Cancer; an induced disease of twentieth century! Induction of tolerance, increased entropy and ‘Dark Energy’: loss of biorhythms (Anabolism v. Catabolism)

Maintenance of human health is the result of an amazingly harmonious, synchronized and autonomous neurophysiological status of body. Health of an adult depends on the reciprocal interactions of positive and negative biological feedback control mechanisms (biological clocks, circadian biorhythms) between and among the immune-vascular-metabolic-genomic-hormonal-neuronal (sympathetic and parasympathetic) pathways that constitute effective immunity (biological laws) for preventing diseases including cancer. As early as the nineteenth century, Paul Ehrlich using the newly invented microscope made fundamental observations that cancer cells are destroyed by immune/inflammatory cells [1]. Furthermore, over a century ago, Peyton Rous through a series of careful and pioneering studies demonstrated that filterable viruses induce cancer; thus the establishment of the field of virology [2]. Later on in 1957, Sir McFarland Burnet conceptualized the important theory of immune surveillance, the protection of body against all unwanted elements including the control of cancer growth [3]. Burnet theory was based on evaluation and integration of a wide range of available data on cellular and molecular biology, embryology and pathology [3]. In 1986, Dvorak proposed that tumors are wounds that do not heal [4]. Furthermore, the analyses of accidental discoveries that Khatami et al. established in 1980s on experimental models of ocular inflammatory diseases, are the only series of direct evidence for an association between inflammation and time-course kinetics of induction of identifiable altered phases of immune response profiles toward multistep tumorigenesis and angiogenesis (see below) [5].

These and related fundamental observations and discoveries that stood the test of time have been practically ignored and minimized or rejected by the decision makers in cancer/medical establishment.¹ In this perspective, the author attempted to analyze, integrate data and identify relevant knowledge gaps on diverse topics of cancer sciences toward a roadmap. The goal was to briefly present evidence that cancer is an induced disease of the twentieth century, facilitated by medical/cancer establishment for huge corporate profits ever since the American public was allowed to consume virus-contaminated polio vaccines in 1955s/1960s. Weakened immunity of public has been reinforced by other pathogen-specific vaccines (e.g., Swine flu, hepatitis B or C, measles, anthrax, meningitis, HPV or even BCG) including vaccines ingredients/adjuvants (e.g., mercury, aluminum, l-histidine, recombinant DNA, embryonic serum), which are ‘antigen overload’ for the immune system to clear. In the last few decades, public has additionally been exposed to a wide range of environmental hazards [e.g., smoking, pesticides, genetically modified organisms (GMOs) and preserved foods, electronic gadgets, low level carcinogens] and other immune disruptors whose cumulative effects adversely influence immunity [5–25].², ³, ⁴

In 1980s, we established experimental models of acute and chronic ocular inflammatory diseases using guinea pigs conjunctival-associated lymphoid tissues (CALTs). Systematic analyses of a series of reported data suggested the first and only evidence for direct association between inflammation and time course kinetics of developmental phases of immune dysfunction (acute, intermediate and chronic phases) in the direction of tumorigenesis and angiogenesis (‘accidental’ discoveries) [5–8, 26–41]. Briefly, in the acute phase (immediate hypersensitivity responses), early clinical and histopathological findings included strong or weak type 1 ocular reactions, tearing, activation and degranulation of mast cells (MCs), vascular hyperpermeability reactions and tissue edema. The release of histamine and prostaglandins (PGF-1α) were reported as primary and secondary mediators of immune responses in acute phase reactions. Animals with strong acute ocular reactions also demonstrated wheezing suggestive of MCs sensitization and activation in lung airways [8, 26, 30, 31]. The intermediate phase (down-regulation phenomena) responses were associated with minimum clinical responses, increased degranulated MCs, heavy infiltration of eosinophils in ocular secretions and goblet cells, induction of neovascularization and tissue atrophy [27, 31]. In the chronic phase responses, clinical appearance of tumor-like lesions in upper and lower bulbar conjunctiva, extensive angiogenesis and massive hyperplastic tissues were reported. Histopathological studies demonstrated loss of capsular integrity in lymphoid tissue, increased presence of various size lymphocytes (proliferation), lymphatic channels, necrosis and growth in epithelial tissues, activated MΦs and presence of histiocytes (activated DCs?). Antibody assays of hyperplastic tissues showed changes in local IgGs biosynthesis (IgG1/IgG2 ratios). New born guinea pigs from highly sensitized animals developed strong clinical reactions upon 1st or 2nd challenge with antigen suggesting antibody transfer and genetic predisposition in newly born animals [8, 28, 29, 31]. Mixing antigen with tumor-promoting agents shifted the induction of tumorigenesis and angiogenesis to earlier time course, compared with using antigen alone, suggesting involvement of growth promoting kinases. Presence of circulating IgE antibodies did not necessarily correlated with strong acute reactions, suggesting sensitization of local and distal MCs including the lung airways or the fetus tissues [8, 26, 31]. In 2014, further analyses and integration of original data led to the first report on interactions and synergies between host/local immune and non-immune cells (e.g., mast cells, mucus-secreting goblet cells, epithelium, B/plasma cells) and the recruitment and infiltration of activated immune cells (e.g., eosinophils, tumor associated macrophages/TAM-M2) via activation of vasculature toward tumorigenesis and angiogenesis at different stages of immune dysfunction [38].

These are the earliest and only series of systematic studies that produced evidence on the role of repeated exposures to immune disruptors (antigen) in the induction of multistep tumorigenesis and angiogenesis. These accidental discoveries on direct role of inflammation in alterations of immune dynamics toward tumorigenesis and angiogenesis deserve to be further studied, validated, confirmed and compared with other experimental models of inflammatory diseases, other tissues [e.g., lung-associated lymphoid tissues (LALTs), gut-associated lymphoid tissues (GALTs)] or other tissues with different cell compositions (e.g., liver, breast, colorectal).

