, the advantage of this strategy lies in the fact that multiple compounds acting synergistically but with different mechanisms give tumor cells few chances to escape or become resistant. This is the strategy that allows plants to beat bacteria, fungi or other aggressors or at least to coexist with environmental invaders. Some evidence shows that secondary metabolites can even be protective against aflatoxin, a well known hepatic carcinogen [119]. Indeed, plant secondary metabolites as potential anti-human hepatocellular carcinoma (HCC) agents have recently been proposed and estimated as increasing anticancer medications in current use [120,121] and preclinical studies conducted [122–125]. The introduction of herbal medication is another new possibility becoming available in HCC treatment [126,127], that could satisfy a wider rationale and the pharmacological basis in our proposed systemic evolutionary approach to cancer.

metabolites at the same time, directed against several molecular targets in a systemic approach to cancer treatment [101]. In this regard, the strategy of using secondary metabolites against cancer could satisfy the theoretical basis of our systemic evolutionary approach to cancer [1] and should receive more basic and preclinical research as well as more evaluation by randomized controlled trials like those to which the more expensive cancer drugs produced by the pharmaceutical industry are subjected. Last but not least, plant-derived compounds meaning a mixture or cocktail of organic compounds or natural products may be an alternative or supportive strategy in cancer pharmacology, compared to what is currently done with protocols encompassing one or few drugs at higher doses. The metaphor of “cancer like a protist” is helpful as an example, to provide the pharmacological basis for the ecosystemic treatment. Therefore, like the plants strategy against aggressor agents, the cancer ecosystem could be kept under control by plant secondary metabolites, comprising a large number of substances that plants use to fight microorganisms including protists. Accordingly, vegetarian diets that utilize plant-derived foods from biologic or biodynamic cultivations, or particularly those which utilize plants cultivated under stressed/natural conditions, might contain enough secondary metabolites to prevent or halt cancer. Electromagnetic fields and potential implications for cancer therapy: Cancer therapies using variable electromagnetic fields

Conclusive remarks

Another anticancer therapeutic approach may rely on cell boundary structures, including the plasma membrane, internal cytomembranes and mitochondrial membranes (external and internal) that function differently in normal cells compared to cancer cells [36]. This therapeutic approach may exploit variable electromagnetic fields of different wavelengths and different time. [117,118]. These studies showed that exposure to a low intensity, time varying EMF, inhibited the proliferation of malignant cells. The mechanisms involved can be different and tentative explanations are proposed. [118]. Malfunctioning and disruption of intracellular symbiosis (between the two endosymbiotic systems) may deplete the energy needed to maintain the coherent state. If the cells involved are excluded from the synergy and the co-operation processes maintaining the coherent state of tissue, their contribution to the emergence of the multicellular tissue order could be abolished or depressed [29]. The immediate consequence of this failure is the mesoscopic appearance of an inflammatory or damaged state of tissue (see the hepatocarcinogenesis paradigm, [1]) and, in the long run, the coherent state on which all cells work to maintain the tissue emergence (the integrative aspect of complex systems) may fail to be restored. The interruption of coherence, synergy and co-operation can also cause a disruption of the electromagnetic field inside tissues that is critical to the intercellular information network, and that must be continuously guaranteed within tissues. This can result in the loss of “dependence” and the “chaotic bifurcation of cells” that may eventually cause dysplasia and cancer. Given the importance of biocommunication from the cell to the organism, it is desirable that the studies of the interaction with electromagnetic fields for therapeutic purposes undergo further developments, carrying out systematic experiments varying frequencies, intensity and duration of these fields.

The concepts presented in this article may seem somewhat provocative, but are intended rather as a contribution to a real change in the way cancer is seen and so treated. We believe our plants systemic evolutionary theory of cancer should be considered as an attempt to frame the complexity of cancer and to provide elements supporting therapeutic interventions, rather than a fancy way of thinking about cancer. It may also offer a new way of understanding our body and how it evolves during life. Medicine should take into serious account each single human being rather than just trying to manage diseases, avoiding the view that cancer is a disease to be treated strictly according to protocols only or to restricted guidelines, sometimes not based on a true critical consensus, or even relying on sponsored studies rather than real scientific evidence. Our body's imperfections are probably what make it perfect. In this sense, this means that we should look at cancer as a way our body displays its inability to control some abnormalities or prolonged insults. A recent and very exciting paper has shown how the environment may continuously change our genome [96]. Of course, the environment is not just the water we drink, the food we eat or the air we breathe, it is also our relationship with everything surrounding us and with other human beings as well. Disclosures The authors have no potential conflicts of interest to disclose. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.mehy.2018.09.033.

