Abstract
Ongoing debates, misunderstandings and controversies on the role of inflammation in cancer have been extremely costly for taxpayers and cancer patients for over four decades. A reason for repeated failed clinical trials (90% ± 5 failure rates) is heavy investment on numerous genetic mutations (molecular false-flags) in the chaotic molecular landscape of site-specific cancers which are used for “targeted” therapies or “personalized” medicine. Recently, unresolved/chronic inflammation was defined as loss of balance between two tightly regulated and biologically opposing arms of acute inflammation (“Yin”–“Yang” or immune surveillance). Chronic inflammation could differentially erode architectural integrities in host immune-privileged or immune-responsive tissues as a common denominator in initiation and progression of nearly all age-associated neurodegenerative and autoimmune diseases and/or cancer. Analyses of data on our “accidental” discoveries in 1980s on models of acute and chronic inflammatory diseases in conjunctival-associated lymphoid tissues (CALTs) demonstrated at least three stages of interactions between resident (host) and recruited immune cells: (a), acute phase; activation of mast cells (MCs), IgE Abs, histamine and prostaglandin synthesis; (b), intermediate phase; down-regulation phenomenon, exhausted/degranulated MCs, heavy eosinophils (Eos) infiltrations into epithelia and goblet cells (GCs), tissue hypertrophy and neovascularization; and (c), chronic phase; induction of lymphoid hyperplasia, activated macrophages (Mϕs), increased (irregular size) B and plasma cells, loss of integrity of lymphoid tissue capsular membrane, presence of histiocytes, follicular and germinal center formation, increased ratios of local IgG1/IgG2, epithelial thickening (growth) and/or thinning (necrosis) and angiogenesis. Results are suggestive of first evidence for direct association between inflammation and identifiable phases of immune dysfunction in the direction of tumorigenesis. Activated MFs (TAMs or M2) and Eos that are recruited by tissues (e.g., conjunctiva or perhaps lung airways) whose principal resident immune cells are MCs and lymphocytes are suggested to play crucial synergistic roles in enhancing growth promoting capacities of host toward tumorigenesis. Under oxidative stress, M-CSF may produce signals that are cumulative/synergistic with host mediators (e.g., low levels of histamine), facilitating tumor-directed expression of decoy receptors and immune suppressive factors (e.g., dTNFR, IL-5, IL-10, TGF-β, PGE2). M-CSF, possessing superior sensitivity and specificity, compared with conventional markers (e.g., CA-125, CA-19-9) is potentially a suitable biomarker for cancer diagnosis and technology development. Systematic monitoring of interactions between resident and recruited cells should provide key information not only about early events in loss of immune surveillance, but it would help making informed decisions for balancing the inherent tumoricidal (Yin) and tumorigenic (Yang) properties of immune system and effective preventive and therapeutic approaches and accurate risk assessment toward improvement of public health.
Highlights
During the evolutionary process, inflammation became known as an inherent self-limiting property of the immune system to protect the body against harmful or foreign agents.Historically, in the 19th century Rudolph Virchow noted that the signs of inflammation were four-―redness, and swelling with heat and pain‖
These findings suggest that the signals originated from exhausted or ―leaky‖ mast cells (MCs)
Further analyses of data on the interactions between MCs and T, B or plasma cells in the induction of inflammatory diseases or cancers, demonstrate that many of the isolated time points that are reported in the study outcomes, indirectly support the systematic time-course kinetics of inflammation-induced tumorigenesis and angiogenesis in conjunctival-associated lymphoid tissues (CALTs) that were established over 20 years ago
Summary
Inflammation became known as an inherent self-limiting property of the immune system to protect the body against harmful or foreign agents (stimuli or irritants). The impact of chronic inflammation in the disruption of cellular compartments [e.g., extracellular/intracellular matrix interactions, autophagy and lysosomal or Golgi apparatus (protein anabolic/catabolic balances, clearance and/or accumulation of abnormal protein folding), oxidative damage to mitochondria and altered oxido-redox ratios in changing the energy or metabolic status of host] in the multistep carcinogenesis, angiogenesis and metastasis are important topics in cancer biology that are not fully understood [3,26,39,40,44,46,56] This perspective focuses primarily on overview of the recent definitions and hypotheses on the role of acute and chronic inflammation and the function of immune surveillance in health and diseases, with emphasis in cancer. Outlines of an NCI-invention on standardizing cancer biomarkers criteria (data elements) as a foundation of a database using M-CSF as a potentially suitable marker for cancer diagnosis, validation and technology development will be presented
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