As detailed elsewhere ([5–7, 38, 39], Khatami, NCI/NIH records and legal documents since 1998), author’s challenging efforts to promote the important role of inflammation in cancer research, diagnosis and therapy initially met with serious oppositions and denials by members of establishment who rejected the submitted concepts and comprehensive proposals that were extension of author’s original discoveries. However, in recent years, it seems that Khatami’s efforts awakened the entire cancer community within and outside NCI/NIH, on the important role of inflammation in cancer science. In the last 2 decades, professionals enjoy significant increased in funding on fragmented submitted ideas in the fields of OMICS (e.g., proteomics, genomics, metabolomics, lipidomics, proteo-genomics) or immunotherapy, using highly expensive specific technologies and experimental models [e.g., genetically or chemically-induced (e.g., comination of azoxymethane (AOM) and dextran sodium sulfate)] of tumors and organizing networking and symposia, with no end in sight [5–7, 38–43]. However, the outcomes of reductionist approaches on identification of hundreds of molecular entities that are used for drug development and claimed as ‘targeted’ therapy or ‘personalized’ or ‘precision’ medicine have been very disappointing, extremely costly and dangerous for patients and society. Majority of expensive projects in cancer research and therapy focus on identification of too many defective molecular species in the landscape of cancer molecular tsunami with little/no efforts to understand what initiate altered immune response profiles that lead to multistep tumorigenesis. The initial immune response alterations were suggested to be correctable, reversible or drugable [5, 7, 16, 39–43].

Ongoing debates, controversies, misinformation and confusions regarding the role of inflammation, whether it is protective in preventing cancer or it is a cause of cancer are among serious factors in failing patients when clinical trials are decided [5–8].⁵

In the following sections, attempts were made to demonstrate and suggest that cancer is a symptom of accumulated violations of time-controlled biorhythms whose disorderly proliferation and mitosis are facilitated by altered mitochondrial bioenergetics, increased glucose utilization and entropy and generation of ‘dark energy’, conditions that are toxic to normal cells. Unlike the popularized notion that cancer is 100, 200 or 1000 diseases!, the author shows that cancer cells are body’s defective cells whose disorderly growth are the results of loss of natural biphasic properties of Yin (tumoricidal) and Yang (tumorigenic) of inflammation, associated with loss of differential bioenergetics (anabolic vs catabolic) in tissues. Evidence is presented that over the last six decades, decision makers in cancer establishment has gradually weakened and manipulated the autonomic biological circadian rhythms, the Yin and Yang of effective immunity, by introducing the public to various pathogen-specific vaccines and ingredients, in addition to exposures to exposures to a wide range of environmental hazards and low level carcinogens that made young and old in America sick and drug-dependent.

Analyses of related data suggest that nearly all diseases, to varying degrees, are the results of altered effective immunity or loss of biological circadian rhythms (on–off switches) that adversely influence tissue bioenergetics (mitochondria), the principal generator of energy and electricity (proton pumping) in organ systems [5, 7, 35–90].

Manifestations of organ-specific diseases that are known as distinct pathological and clinical complications such as polyps, pre-cancer, cancer metastasis and angiogenesis, or neurodegenerative and autoimmune diseases, diabetes and cardiovascular complications, are generally the outcomes of cumulative damages in the immune-responsive tissues (e.g., epithelial, endothelial, mucus secreting goblet cells, stroma) or immune-privileged tissues (e.g., CNS, BBB, neuroretina, cornea, reproductive system) and/or insulin-dependent (e.g., muscle, adipose tissue, liver) and insulin-independent tissues (e.g., vasculature, neuronal and endothelial cells, fibroblasts) for glucose transport and metabolism [5–8].

Overview and integration of data on diverse experimental models of chronic illnesses or cancer research and clinical studies suggest that all diseases share features of one or more defects in innate (intrinsic, constituent) and/or adoptive (extrinsic or induced) pathways including cellular [e.g., genomic/chromosomal (DNA/RNA, epigenetic modifications), cell mediated or humoral immunity (CMI/HI), hormonal, metabolic, neuronal (sympathetic and parasympathetic)] activities that contribute to the complex signal communications of altered immunity and manifest in different tissues as different diseases [5–8, 34–80]. We proposed that effective immunity (synchronized biorhythms, sympathetic and parasympathetic, or Yin and Yang of acute inflammation) is responsible for protection of body against all intrinsic (e.g., defective cancerous cells, useless proteins/peptides/lipids, accumulated oxidized materials, lymphocyte-derived clonal complexes, abnormal repair mechanisms in chromosomal-histone proteins-genetics, DNA/RNA mutations, or hypo/hyper epigenetic modifications) or extrinsic elements (e.g., pathogens/microbiomes, allergen/antigens, low level carcinogens) that are perceived harmful to individual’s survival [5–8, 20, 35–39].

As detailed elsewhere [5–8, 35–40], effective immunity follows complex and precise rules of molecular engagements and require development of differential bioenergetics for body’s defense and survival after birth. Effective immunity was defined as a highly regulated signal transductions between 2 biologically opposing arms, termed Yin (tumoricidal) and Yang (tumorigenic) that intimately engage the activities of immune-metabolic–vasculature–hormonal–neuronal (sympathetic and parasympathetic) systems.

In an acute inflammation, autonomic crosstalk between innate and adaptive immune cells and non-immune pathways has a 2-fold mission with differential energy requirements from mitochondria and cytosol as outlined below [5, 35–40].

The crosstalk in Yin and Yang of effective immunity occurs continuously and simultaneously between and among cells, tissues, organs and glands (e.g., skin, liver, kidney, eyes, lung, heart, thymus, lymphoid organs, vasculature, neuronal, and gastrointestinal tract) for maintenance of health. In 2016, we proposed a working model for differential bioenergetics requirements of Yin and Yang pathways from fetus orderly growth, after birth and all the way to adulthood, aging process and development of chronic diseases and cancer [39]. The following sections briefly reflect further extension of the recently proposed model on analyses and integration of a large body of valuable scattered data pertaining to basic and clinical studies on developmental biology, immunity, aging, hormonal, metabolic and neuronal activities, to better appreciate induction of immune tolerance and cancer bioenergetics [5–7, 35–190]:

1. 1.

   The body is a dynamic and energy consuming system involving highly complex interactions between and among multi-organs whose function continually evolves, from conception, placentation, embryonic and fetal growth, after birth, puberty and adulthood and aging or disease processes. The anabolic (regeneration, tumorigenesis or Yang) and catabolic (apoptosis, tumoricidal or Yin) arms of effective immunity follow highly organized biological circadian rhythms (biorhythms) requiring on–off switches of immune and non-immune responses that constitute the human health. Insufficient circadian rhythms (skewed biological clocks or loss of sympathetic or parasympathetic activities) are perhaps the result of one or more mutations or deficiencies in the circadian clock genes that influence the amazingly synchronized and interdependent features of biological oscillators in Yin–Yang or ‘effective acquisition time’ of immunity [5, 7, 39].