Liver cancer as a paradigm for potential applications of the systemic evolutionary approach to cancer

References As in our previous report [1], the process of hepatocarcinogenesis leading to liver cancer formation once again offers an excellent model for studying the systemic evolutionary approach to cancer paradigm and its potential applications, especially in terms of therapeutic interventions. Liver cancer is a tumor that normally develops in fibrotic or cirrhotic liver, in which the liver function is often abundantly compromised due to the underlying disease. This is the reason why most anticancer drugs, although theoretically active, cannot actually be used

[1] Mazzocca A, Ferraro G, Misciagna G, Carr BI. A systemic evolutionary approach to cancer: hepatocarcinogenesis as a paradigm. Med Hypotheses 2016;93:193–1137. [2] Kozo-Polyansky BM. The new principle of biology: an assay on the theory of symbiogenesis. Leningrad-Moscow: Puchina 1924, translated in English, Symbiogenesis, a new principle of evolution. Cambridge: Harvard University Press; 2010. [3] Margulis L. Symbiosis in cell evolution. 2nd ed. New York: Freeman & Co; 1993. [4] Lane N. The vital question. London: Profile Books; 2015.

85

Medical Hypotheses 121 (2018) 80–87

A. Mazzocca et al.

[45] Ohno S. Evolution by gene duplication. London: Allen & Unwin; 1970. [46] Noble D. A theory of biological relativity: no privileged level of causation. Interface Focus 2012;2:55–64. [47] De Gregori J. Adaptive oncogenesis. Cambridge, Ma: Harvard University Press; 2018. [48] Setala K. Carcinogenesis-devolution towards an ancient nucleated pre-eukaryotic level. Med Hypotheses 1984;15:209–30. [49] Okuyama S, Mishina H. Evolution of cancer. Tokyo, Japan: University of Tokyo Press; 1990. [50] Merlo LMF, Pepper JW, Reid BJ, Maley CC. Cancer an evolutionary and ecological process. Nature Rev Cancer 2006;6:924–35. [51] Arguello F. Atavistic metamorphosis. Copyright Frank Arguello 2011. [52] Davies PCW, Lineweaver CH. Cancer tumors as metazoan 1.0: tapping genes of ancient ancestors. Phys Biol 2011;8:1–10. [53] Alfarouk KO, Shayoub MEA, Muddathir AK, Elhassan GO. Bashir Ahh. Evolution of tumor metabolism might reflect carcinogenesis as a reverse evolution process -dismantling of multicellularity. Cancers 2011;3:2002–17. [54] Fernandes J, Guedes PJ, Lage CLS, Rodrigus JCF, Lage CdeAS. Tumor malignancy is engaged to prokaryotic homolog toolbox. Hypotheses 2012;78:435–41. [55] Home SD, Pollick SA, Heng HHQ. Evolutionary mechanism unifies the hallmarks of cancer. Int J Cancer 2015;136:2012–21. [56] Bussey KJ, Cisneros LH, Lineweaver CH, Davies PCW. Ancestral gene regulatory networks drive cancer. PNAS 2017;114:6160–2. [57] Niculescu V. Carcinogenesis: recent insights in protist stem cell biology lead to a better understanding of atavistic mechanisms implied in cancer development. MOJ Tumor Res 2018;1(1):18–9. [58] Domazet-Loso T, Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoan. BMC Biol 2010;8:66–75. [59] Chen H, Lin F, Xing K, He X. The reverse evolution from multicellularity to unicellularity during carcinogenesis. Nat Commun 2015;6. art.6367. [60] Trigos AS, Pearson RB, Papenfuss AT, Goode DL. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. PNAS 2017;114:6406–11. [61] Cisneros L, Bussey KJ, Orr AJ, Miocevic M, Lineweaver CH, Davies P. Ancient genes establish stress-induced mutation as a hallmark of cancer. PLoS One 2017;12(4). https://doi.org/10.1371/journal.pone.0176258. e0176258 eCollection. [62] Trigos AS, Pearson RB, Papenfuss AT, Goode DL. How the evolution of multicellularity set the stage for cancer. Br J Cancer 2018;118:145–52. [63] Diaz-Ruiz R, Uribe-Carvajal S, Devin A, Rigoulet M. Tumor cell energy metabolism and its common features with yeast metabolism. Biochim Biophys Acta A 2009;1796:252–65. [64] Fais S, Fauvarque MO. TM9 and cannibalism: how to learn more about cancer by studying amoebae and invertebrates. Trends Mol Med 2012;18:4–5. [65] Fais S. Cannibalism: a way to feed on metastatic tumors. Cancer Lett 2007;258:155–64. [66] Epstein T, Gatenby RA, Brown JS. The Warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand. PLoS One 2017;12(9):e0185085. [67] You L, Brown JS, Thuijsman F, Cunningham JJ, Gatenby RA, Zhang J, et al. Spatial vs. non-spatial eco-evolutionary dynamics in a tumor growth model. J Theor Biol 2017;435:78–97. [68] Gravenmier CA, Siddique M, Gatenby RA. Adaptation to stochastic temporal variations in intratumoral blood flow: the warburg effect as a bet hedging strategy. Bull Math Biol 2018;80(5):954–70. [69] Ibrahim-Hashim A, Robertson-Tessi M, Enriquez-Navas PM, Damaghi M, Balagurunathan Y, Wojtkowiak JW, et al. Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution. Cancer Res 2017;77(9):2242–54. [70] Gatenby RA, Brown J. Mutations, evolution and the central role of a self-defined fitness function in the initiation and progression of cancer. Biochim Biophys Acta 2017;1867(2):162–6. [71] Spugnini EP, Sonveaux P, Stock C, Perez-Sayans M, De Milito A, Avnet S, et al. Proton channels and exchangers in cancer. Biochim Biophys Acta 2015;1848:2715–26. [72] De Milito A, Canese R, Mrino ML, Borghi M, Iero M, Villa A, et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 2010;127:207–19. [73] Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008;118(12):3930–42. [74] Supuran CT, Winum JY. Carbonic anhydrase IX inhibitors in cancer therapy: an update. Future Med Chem 2015;7(11):1407–14. [75] Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, et al. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 2005;24(24):3923–31. [76] Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009;284:34211–22. [77] Logozzi M, Angelini DF, Iessi E, Mizzoni D, Di Raimo R, Federici C, et al. Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. Cancer Lett 2017;403:318–29. [78] Fais S, O'Driscoll L, Borras FE, Buzas E, Camussi G, Cappello F, et al. Evidencebased clinical use of nanoscale extracellular vesicles in nanomedicin. ACS Nano 2016;10(4):3886–99. [79] Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, et al. Exosome release and low pH belong to a framework of resistance of human melanoma cells

