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.
Highlights
Non-resolving inflammation, which is frequently related to chronic infection, chronic pollution, metabolic syndrome, ageing, and physical inactivity, is a prerequisite for the development of most cancers
Cancer is a complex disease characterized by significant heterogenicity
Significant differences exist in the outcomes of cancer patients with the same histological classification, which highlights the heterogeneity of molecular types among the same histological cancers
Summary
Non-resolving inflammation, which is frequently related to chronic infection, chronic pollution, metabolic syndrome, ageing, and physical inactivity, is a prerequisite for the development of most cancers. Since the association between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) was determined in 1975, hepatitis C virus (HCV), food contaminants, tobacco smoking, and environmental toxins are identified to cause HCC via inducing chronic inflammation [1, 2]. Most of these studies provide segmental and fragmental evidence, while only a few present a theoretical hypothesis that deciphers the fundamental laws involved in inflammation-induced carcinogenesis. In 2013, some mutation patterns in the cancer genome were linked with a group of specific mutagenic factors, such as age, inflammation, smoke, and ultraviolet radiation. The theory of Cancer EvoDev enriches the understanding of the inherent law of carcinogenesis and promotes the development of specific prophylaxis and targeted therapy
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