    
2. 2.
   Growth requirements of embryo-fetus development are orderly processes (basically a one-way growth) occurring under protected environment of placenta during embryonic development involving expression of constituent receptors, projected from trophoblasts that anchor embryo and during fetus growth under limited oxygen tension (hypoxic condition). Angiogenesis and organogenesis, including development of lymphoid organs and generation of naïve pluriepotent stem cells or mesenchymal stem cells (MSC) require growth factors and metabolism, primarily using glycolysis for energy requirements. The energy production for growth involves constituent growth pathways such as expression of pyruvate kinases, aspartyl-asparginyl β-hydroxylases (ASPH or HAAH), mTOR/PI3Ks, insulin and insulin-like growth factor (IGF) [5, 39, 69–76]. The author proposed that the protection of fetus growth must occur in the absence of fully functional mitochondria and limited Yin (tumoricidal, growth-arrest) pathways to avoid necrosis that is dangerous to fetus survival and could lead to abortion [5, 39]. Thus, fetus orderly growth is practically established by anabolic pathways (Fig. 1). The growth-promoting events (Yang) are also required after birth for wound healing pathways and establishment of effective immunity. The overall features of fetus orderly growth include.

   1. a.

      The earliest features in fetus growth are vasculogenesis and organogenesis, events that are completed and functional after birth [5, 39]. In the process of fetus growth, naïve or undifferentiated immune T and B cells are transported from placenta through fetus circulation to develop lymphoid organs. Being in the protective environment of placenta, fetus is not directly exposed to the atmospheric oxygen and is not challenged by the environmental hazards. The hypoxic conditions of placenta provide fetus natural/constituent tolerance. Therefore, there is no need for an effective immune surveillance (Yin and Yang), nor for functional mitochondria.

       
   2. b.

      Majority of the required fetus constituent growth factors, receptors and enzymes (e.g., pyruvate Kinases, mTORs, hormones) also share features of wound healing, tolerance or tumorigenic (Yang) arm of effective immunity after birth.

       
   3. c.

      Features of rapid aging and maturation in prenatal-embryonic tissues and postnatal development of childhood cancers [e.g., neuroblastoma, B-lineage infant acute lymphoblastic leukemia (ALL), mixed lineage leukemia (MLL), myeloid leukemia-Downe syndrome-ML-DS or medulloblastoma] have been reported [5, 39, 73–76]. The rapid childhood aging are associated with increased and progressive genomic mutations and instability and fusion, as evidenced by embryonic hyperplastic cell growth patterns that favor abnormal proliferations of cell survival under hypoxic conditions. Over expression of several genetically identified mutated growth factors (e.g., MYC, PI3K, MAPK, erythropoietin receptor-B cell factor-1-EBCR1 or BCR, Notch1, Notch2, FBXW7 and polymerases) or perhaps low level histamine [e.g., independent from MCs activation (‘leaky’ MCs), or in the absence of functional MCs] that trigger oncogenesis in childhood cancers are characteristics of adult cancers [5, 39, 73–76, 89].

       
    
3. 3.
   After birth and during infancy the most pronounced biological changes and reprogramming relate to newborn’s exposure and adaptation to atmospheric O₂ and completion of organs development. It is proposed that independent life of individual after birth requires the following major biological changes, adaptations and reprogramming (Figs. 1, 2).

   1. a.

      Completion of mitochondria, the double membrane-bound organelles, for establishing the many biological events for production of energy and maintenance of bioenergetics. Among major pathways in mitochondrial development are the establishment of pyruvate-shuttle between cytosol-mitochondria, induction of pyruvate-carrier proteins, development of TCA cycle enzymes and generation of ROS that are byproducts of routine tissue metabolism (wear and tear), metabolism of essential branched amino acids (e.g., leu, isol, val) for biosynthesis of structural proteins and ribosomal recycling activities or perhaps chromatin remodeling-related events. It was proposed that biosynthesis of structural proteins after birth are required for maintaining architectural integrities and boundaries among and between cells and tissues (e.g., cell–cell-contact inhibition, vascular tight junctions, inhibition of epithelial–mesenchymal transition). Fully functional mitochondria have the capability for production of high energy (burst of ATPase hydrolysis) that are required by Yin events (e.g., activation of MCs, DCs, MΦs or T and B lymphocytes) at moment notice to combat foreign elements [5, 7, 39, 70–77, 82–119].

       
   2. b.

      Exposure of newborn to outside environment and independent living demand establishment of fully functional biological circadian rhythms or the catabolic and anabolic responses in tissues. How the effective immunity and signal transduction between and among immune and non-immune pathways are completed after birth are among crucial knowledge gaps that deserve systematic, insightful and integrated understanding. It is likely that completion of many organs (e.g., lungs, heart, brain or gastrointestinal tract) functionality and reprogramming of tissues, cellular and subcellular components [e.g., mitochondria and TCA cycle, mucosal barriers (e.g., aryl hydrocarbon), transcriptional factors for numerous receptors and surface molecules, enzymes, epigenetic modifications, activation or protection of histone proteins and chromatin, recycling pathways in ribosomes, mucosal–flora interactions in gastrointestinal tract, maturation of immune and non-immune systems (biorhythms)] are not fully activated during orderly fetus growth. The molecular/cellular and subcellular adaptation and reprogramming could occur simultaneously after birth and at the interface between host and environment. The fact that during the first few months after birth, newborn limited immunity depends on mother’s immunity supports the above suggestions.

       
   3. c.

      After birth, the complex establishment of effective immunity (fully functional Yin and Yang) and mitochondrial-related cellular functions are likely to take a few months to be completed. It is possible that the majority of components that contribute to catabolic pathways are genetically (innately) present as constituent elements but they are not functional or not expressed until after birth. Potential examples of such constituent pathways are structurally naïve immune and none immune cells, sympathetic and parasympathetic neuronal systems, inactive/inhibited apoptotic factors and components of double membrane in mitochondria. Examples of constituent components that are likely to be functional after birth include immature or naïve lymphocytes, oxidases, pro-inflammatory cytokines, toxins, pyruvate-shuttle, pyruvate carrier proteins, TCA cycle proteins/enzymes, metabolic pathways of essential amino acids (e.g., leu, ileu, val) and biosynthesis of structural proteins for cell–cell contact inhibition and vasculature tight junctions, components of epigenetic modifications, hypo- or hypermethylated genomic materials.