[5] Pauli G. Upsizing: the road to zero emissions. Greenleaf Publishing; 1998. [6] Nelson DL, Cox MM. Lehninger principles of biochemistry. 6th ed. New York: Freeman & Co; 2016. [7] Warburg OH. On the origin of cancer cells. Science 1956;12:309–14. [8] De Berardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016;2(5). https://doi.org/10.1126/sciadv.1600200. e1600200 eCollection. [9] Del Giudice E, Preparata G, Vitiello G. Water as a free electric dipole laser. Phys Rev Lett 1988;61:1085–8. [10] Preparata G. QED coherence in matter. Singapore: World Scientific; 1995. [11] Preparata G. QED and Medici. In: Valenzi VI, Messina B, editors. Proceedings meeting 14/12/1999: the role of QED in medicine. Roma: La Sapienza; 2000. p. 2–27. [12] Del Giudice E, Preparata G, Fleischmann M. QED coherence and electrolyte solutions. J Electroanal Chem 2000;482:110–6. [13] Del Giudice E, Vitiello G. Role of the electromagnetic field in the formation of domains in the process of symmetry-breaking phase transitions. Phys Rev A 2006;74(1–9):022105. [14] Del Giudice E. Old and new views on the structure of matter and the special case of living matter. J Phys: Conf Ser 2007;67(1–8):012006. [15] Plankar M, Jerman I, Krasovec P. On the origin of cancer: can we ignore coherence? Prog Biophys Mol Biol 2011;106:380–90. [16] Plankar M, Del Giudice E, Tedeschi A, Jerman I. The role of coherence in a systems view of cancer development. In: Serra F, editor. Theoretical biology forum. Romapisa: F.S; 2012. p. 15–46. [17] Del Giudice E, Tedeschi A, Vitiello G, Voeikov V. Coherent structures in liquid water close to hydrophilic surfaces. J Phys Conf Ser 2013;442(1-7):012028. [18] Bischof M, Del Giudice E. Communication and the emergence of collective behavior in living organisms: a quantum approach. Mol Biol Int 2013(1–19). ID987549. [19] Del Giudice E, Voeikov V, Tedeschi A, Vitiello G. The origin and the special role of coherent water in living systems. In: Fels D, Cifra M, Scholkmann F, editors. Fields of the cell. 2015. p. 95–111. [20] Pokorny J. Excitations of vibrations in microtubules in living cells. Bioelectrochemistry 2004;321:321–6. [21] Pokorny J, Haisek J, Vanis J, Jelinek F. Biophysical aspects of cancer –electromagnetic mechanism. Indian J Exp Biol 2008;46:310–21. [22] Pokorny J. Electrodynamic activity of healthy and cancer cells. J Phys: Conf Ser 2011;329(1–15):012007. [23] Pokorny J. Physical aspects of biological activity and cancer. AIP Adv 2012;2(1–12):011207. [24] Pokorny J, Foletti A, Kobilkova J, Jandova A, Vrba J, Vrba Jr. J, Nedbalova M, Cocek A, Danani A, Tuszynski JA. Biophysical insights into cancer transformation and treatment. Sci World J 2013(1-11). ID 195028. [25] Pokorny J, Pokorny J, Kobilkova J. Postulates on electromagnetic activity in biological systems and cancer. Integr Biol 2013;5:1439–46. [26] Pokorny J, Pokorny J. Biophysical pathology in cancer transformation. J Clin Exp Oncol 2013;S1:1–9. [27] Pokorny J, Pokorny J, Kobilkova J, Jandova A, Vrba J, Vrba Jr. J. Cancer –pathological breakdown of coherent energy states. Biophys Rev Lett 2014;9(1):1154–2133. [28] Pokorny J, Pokorny J, Vrba J, Vrba Jr. J. Measurement of electromagnetic activity of living cells. Proceedings of progress in electromagnetic research symposium (PIERS), Prague. 2015. July 6-9. 2863-2867. [29] Pokorny J, Pokorny J, Foletti A, Kobilkova J, Vrba J, Vrba Jr. J. Mitochondrial dysfunction and disturbed coheremce: gate to cancer. Pharmaceuticals 2015;8:675–95. [30] Vitiello G. Onthe isomorphism between dissipative systems, fractal self-similarity and electrodynamics. Toward an integrated vision of nature. Systems 2014;2:203–16. [31] Bertolaso M, Capolupo A, Cherubini C, Filippi S, Gizzi A, Loppini A, et al. The role of coherence in emergent behavior of biological systems. Electromagn Biol Med footnotes 2015:1–8. [32] Olaya-Castro A. Lee CF. Fassioli F. Johnson NF. Efficiency of energy transfer in a light-harvesting system under quantum coherence. arXiv:0708.1159v3 [quantph]: 1-7. [33] Scholes GD, Fleming GR, Olaya-Castro A, van Grondelle R. Lessons from nature about solar light harvesting. Nat Chem 2011;3:763–74. [34] Fassioli F, Dinshaw R, Arpin PA, Scholes GD. Photosynthetic light harvesting: excitons and coherence. J Royal Soc Interface 2013;11(1–22):20130901. [35] Haken H. Synergetics –. An Introduction Berlin: Springer Verlag; 1978. [36] Yang M, Brackenbury WJ. Membrane potential and cancer progression. Front Physiol 2013;4(2–11):art.185. [37] Agoramurthy P. Sundararajan R. Electric field distribution of human breast tissue. Electrical Insulation and Dielectric Phenomena (CEIDP) 2010; Annual Report on doi: 10.1109/CEIDP.2010.5724064. [38] Huston RH. Using the electromagnetic of cancer's centrosome clusters to attract therapeutic nanoparticles. Adv Biosci Biotechnol 2015;6:172–81. [39] Dawkins R. The selfish gene. Oxford: Oxford University Press; 1999. [40] Hawkins S. The mechanisms of evolution. Reading, England: Light Press; 2011. [41] Noble D. Evolution beyond neo-Darwinism: a new conceptual framework. J Exp Biol 2015;218:7–13. [42] Rapp RA, Wendel JF. Epigenetics and plant evolution. New Phytol 2005;168:81–91. [43] Shapiro JA. Genome system architecture and natural genetic engineering in evolution. Ann NY Acad Sci 1999;870:23–35. [44] Fall S, Mercier A, Bertolla F, Calteau A, et al. Horizontal gene transfer: regulation in bacteria as a spandrel of DNA repair mechanisms. PLoS One 2007;2:e1055.

