Cancer Evo–Dev: A Theory of Inflammation-Induced Oncogenesis

Abstract

Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil–DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of “mutation-selection-adaptation”. Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.

Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients

“…Telomeres are repetitive DNA sequences located at the ends of the chromosomes and intact telomeres are essential for genomic integrity and the maintenance of the cellular proliferative potential ( 36 ). Inflammation and telomere shortening are hallmarks of the early stages of chronic liver disease and play a pivotal role in the early onset of neoplasia ( 37 , 38 ). In a previous study, we found that low telomere length is associated with a higher risk of tumor onset ( 17 ).…”

The Modulation of Adipokines, Adipomyokines, and Sleep Disorders on Carcinogenesis

“…Some of the peptides excreted by adipocytes and/or myocytes have pro-inflammatory proprieties (leptin, resistin, chemerin, vaspin, RBP-4 [ 202 ]) or anti-inflammatory proprieties (adiponectin, omentin, vaspin and irisin [ 202 , 214 ]). Cancer development and evolution may depend on chronic inflammation [ 215 ]; thus, an imbalance in the pro-inflammatory and anti-inflammatory effects of adipokines/adipomyokines may also be one of the factors influencing cancer development.…”

The coevolution between APOBEC3 and retrotransposons in primates

“…This activity leaves signatures along the double helix that are clearly traceable to A3 family members and are found predominantly in cancer cells [73]. As the structural details of A3s interaction with nucleic acids are being unveiled [74], the ambivalent effect of these protective enzymes is also being highlighted, as an elevated expression of APOBEC3s may provide a reason for aberrant cancer-inducing somatic mutations in human papilloma virus (HPV) [75][76][77] and HBV [78] infections, as well as an extensive range of other tumor types [73,79,80], even in the context of inflammation [81].…”