       
    
4. 4.

   It is noteworthy that biological development and reprogramming and responding to environmental conditions continue through puberty for hormonal regulations and reproductive cycles and adulthood; many of which processes decline or change during aging process (senescence).

    
5. 5.

   Continued proton pumping and generation of electricity across the membrane, are crucial for establishing pH gradients and differential acidity among extra-, and intra-cellular membrane components and cytoplasm for numerous routine biological activities [e.g., transport of solutes/osmolytes and nutrients, stimuli-induced expression of danger signals and activation of immune cells, degradation and growth-arrest of defective cells (e.g., cancerous cells), inappropriate synthesis of proteins and mutated DNAs/RNAs, detection and destruction of pathogen’s structural components, immune cell recognition and activation, proliferation, wound healing and growth, lysosomal activities for digestion and recycling of proteins and lipids] as well as, numerous biosynthetic pathways in mitochondria. It is likely that the extent of proton pumping provided through vascular or cellular membrane by ATPases or exchangers (e.g., Na⁺/H⁺ exchanger, Ca²⁺/ATPase) alter, to varying degrees, from the time of fetus growth, after birth, during reproductive period and adulthood, in aging or disease processes (e.g., neurodegenerative and autoimmune complications or carcinogenesis).

    
6. 6.

   Intrinsic or extrinsic components that are recognized as foreign agents (e.g., pathogens, allergen, cancerous and defective cells, useless proteins, lipids, low level carcinogens or pathogen-specific vaccines and ingredients/adjuvants), as well as, aging process, could temporarily or permanently disturb the effective membrane potential or pH gradient (proton pumping) across the extracellular or intracellular membranes that would skew signal transductions and auto-regulatory processes of cellular biorhythms [5, 7, 15, 20, 36–39, 45, 82, 83, 89, 140, 151, 179–185].

    
7. 7.

   Innocuous substances and occasional exposures to a wide range of foreign elements are ordinarily and differentially ignored by tissues that are immune-responsive or immune-privileged (natural immune tolerance). The immune-privileged tissues (e.g., CNS, BBB, avascular cornea, neuroretina, reproductive organs) are highly sensitive toward oxidative damage. These tissues possess special anatomical or molecular features to minimize response to oxidative damage [5, 7, 36–40, 89]. These tissues present higher levels of tolerance compared with the immune-response tissues (e.g., epithelium, endothelium, mucus-secreting goblet cells). However, the levels of immune tolerance are limited in both types of tissues [5, 36, 37]. Persistent tissue stimulation and exposure to potent pathogens or treatment of patients with combination of radiation and chemotherapy that are claimed as ‘targeted’ therapy, ‘personalized’ or precision’ medicine, using potent apoptotic factors, monoclonal antibodies against specific growth factors, are deemed hazardous (biological terrorists) to the immunity. These conditions stimulate a wide range of immune responses causing ‘mild’, ‘moderate’ or ‘severe’ acute or delayed hypersensitivity reactions (immune disorders) that could lead to manifestation of different diseases, organ dysfunction, multiple organ failures (MOFs) or death [5, 7, 35–39, 43, 89].

    
8. 8.

   Oxidative stress and alterations of Yin and Yang properties of effective immunity often differentially facilitate growth promotion (anabolism) or growth arrest (catabolism) in different tissues. The processes are natural/inherent properties of immunity (biorhythms) to resolve inflammation. Potential adverse influence of extensive oxidative stress in immune-responsive tissues includes epithelial–mesenchymal transition (EMT), changes in extra- and intra-cellular membrane matrix [e.g., MMPs, IV collagen biosynthesis, cellular transport activities, aqueous charges (altered H bonds)] further affecting cellular hydrophobicity or hydrophilicity, protein foldings and cellular function. Extensive oxidative stress is the results of exaggerated expression and co-expression of growth and apoptotic factors that result in immunological chaos (immune tsunami) that could damage the tissue integrity at multiple levels of biological, mechanical, physical and bioenergetics. Serious damages in immune-responsive tissues lead to changes in bioenergetics and metabolism and proton pumping in the direction of initiation of tissue growth, neoplasia, precancer-polyps, invasive cancer growth and angiogenesis. In immune-privileged tissues, exaggerated expression of tumoricidal mediators (catabolic or apoptotic factors) causes necrosis and local immune responsiveness in tissues in the direction of neurodegenerative and autoimmune diseases (e.g., Alzheimers, Parkinson’s, multiple sclerosis, atherosclerosis).

    
9. 9.

   Glucose toxicity-induced changes in immune response dynamics could additionally and adversely influence tissues that are insulin-dependent (e.g., muscle, liver, adipocytes) or insulin-independent (e.g., vasculature, BBB, retina, cornea, kidneys) for glucose transport, metabolism or growth as contributing factors in the induction of tolerance and initiation of chronic diseases such as diabetes and cardiovascular complications, hypertension, stroke, as well as increased risk of carcinogenesis [5].

    
10. 10.

    Aging processes (immunosenescence) induce minor or major alterations in immune function [e.g., changes in age-induced cell death (AICD) and damage-induced cell death (DICD)] and enhance the vulnerability of host tissue toward loss of balance between apoptosis and wound healing processes, increased memory B or T cells, clonal expansion and increased hypersensitivity of humoral or cellular responses toward new or old stimuli (e.g., histamine intolerance, autoimmunity), additionally contributing to the mitochondrial and ribosomal dysfunction (mitophagy, autophagy) [5, 7, 35–39, 52, 53, 59–61, 65–68, 83, 88, 89, 109]. Longevity and continuous exposures to microbiota or pathogen-specific vaccines and adjuvants/ingredients (e.g., mercury, aluminum phosphate, aluminum hydroxide, l-histidine, embryo serum) to varying degrees, could induce polarization of immune cells (e.g., MΦs, MCs, DCs, T or B cells) and direct expression of wound healing factors, decoy or pattern recognition receptors [e.g., IL-1dRs, IRAK-M), surface molecules (e.g., CD-11, CD-73), low level circulating histamine (independent from antigen-specific MCs IgE-fcεR aggregation and degranulation)] ([5, 7, 35–39], manuscript in preparation).

     
11. 11.