86

Medical Hypotheses 121 (2018) 80–87

A. Mazzocca et al.

[104] Day P. B17 metabolic therapy in the prevention and control of cancer. Tonbridge, Kent, England: Credence Publications; 2002. [105] Burke MD, Potter G. Salvestrols, natural plants and cancer agents. Br Naturopathic J 2006;23:10–3. [106] Schaefer AB. Salvestrols, nature’s defense against cancer. Canada: Clinical Intelligence Co.; 2012. [107] Leenders M, Sluijs I, Ros MM, et al. Fruit and vegetable consumption and mortality. European prospective investigation into cancer and nutrition. Am J Epidemiol 2013;178:590–602. [108] Pergentino de Souza D. Bioactive essential oils and cancer. Heidelberg: Springer; 2015. [109] Fields J. Cancer and CBD oil. Understanding the benefits of Cannabis and medical. Marijuana 2018. [110] Tu Y. From artemisia annua L. to artemisinins. London: Academic Press; 2017. p. 397–399. [111] Iscador MC. Mistletoe and Cancer Therapy. London: Lantern Books; 2001. [112] Portalupi E, Frisia N. IL viscum album fermentatum Esperienze nella pratica di medicina oncologica integrata. Milano: Edra; 2017. [113] Bloom R. Cancer medicine from nature. 2nd ed. Virginia Beach, Virginia, USA: Eco Images; 2012. [114] Coats BC, Ahola RJ. The silent healer. A modern study of Aloe vera. Martinsville, Indiana, USA: Fideli Publishing Inc.; 2010. [115] Snow S, Klein M. Essiac essentials. Lithia Spring, Georgia, USA: New Leaf Publishing Group; 1999. [116] Yu R, Hai H. Cancer management with chinese medicine. Hong Kong, China: World Scientific Publishing Company; 2012. p. 45–58. [117] Buckner CA, Buckner AL, Koren SA, Persinger MA, Lafrenie RM. Inhibition of cancer cell growth by exposure to a specific time-varying electromagnetic field involves T-Type calcium channels. PLoS One 2014;10(4):1–16. e0124136. [118] Lucia U, Ponzetto A. Some thermodynamic considerations on low frequency electromagnetic waves effects on cancer invasion and metastasis. Physica A 2017;467:289–95. [119] Odongo GA, Schlotz N, et al. Food Nutr Res 2017;61(1). https://doi.org/10.1080/ 16546628.2017.1271527. eCollection 1271527. [120] Martinez MJ, Andreu A, Barbini L. Plant polyphenolic extracts as potential antihuman hepatocarcinoma agents. Plant Sci Today 2014;1(4):213–8. https://doi. org/10.14719/pst.2014.1.4.62. [121] Rawat D, Shrivastava S, Naik RA, Chhonker SK, Mehrotra A, Koiri RK1. An overview of natural plant products in the treatment of hepatocellular carcinoma. Anticancer Agents Med Chem 2018. https://doi.org/10.2174/ 1871520618666180604085612. [122] Manosroi A, et al. Evid Based Complement Alternat Med 2015:397181https://doi. org/10.1155/2015/397181. [123] Nevzorova, et al. Biomed Pharmacother 2017;89:386–95. https://doi.org/10. 1016/j.biopha.2017.02.035. [124] Chen YS. Steroids 2014;83:39–44. https://doi.org/10.1016/j.steroids.2014.01. 014. [125] Li Y, et al. Int J Oncol 2014;44(2):505–13. https://doi.org/10.3892/ijo.2013. 2184. [126] Rasool M, et al. Anticancer Res 2014;34(4):1563–71. [127] Thoppil RJ, Harlev E, Mandal A, Nevo E, Bishayee A. Antitumor activities of extracts from selected desert plants against HepG2 human hepatocellular carcinoma cells. Pharm Biol 2013 May;51(5):668–74. https://doi.org/10.3109/13880209. 2012.749922.

