Recent data on computational biology or histobiological experiments by West and colleagues  or Pitt  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, 35,36,37,38,39,40, 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, 35,36,37,38,39,40, 79, 89, 92, 121, 175, 193,194,195,196,197,198,199,200, 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, 191,192,193,194,195,196,197,198,199,200,201]. 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, 139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154, 168,169,170, 174, 178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201]:
Role of mTOR/PI3K, decoy receptors and IRAK-M in induction of tolerance in carcinogenesis
The mammalian or mechanistic target of rapamycin (mTOR) is a serine/threonine kinase (also known as DRAK2) and member of the phosphoinositide 3-kinase (PI3K)-family of kinases (PIKK). The super-family of mTOR/PIKK pathways is directly and indirectly involved in regulation of a wide range of tissue activities; metabolism, proliferation, differentiation, membrane lipid biosynthesis, growth and development, autophagy and immune cell responses [5, 39, 79, 178, 201, 260,261,262,263,264,265,266,267]. The two major constitutive (innate, embryonic) and induced complexes of mTORC1 and mTORC2 seem to contribute to tissue function and longevity. Molecular defects or immature biosynthesis of any members of these complex pathways have been involved in initiation of a wide range of metabolic disorders (e.g., diabetes and cardiovascular complications), infectious diseases (e.g., tuberculosis, COPD), neurological problems (e.g., autism, epilepsy, Alzheimer’s, Parkinson’s), site-specific cancers (e.g., breast, bladder, peritoneal metastasis) and other age-associated chronic illnesses. The pathways involving immune cell tolerance (immune suppression) are implicated in clinical trials such as allograft acceptance in transplanted host tissues in models of skin allograft, bone marrow or stem cell transplantation for chemotherapy-treated soft tissue sarcoma [5, 39, 79,80,81,82,83, 89,90,91,92,93,94,95,96,97,98,99,100, 116, 129,130,131,132,133, 245, 247,248,249]. However, mechanism of actions or usefulness of embryonic stem cell transfer for cancer therapy are debatable and yet to be understood or confirmed.
In general, growth hormones (GHs) modulate glucose uptake in insulin-dependent tissues (e.g., muscle, adipocytes). The growth hormones promoting signals involve IGF-1-independent pathways and mTORC1 complex to activate Rag-GTPase family of enzymes and lipid metabolism. Low levels of plasma lipid were suggested to promote insulin sensitivity and signaling of PI3K/AKT/mTOR [5, 7, 39, 40, 79, 193, 201,202,203,204,205,206,207]. Furthermore, longevity seems to be associated with altered activities of membrane-enzyme complex PI3k-AKT-mTOR pathways.
Integration of relevant data shows that PI3K/AKT is a common signaling pathway for activation of oncogenes through hypoxia, a major stimulus for expression of VEGF. Several selective inhibitors of PI3Ks (e.g., LY294002, ZSTK474, idelalisib, rituximab, SAR405, VPS34-IN1) with different effects on genetic alterations are being examined for control of inflammation in COPD, other respiratory diseases or autoimmune and neurodegenerative diseases, or for treating several cancers (e.g., CLL, non-hodgkin’s lymphoma, follicular lymphoma, breast cancer, osteoclast survival) [5, 43, 217, 218, 233, 241,242,243,244,245, 249]. The diverse roles of these inhibitors have primarily been shown in HIF-1α and HIF-2α and endogenous VEGF response to hypoxia and suggest that the inhibitors of different classes of PI3Ks inhibit and induce synergistically the common oncogenes, while basal hypoxia-inducible VEGF was partially inhibited.
Tolerance in gastrointestinal (GI) tract
About 70% of body’s complex immune system is in the crucial position of digestive/gastrointestinal track. The immune composition in gut-associated lymphoid tissues (GALTs) shares some features with other tissues that are responsible for confronting and combating external harmful agents. Examples of such tissues are the skin, respiratory lung-associated lymphoid tissues (LALTs) or conjunctival-associated lymphoid tissues (CALTs) that are targets for early sensitization and tolerance (induction of Th2 phenotypes) against perennial allergens (e.g., dust mites, cat epithelium or certain environmental components) [5, 7, 8, 31, 36–41, 64, 69, 72, 79, 80, 83, 101, 106, 137, 156]. The special features of immunity and tolerization in GALTs (e.g., increased numbers of plasma cells lining of the gut epithelium for production of IgA and IgE, TLRs, enzymes and hormones) are required for maintenance of homeostasis of gut microbiota (intrinsic foreign elements) and ingested foods. In the gastrointestinal tract, tolerance against various GI bacteria (GI flora) is likely due to several regulatory/inhibitory complex molecules with IRAK-M and related immune suppressive pathways (e.g., dILRs, TNFRs or surface molecules receptors) [5,6,7,8, 36,37,38,39,40,41, 64, 69, 72, 79, 142]. Interestingly, expression of regulatory receptor molecules (IRAK-M) in epithelial lung tissue of asthmatic patients suggests induction of immune suppression also involves expression of adenosine receptors (A2A) and surface molecules of CD4+ T lymphocytes that could signal for mitochondrial shutdown to prevent damage to the tissue [5, 79, 142].