    As noted above, the growth promoting events often occur under hypoxic conditions and low energy consumption from glycolysis. The conditions are characteristics of Yang pathways during normal fetus growth or wound healing events and neovascularization as well as, cancer growth and angiogenesis. Therefore, induction of tolerance, while a feature of effective immunity (Yang, anabolic or growth-promoting), under oxidative stress represents extended wound healing processes. Continued activities of Yang (tumorigenic) are associated with mitochondrial dysfunction (mitophagy) causing damages to tissue recycling processes and ribosomal activities (autophagy) that are features of skewed immune responses or immune suppression (Figs. 1, 2, 3).

     
12. 12.

    In immune-responsive tissues, enzymes or other factors that modulate senescence negatively regulate differentiation of tumor cells (mitosis) through epithelial–mesenchymal-transition (EMT) often involving polarization, unscheduled or immature synthesis and activation of immune cells, or expression of factors and receptors [e.g., TGFβ-R1, peroxidasin (PXDN), collagen IV], selective membrane catalysis of sulfimine or changes in H bonds with protein structures that create “dual negative feedback loop” and further influence tissue metabolism, fibrosis or cancer.

     
13. 13.

    During EMT, polarized immune cells are capable of expression of a panel of growth-promoting factors and decoy receptor molecules that are immune suppressive and signal for mitochondrial shutdown, inhibiting pro-inflammatory responses, leading to tolerance in favor of tumorigenesis and enhanced activities of cytosolic glycolysis.

     
14. 14.

    Stimuli-induced activation and polarization of immune cells are accompanied by activation of several other metabolic pathways and expression of factors [e.g., carbonic anhydrase 2 (CA2), constituent or induced pyruvate kinases (PKM1, M2), phsosphoenol pyruvate (PEP), PEP carboxy kinase (PEPCK)] with potential different bioenergetics requirements that could influence cellular function. For example, changes in PKM1 and PEP in red blood cells, whose principal energy source is from glycolysis could lead to altered hemoglobin metabolism, anemia, hemophilia, hemolysis, cardiovascular complications, jaundice (bilirubin) and blood-related diseases including cancers (e.g., hepatocellular carcinoma) or severity of Guillian–Barre syndrome ([5], manuscript in preparation);

     

In summary, disturbance of the well orchestrated crosstalk in effective immunity by frequent exposures to immune disruptors and aging processes cause minor or major degrees of retardation in immune response dynamics that could increase the risks of initiation and progression of a wide range of ‘mild’, ‘moderate’ or ‘severe’ immune disorders in susceptible tissues. Low level circulating histamine was proposed as a blueprint in the induction of tolerance leading to diverse immune disorders and alterations of acid–base balance and tissue bioenergetics [5, 39]. Cancer was hypothesized as a ‘severe’ accumulation of delayed hypersensitivity responses in tissues. Oxidative stress-induced skewed biological circadian rhythms and dysfunction of mitochondria (mitophagy), peculiarly provide opportunities for cancerous cells to utilize enhanced activities of cytosolic glycolysis pathways for consumption of energy from Crabtree or Pasteur Effects (induction of 'dark energy'), conditions that are toxic to normal cell survival, but facilitate cancer cells lawless proliferation and increased entropy (see below).

The principal free energy source that is required for all body’s biochemical pathways is the universally known molecule of ATP. In general, the normal function of organ system uses ATP as both an intracellular energy source and an extracellular messenger for energy requiring transmission of signals in CNS or optic nerve or other immune and non-immune cells for exocytosis, formation of Golgi complex, delivery of vesicles, as well as active transport of solutes/osmolytes and nutrients (e.g., glucose, Ca²⁺, ascorbate, myo-inositol), enzymatic processes (e.g., oxidases, kinases, lipases, hydrolases), protein biosynthesis and other physiological pathways, and physical, mechanical or locomotion and architectural integrity of cells/tissues/organs (Figs. 2, 3) [5, 7, 35–39, 78, 82, 83, 89, 101, 139, 140, 142–150, 178–220].

Detailed analyses of related data suggest that cancer oncogenes mutations and growth dysregulation, along with associated enhanced expression of PI3K/Akt and altered balance in c-MYC, HIF or p53 pathways, adversely influence transport and metabolism of glucose, amino acids, ions or water channels (aquaporins) of the surrounding normal tissues that impair extra- and intracellular components (e.g., mitochondria, ER, nucleus). For example, loss or leak of cardiolipin, a key mitochondrial lipid, located in the inner membrane of mitochondria has been demonstrated in damaged mitochondria in cancer environment [5–8, 39, 53–55, 60, 81–84, 102, 143, 144, 152, 166, 174, 178–191]. Cardiolipin is among several other necessary components that are needed for efficient cellular respiration and maintenance of chemiosmosis (aquaporin channel). While details of the role of mitochondria and inflammation in diseases of aging are not well understood, it is likely that acute inflammation initially causes a burst of energy (ATP hydrolysis) in mitochondria of activated immune cells to generate sufficient energy for induction of oxidants and toxins during apoptosis (Yin). In the process, cardiolipin molecules oscillate/move from the inner to outer mitochondrial membrane and signal to facilitate termination of inflammation during wound healing (Yang) events and to preserve regeneration and function of mitochondrial TCA cycle intermediates.

Induction and completion of acute of acute inflammatory responses always require participation of lysosomes and proper recycling of proteins and lipids of phagocytised materials, expression of lysosomal hydrolases and proteases during autophagy. Among numerous biological alterations that occur under oxidative stress and aging, the body’s ‘self-eating’ processes of lysosomes and associated impaired activities in mitochondria or Golgi play crucial roles in homeostasis of immunity or immunosenescence, chronic diseases or cancer [5, 39, 88, 89, 126, 184, 220]. For example, the early events in stimuli-induced activation of MCs via receptor (FcεR) aggregation and degranulation (pharmacological effects) require membrane fusion for exocytosis of granules. The processes involve secretory lysosomal activities and expression of several protein receptor molecules, at different stages of membrane fusion and require ATP hydrolysis and mobilization of Ca²⁺ from intracellular stores. Lysosomal exocytic activities are triggered following an increase in free Ca²⁺ (cation) concentration, acidified by H+/ATPase hydrolysis for fusion and flux at the plasma membrane level [5, 39, 88, 89, 184, 220]. The complex pathways during degradation, clearance and recycling of proteins require energy-dependent biosynthesis of a number of acidic hydrolases or proteases and surface molecule, signaling within lysosomes, endoplasmic reticulum (ER), Golgi apparatus and mitochondria [5, 38, 39, 88, 89, 92, 143, 144, 150, 152, 169, 171, 180–184, 192]. These interdependent catabolic and anabolic activities are universal in living cells and influenced by aging and disease processes. Data using inhibitors of MCs degranulation, antihistamine agents, oxidative phosphorylation or glycolytic pathways (e.g., glucose or pyruvate oxidation), under a wide range of immune dysfunction or carcinogenesis suggest that MCs activation and release of histamine and other preformed or newly synthesized mediators, require activation of lysosomal exocytosis and Ca²⁺ flux from the stored-operated Ca²⁺ channels as part of effector function of MCs. Use of antihistamine or anti-allergic agents (e.g., oxatomide, astemizole, olopatadine) in the in vitro models of allergies or basophilic leukemia cells (RBL-2H3) seem to suppress one or a combination of interdependent MCs responses such as inhibition of AA pathways, cytokines (e.g., IL-4) or Ca²⁺ influx through receptor-operated channels (ROC), phosphorylation of P38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase, pathways that are involved in IL-4 gene expression and tumorigenesis (anabolic pathways?).