to cisplatin. PLoS One 2014;9:e88193. [80] Cappello F, Logozzi M, Campanella C, Bavisotto CC, Marcilla A, Properzi F, et al. Exosome levels in human body fluids: a tumor marker by themselves?“. Eur J Pharm Sci 2017 Feb;15(98):64–9. [81] Zhao H, Achreja A, Iessi E, Logozzi M, Mizzoni D, Di Raimo R, et al. The key role of extracellular vesicles in the metastatic process. Biochim Biophys Acta 2018;1869:64–77. [82] Chan HSL. Understanding cancer therapies. Jackson, Mississippi: University Press of Mississippi; 2007. [83] Carta A, Murineddu G, Pinna GA. Approcci terapeutici contro il cancro. Roma: Aracne Editrice; 2016. [84] Davis P, et al. BMJ 2017;359. https://doi.org/10.1136/bmj.j4530. j4530. [85] Cohen D. Cancer drugs: high price, uncertain value. BMJ 2017;359:4543–6. [86] Prasad V. Do cancer drugs improve survival or quality of life? BMJ 2017;359:4528–9. [87] Hahn WC, Weinberg RA. Mechanisms of disease: rules for making human tumor cells. New Engl J Med 2002;347:1593–603. [88] Soto AM, Sonnenschein C. The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. BioEssays 2011;33:332–40. [89] Seyfried TN, Flores RF, Poff AM, D’Agostino DPD. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 2014;35:515–27. [90] Fais S. A nonmainstream approach against cancer. J Enzyme Inhib Med Chem 2016. [91] Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev 2014;33:1095–108. [92] Federici C, Lugini L, Marino ML, Carta F, Iessi E, Azzarito T, et al. Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells. J Enzyme Inhib Med Chem 2016;31(sup1):119–25. [93] Fais S. Evidence-based support for the use of proton pump inhibitors in cancer therapy. J Transl Med. 2015;13:368. [94] Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348:56–61. [95] Seyfried TN, Yu G, Maroon JC, D’Agostino DP. Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab 2017;14:19–35. [96] Favé MJ, Lamaze FC, Soave D, Hodgkinson A, Gauvin H, Bruat V, et al. Gene-byenvironment interactions in urban populations modulate risk phenotypes. Nat Commun 2018;9(1):827. [97] Friedman M, Friedman GW. Medicine’s ten greatest discoveries. New Haven, CT: Yale University Press; 1998. [98] Ozsvari B, Lamb R, Lisanti MP. Repurposing of FDA-approved drugs against cancer– focus on metastasis. Aging 2016;8:567–8. [99] Ozsvari B, Fiorillo M, Bonuccelli G, Cappello AR, Frattaruolo L, Sotgia F, et al. Mitoriboscins: mitochondrial-based therapeutics targeting cancer stem cells, bacteria and pathogenic yeasts. Oncotarget 2017;8:67457–72. [100] Gutzeit Ho, Muller JL. Plant natural products. Weinheim, Germany: Wiley VCH Verlag; 2014. p. 132–54. [101] Silverman EK, Loscalzo J. Systems pharmacology in network medicine. In: Loscalzo J, Barabasi AL, Silverman EK, editors. Network medicine. Boston, Ma: Harvard University Press; 2017. p. 324–40. [102] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [103] Reichle A, Vogt T. Systems biology: a therapeutic target for tumor therapy. In: Reichle A, editor. From molecular to modular tumor therapy. Berlin: Springer; 2010.

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