An overall review of numerous reports on mechanisms of tolerance or ‘intolerance’ (e.g., histamine intolerance) suggests that the initial immunity and tolerance occur during embryonic-fetus growth in lymphatic-vascular tissues, thymus, respiratory and gastrointestinal tracts under the low oxygen tension for protection of orderly growth. Fetus immunological system, studied in cord blood, has Th2 phenotypes; thus bases for protection of ‘graft-versus-host’ reactions or ‘tolerization’ [5, 69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85, 202]. After birth and during adulthood and aging process, tolerance develops toward commensal microbiota and certain endotoxins (e.g., LPS) or infective agents. Review of related data suggests that oxidative stress and aging (senescence) lead to development of tolerance (e.g., expression of IRAK-M, IL-1dRs, TNFdRs, PGE2) and/or ‘intolerance’ (e.g., increased allergic responses to innocuous or self-components) as contributing factors in skewed response network of effective immunity and induction of autoimmune or neurodegenerative diseases or cancer [5, 7, 36,37,38,39,40, 67, 75, 157,158,159,160,161,162,163,164,165,166, 218]. Numerous defects in cellular and membrane functions, biological components and receptor molecules [e.g., histamine, hormones (e.g., insulin-resistance, resistin), enzymes (e.g., kinases, diamine oxidase, HNMT), mutated genes, hypo-, or hypermethylated epigenetic modifications, polarized innate or adaptive immune cells and over-, or under-expressed inflammatory factors (e.g., M-CSF, IL-1dR, TNF) myeloid-derived suppressor cells, cells, impaired DNA repair pathways, autophagy or mitophagy] may be considered factors for induction of tolerance or intolerance in the development of ‘mild’, ‘moderate’ (intermediate) or ‘severe’ immune disorders including cancers [5, 39, 58, 59, 69, 84, 88, 108, 109, 116, 126, 129, 153, 154, 156,157,158, 164, 201,202,203, 215, 229, 231, 249, 250]. In the experimental models of acute and chronic ocular inflammatory diseases that we established in CALTs [5, 29, 31], whether the chronic stimulation of tissues that led to tumorigenesis and angiogenesis involved induction of tolerance by decoy receptors or IRAK-M during polarization of immune cells (e.g., TAM) are among important knowledge gaps that remain to be studied.
Nearly all age-associated chronic diseases such as metabolic disorders [e.g., type 2 diabetes mellitus (adult onset, T2-DM), cardiovascular complications, stroke] or neurodegenerative and autoimmune diseases are features of altered immunity involving polarization of immune cells and skewed expression of pro-inflammatory mediators, receptors or surface molecules (e.g., IL-6, TNFRs, M-CSF, CD11, CD34). In the case of diabetes mellitus, insulin-insensitivity are reported to increase the risk of several cancers, while it reduces risks of other cancers [5,6,7, 36, 202,203,204,205,206,207,207]. Whether accessibility of specific tissues to the released apoptotic factors cause reduced risk of specific cancers in diabetes are among questions that await future investigations. Related reports show that PI3K/AKT pathways are involved in glucose transporter-1 (GLUT-1) activities [5, 53,54,55, 81, 127, 175, 187,188,189,190]. Other kinases such as glycogen synthase kinases (GSK-3α, GSK-3β) play dual roles (activation and deactivation) in diverse biological activities, for growth-promoting and differentiation or growth-arresting (apoptosis), metabolism and neuronal function, embryonic development or carcinogenesis. The mechanisms of action of GSK-3 are additional examples of biorhythms or Yin–Yang of immunity, playing as tumor suppressor or tumor promoter and involving pathways of PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK [5, 39, 98,99,100,101, 127, 128].
Use of diabetes drugs such as sulfonylurea and metformin seems directly influence ATP-sensitive k+ channels for enhancing membrane depolarization of pancreatic beta cells and stimulating exocytosis of insulin granules [5, 54, 89, 180, 202–207, 253]. The suggested mechanisms and clinical values or efficacy and safety of such agents in diabetes are controversial. In general, these agents seem to support that cellular exocytosis is energy-dependent processes in immune and non-immune cells/tissues. Diabetes (hyperglycemia) and related metabolic disorders are considered immune disorders that initially influence the metabolic pathways for glucose transport and metabolism. Impaired glucose transport and utilization in these metabolic disorders, are associated with induction of Il-6, T cell activation and generation of memory or regulatory cells (Treg), pathways that require additional sources of energy from fatty acid oxidation for glycolysis and glutaminolysis, as alternative or compensatory mechanisms for impaired mitochondrial oxidative phosphorylation. Under these conditions, cell surface ligation and activation of membrane phospholipases (e.g., PLC) or perhaps metabolism of arachidonic acid (AA) and activation of cyclooxygenase/lipooxygenase pathways, as well as, release of low level histamine, would allow mobilization of intracellular Ca2+ under impaired ER and T cell-dependent plasma membrane influx of Ca+2 and other ion channels [e.g., calcium release-activated channels (CRAC), H+/Ca2+/K+ or Na+ exchangers] [5, 39, 47, 81, 140,141,142,143, 179, 180, 184, 203, 239, 253]. Hyperglycemia of diabetes could differentially interfere with transport and metabolism of nutrients, amino acids or solutes/osmolytes, (e.g., vitamin C, pyridoxine/pyridoxal phosphate, myo-inositol, leu, ala, gly) in tissues that are insulin-dependent or insulin-independent for glucose transport and metabolism and could change extra-, intracellular structures (e.g., protein/lipid glycosylation, basement membrane collagen synthesis) [5, 7,