Inflammatory conditions such as potent pathogen-induced severe immune reactions (e.g., sepsis, meningitis, pneumonia, anaphylaxis), major trauma as well as, the claimed cancer ‘targeted’ drugs, ‘personalized’ or ‘precision’ medicine (in combination with partial or total body radiation) that are potent apoptotic factors or monoclonal antibodies induce a vicious cycle of immune cell activation (immune tsunami or cytokine storm) [5–8, 39, 43]. Potent immune disruptors require high energy demands not only from local tissue mitochondria, but they also cause induction of systemic or intraperitoneal exaggerated expression of pro-inflammatory cytokines and toxins such as ROS, caspases, oxidases, damage-associated molecular pattern (DAMP), increased C-reactive protein (CRP), altered muscle F-actin filaments and high-mobility group box 1 (HMGB1). Drug-induced accumulation of inflammatory responses often cause serious damages to the function and integrity of tissues and multiple organ failures (MOFs) in muscle, liver, kidney, lung, brain and heart and patient’s death. Therefore, stimuli-induced frequent expression and co-expression of growth-arresting (Yin, tumoricidal) and growth promoting (Yang, tumorigenic) cytokines such as TNF-α, ROS, interleukins (e.g., IL-4, IL-6, IL-8, IL-10, IL-12,IL-18), monocyte chemoattractant protein 1 (MCP-1), CXCR3, neutrophil extracellular traps (NETs), abnormal expression of vasculature components (e.g., P- and E-selectins, ICAM-1, VCAM-1) damage mitochondrial oxidative metabolism and DNA [5–8, 35–43, 169–175, 178–194].

Pattern recognition receptors (PRRs) and surface molecules play crucial roles in signal transduction mechanisms and contribute to all aspects of cells/tissues functions such as visual transduction, bone and lipid biosynthesis, bioenergetics, cellular trafficking and infiltration, differentiation and growth, nuclear/chromosomal or chromatin activities, neuronal pathways, tissue necrosis or growth in immune and non-immune systems for maintenance of health or induction of diseases [5–8, 35–39, 191–202]. Discussion on the time course kinetics and mechanisms of actions of receptor molecules presents a complex molecular universe with unique or shared features that is beyond the scope of this perspective. Suffice to note that defining only the roles that insulin receptors play in health or induction of major diseases such as diabetes and cardiovascular complications or carcinogenesis is a huge topic and yet to be fully understood [5–8, 39, 89, 202–207]. Analyses of a wide range of receptors or pattern recognition molecules (‘biological signatures’) that were defined as constituent or designer receptor molecules [5] are outlined below to better appreciate the crucial roles that these molecules play in maintenance of health or induction of tolerance in carcinogenesis: [5, 39, 126, 174, 202–208, 212–215].

In this section, it is important to first remember that the role of pathogens (viruses, parasites and bacteria) in the induction of acute or chronic inflammatory and infectious diseases or cancer has been documented for over a century [2, 5, 7, 10, 20–24, 39, 40, 56, 122, 123, 128, 155, 169, 216]. Secondly, while in the last century advances in development of antibiotics, better hygiene and modern technologies improved longevity, the aging populations in America (current baby boomers) and the younger generations are not healthier compared with the previous generations at the same age [5, 7, 16, 20, 39, 175, 176, 219, 222–224]. In 1900s, the estimated risk of cancer was one in every 20 individuals (5%). The rate coincided with the normal low risk of cancer as a hereditary disease in the general population. Furthermore, in 1940s (four decades later), before vaccinating the American public with virus-contaminated polio vaccines, 1/16 individuals (approximately 6%) developed cancer (1% increase in cancer incidence over 4 decades), according to available statistics. However, since 1955s/1960s after public (current baby boomers) consumed virus-contaminated polio vaccines (injection or ‘sugar pills’), the cancer incidence and mortality and numerous other neurological and autoimmune diseases sharply increased [5, 7, 16, 39, 79, 89, 175, 176, 219, 222–224]. In 2013 (six decades after initial consumption of contaminate vaccines), the American Association for Cancer Research (AACR) announced that 1/3 (33%) of all women and 1/2 (50%) of all men develop cancer in their life time; that is up to 10 folds increase in the deadly incidence of cancer in the last six decades! [5, 7, 16, 20]. In 1955, decision makers in medical/cancer established ignored the existing data that viruses cause cancer. They also downplayed the serious safety concerns and warnings of a competent and devoted professional at NIH (Bernice Eddy, MD, microbiologist) who discovered that Sabin polio vaccines (prepared in monkeys’ kidneys) were contaminated with live viruses [e.g., simian virus (SV-40) and other filterable viruses]. This American tragedy significantly damaged the health of the last 3 generations in America and to lesser extent, health of other developed nations who consumed the contaminated vaccines [5, 7, 11, 13, 14, 16]. Since the 1955s, the immunity of old and young have been further weakened by heavy publicity to inoculate the individuals with other pathogen-specific vaccines and their unhealthy ingredients and adjuvants (e.g., Swine flu, HPV, hepatitis B or C, measles, meningitis, EBOLA, herpes) or even BCG, whether or not the vaccines are contaminated with live pathogens. The younger generations who are also exposed to a wide range of biological and environmental hazards or low level carcinogens suffer from a wide range of immunological disorders (e.g., allergies, asthma, neurological and autoimmune diseases), conditions that are features of age-associated chronic illnesses [5, 7, 11, 12, 15–25, 74, 78, 89, 155, 202, 223–225, 246].⁶, ⁷, ⁸, ⁹ While the decision makers insist that cigarette smoking is the major factor in the increased risk of cancers, several studies suggest that not all smokers, even heavy smokers develop lung cancers. Reports on none-smokers or never smokers who develop lung cancer suggest that such data overlook other more important contributing factors, particularly infective agents or pathogen-specific vaccines in the development of asthma, tuberculosis, lung and other site-specific cancers [5, 7].¹⁰ American health status ranks last among other healthy nations, despite the fact that USA invests the highest amount of resources for healthcare [7, 16, 20, 219, 222].

In the last six decades significant increased in soft tissue B cell-derived lymphomas (e.g., aggressive or non-aggressive forms of acute leukemia, lymphocytic leukemia, Burkett’s’ lymphoma, myelocytic leukemia, EBV-positive large B cell lymphoma in elderly, germinal center lymphoma or Kaposi sarcoma-associated herpes virus-encoded proteins in lymphoma) as well as solid tumors (e.g., liver, lung, breast, prostate, thyroid, pancreas, colon, ovarian) have been reported [5, 7, 13, 16, 20, 67, 72, 89, 101, 175, 223].

In describing cancer, every few years, cancer decision makers come up with some number and story and state that cancer is ‘too complex’; cancer is too many diseases (100 or 200 diseases). Recently, cancer was claimed to be 1000 diseases to legitimize spending funding on data sharing and aggregates!¹¹ It seems that finding too many pieces of broken molecules in the cancer immune tsunami make decision makers to claim that cancer is 1000 diseases! What and how data sharing would help solving cancer problems is another puzzule! All data that are worthy (or not worthy) are published in various formats. Computational biology and data aggregation have their limits to make sense of biological activities to solve cancer problem or think about the solution. This is just another game to further postpone solving the mystery of cancer that the cancer establishment created six decades ago for maintaining control of a sick and drug-dependent society. Cancer has been made as a myth (100 or 1000 diseases) and money machine that cannot be solved. This reminds us of Phillip Zelikow “The creation and maintenance of public myths exert a powerful influence” [7].¹²

The clinical features, morphologies and pathogenicities of site-specific cancers and how to treat them, are the topics of numerous highly expensive clinical trials and basic science investigations, using modern specific technologies and models of tumors [5, 7, 16, 20, 39, 76, 79, 80, 81, 90, 92–100, 115, 116, 119–134, 182, 226–243]. However, the rates of failure in claimed ‘targeted’ drugs, ‘precision’ or ‘personalized’ medicine for solid tumors are 90% (± 5) according to governmental or private organizations [5, 7, 16, 39, 43, 79, 227–235, 237].¹³, ¹⁴. ¹⁵, ¹⁶ Decision makers in cancer/medical community continue to fraudulently use wrong approaches (‘molecular false flags’, based on false foundations) in cancer research and clinical trials. Endless genetic mutations have been identified in the molecular tsunami of site specific cancers for drug development that at best postpone death-sentence of patients for short durations [5, 7, 20, 45]. In such projects little regards are given to consider the serious compensatory immune mechanisms when such drugs (poisons) cause cancer relapse, cachexia, thromboembolisms, metastasis and multiple organ failures that kill patients (Fig. 4) [5–7, 16, 38, 39, 43].

A great deal of taxpayers funding are directed on detailed mechanisms of structures and substructures or potencies of tens of thousands of evolving microorganisms (viruses, bacteria, parasites) or chemical and biological carcinogens and environmentally hazardous agents, as well as endless mutated genes of growth factors or enzymes in the molecular tsunami of cancer environment. However, little/no efforts have been invested to understand what initiates pathogen-induced alterations of immune response dynamics that lead to immune tolerance, loss of mitochondrial bioenergetics (biological rhythms) and multistep carcinogenesis [5–8, 16, 39, 43, 79].

Unlike the stories that are made up by decision makers in cancer community that cancer is 100 or 1000 diseases which drag solving cancer problem, our accidental discoveries on experimental models of acute and chronic inflammatory responses demonstrated systematic developmental phases of immune dysfunction that resulted in tumorigenesis and angiogenesis. Analyses of related data and extension of these fundamental studies demonstrate that cancer is only ONE disease. Cancer is induced as the results of loss of balance in tumoricidal (Yin) vs tumorigenic (Yang) properties of effective immunity (immune tolerance) or loss of differential bioenergetics to destroy cancerous cells (Fig. 4) [5–7, 20, 39, 43].

Although recent attempts in immunotherapy seem more logical, the same reductionist views to target one or two pathways [e.g., promote dendritic cells program death ligand 1 (PDL-1) or T cell receptors] failed patients [5, 7, 20, 39, 43]. These expensive projects are not properly designed, validated or evaluated by competent and independent scientists.

Policy makers who appropriate funding for cancer research and therapy have no clue on how to assess worthiness of the tremendously expensive projects that are highly promoted by members of the cancer establishment. Such projects are considered ‘molecular false flags’, based on false foundations that destroy the precious lives of patients and drain resources to create huge corporate profits for the establishment (Fig. 4) [5, 7, 16, 20, 39, 40, 79, 95, 96, 175, 176, 226–235, 237–241].

Milton Friedman best described the situation “If the government is put in charge of Sub Sahara, in 5 years there will be a shortage of sands”.¹⁷

Recent data on computational biology or histobiological experiments by West and colleagues [78] or Pitt [208] provide insightful information that cancer entropy and higher temperature are the results of perturbations in mitosis, cell plasticity and aneuploidity in site-specific tissues. As detailed above, dysfunction of mitochondrial bioenergetics parallels loss of effectiveness in Yin (tumoricidal) and Yang (tumorigenic) properties of acute inflammation leading to polarization of immune and non-immune systems in favor of growth promotion pathways. The increased utilization of glucose by Crabtree and/or Pasteur Effects promotes disorderly growth of cancer masses, conditions that are toxic to normal cell survival [5, 55, 79, 92, 139, 185, 188, 189]. Abnormal cell division/proliferation (mitosis), aneuploidity and increased phenotype plasticity in cancer are associated with genomic instability, increased entropy and temperature, compared with surrounding tissue [5, 39, 78, 79, 208]. It is suggested that disturbance in the synchronized biological circadian rhythms of tissues could increase entropy (chaos) and temperature and create ‘dark energy’ for enhanced growth of cancer masses. Induction of ‘dark energy’ and entropy in cancer masses could draw energy from surrounding normal cells (starvation), a potentially important factor in patients’ fatigue. The use of anti-inflammatory agents (e.g., aspirin) for correcting the cancer entropy or perhaps influencing stability of chromosomal function [5, 7, 35–40, 78, 79, 208] is intriguing. Whether expression of intrinsic factors [e.g., constituent or induced receptors (PM1K, PM2K), mTOR/PI3K, IRAK-M, IL-1dRs, CAMs, PGE2, indolamine 2,3-dioxygenase, NFkB] that are anabolic during wound healing or induction of cancer growth act differently from those anti-inflammatory agents (e.g., aspirin) that are reported to improve or lower cancer entropy are among important knowledge gaps that deserve further study. The findings that NO donor molecule (S-nitrosoglutathione-GSNO) induces IRAK-M in LPS-activated monocytes in the presence of TNF-α are also interesting and support our definitions of tumoricidal and tumorigenic arms acute inflammation [5, 7, 35–40, 79, 89, 92, 121, 175, 193–200, 209–211].

These and related reports demonstrate elevated levels of IRAK-M in blood monocytes of patients with chronic inflammatory bowel disease or myeloid leukemia and metastasis or models of influenza also support the wound healing effects of IRAK-M [5, 39, 79, 89, 175, 191–201]. The reports that monocytes co-cultured with tumor cells or supernatant of tumor cells demonstrated significant decrease in expression of apoptotic factors such as TNF-α while increased expression of IRAK-M further support induction of immune suppression in carcinogenesis. Tumor inoculation studies of IRAK-M deficient models showed resistant to melonoma and fibrosarcoma tumor growth suggesting enhanced anti-tumor function of effector lymphocytes in the absence of IRAK-M [5, 196, 198, 213, 214]. Tumor-derived factors such as acidic gangliosides (sialic acid-containing glycosphingolipids), hyaluronan, glycosaminoglycan or C-type lectin that are generated in the extracellular matrix or plasma membrane of different cell types (e.g., chondriocytes, MΦs or DCs) are capable of stimulating expression of IRAK-M that would inhibit danger signals (e.g., TLRs) in monocytes leading to immune suppression.

The following further summarizes insights into the pathways that are involved in induction of tolerance and loss of bioenergetics in chronic diseases or cancer [5, 7, 39, 79, 89, 125–133, 139–154, 168–170, 174, 178–201]:

As noted above, continued proton pumping and generation of electricity are required for numerous routine cellular activities such as transport of ion/solute and metabolites, lysosomal digestion and protein recycling, degradation of pathogens’ structural proteins-lipids-genes for immune recognition, activation and cellular proliferation. Proper functioning of mitochondria as energy power plant is crucial for proton pumping during routine metabolism or fighting against harmful elements (intrinsic and extrinsic). Mitochondrial function depends on presence and function of essential basic building blocks (e.g., pyruvate-shuttle, pyruvate carrier proteins, TCA cycle mediators) to generate energy and maintain crosstalk between cytoplasm and mitochondria, at moment notice for production of high energy and oxidants to fight pathogens (Yin) and also during downtime (Yang) for biosynthesis of intermediates of TCA cycle and preservation of energy.

Loss of synchronized network of Yin and Yang of effective immunity is intimately entangled with energy drain and electronic charges of important proteins for integrity of intra-, extra-cellular membrane structures. It is suggested that the altered (increased) entropy or temperature creates ‘dark energy’ around cancer masses and drain energy from neighboring normal tissues. The differential bioenergetics that are required for maintenance of circadian rhythms in health could be shifted/switched under oxidative stress, during the induction of tolerance and mitochondrial shutdown in exchange for increased glycolysis, enhanced growth of cancer cells and associated increase in entropy and temperature. The shifts in energy distribution and enhanced entropy around cancerous cells (‘dark energy’) could alter energy requiring events of protein electrical charges (e.g., negative charges, H-bonds, hydrophobic/hydrophilic ratios) for proper cellular functions. It is further suggested that impaired electrical charges could adversely influence protein folding that would alter a number of cellular activities (e.g., water, nutrient and ions channels, transporters, structural proteins). Cumulatively, altered energy-requiring biological activities could limit energy utilization in normal neighboring cells, a potential factor in symptom of fatigue observed in cancer patients. Enhanced ‘dark energy’ and entropy create asymmetry that could force the normal cells from oscillating at required energy (loss of biorhythms) for cell survival (Fig. 5) (manuscript in preparation). The extent of progressive complex interactions between growth of tumor cells and host environment could dictate and direct clinical response outcomes. Potential influence of oxidative stress in shifting the ratios of innate/adaptive production of mTORC1/mTORC2 during induction of tolerance and activation of Crabtree and/or Pasteur Effects in creating differential entropy and ‘dark energy’ and disorderly growth of cancer masses are important topics that require systematic studies for effective control of cancer cell growth.

For over six decades the reductionist approaches of decision makers in cancer science popularized the notion that cancer is too many diseases (100, 200 or 1000); cancer is too complex to solve; that they have made ‘extraordinary advances’ and need more money to further progress on the war against cancer. The decision makers now make up other stories that they need to aggregate and share data and require more resources and time to solve cancer mystery. The truth about claims of ‘targeted’ therapy based on identification of endless defective molecular entities is that such mindless and chaotic approaches failed patients at the rate of 90% (±5), costing the loss of millions of precious lives and financial toxicity to the society. All relevant data are available in various medical and basic science disciplines. Integration of quality data on how cancer is initiated has been practically ignored and its systematic investigations are not allowed when competent professionals propose more logical and cost-effective studies to help understand cancer biology and how to prevent or treat it. As author presented in the last couple of decades, analyses of data from her accidental discoveries on experimental models of ocular inflammatory diseases and extension of relevant data on multidisciplinary fields of medical and immunological sciences suggest that cancer is only one disease. Disorderly growth of cancer cells is the results of loss of autonomic and synchronized balance in tumoricidal (Yin) and tumorigenic (Yang) properties of immunity to arrest cancer cells. Loss of differential bioenergetics in Yin (high energy, tumoricidal) and Yang (low energy, tumorigenic) pathways often leads to ‘mild’, ‘moderate’ or ‘severe’ immune disorders or cancer.