Introduction of inflammation
Inflammation is a defense response to harmful stimuli (such as pathogens, damaged cells, or irritants) in living tissue with a vascular system, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged, and initiate tissue repair. Inflammation has five classical signs, which are heat, pain, redness, swelling, and loss of function. Inflammation is a generic response, and therefore it is regarded as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, chronic inflammation may result in a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is normally closely regulated by the body. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of biochemical events and the inflammatory response propagates and matures, involving the local vascular system, the immune system, and numerous cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
In 1800, Galenus pioneered the hypothesis of inflammation and tumor correlation, suggesting that tumors can occur in tissues of inflammation and injury. In 1863, Vicrhow confirmed the hypothesis of Galenus and observed that lymphatic reticulocyte infiltration was observed before tumor development. Later, it also raised the hypothesis that chronic inflammation induces tumors, which have attracted the attention of researchers. With the deepening of research, more and more evidence indicates that there is an inseparable relationship between inflammation and tumors, and this relationship has certain significance for the prevention and treatment of tumors.
The Relationship between Cancer and Inflammation
Studies have demonstrated that chronic inflammation predisposes individuals to various types of cancer. It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. There are many triggers of chronic inflammation that increase the likelihood of developing cancer. Such triggers include microbial infections (for example, infection with Helicobacter pylori is associated with gastric cancer and gastric mucosal lymphoma), autoimmune diseases (for example, inflammatory bowel disease is associated with colon cancer) and inflammatory conditions of unknown origin (for example, prostatitis is associated with prostate cancer). Accordingly, treatment with non-steroidal anti-inflammatory agents decreases the incidence of, and the mortality that results from, several tumor types.
In recent years, it is generally believed that about 80% of tumor tissues except tumor cells are mainly composed of stromal cells and inflammatory cells. When the body is damaged or invaded by pathogens, the immune system is activated and induces a large number of inflammatory cells, and then the inflammatory will secrete a variety of cytokines (such as chemokines, adhesion molecules, etc.) locally form a microenvironment that trigger tumor. Under normal circumstances, tissue regeneration promotes cell proliferation in the wound caused by tissue damage, and when regeneration is completed, cell proliferation is reduced and inflammation is weakened. When the factors inducing inflammation persist, the inflammatory response develops into a chronic inflammation dominated by monocyte infiltration. Inflammatory cells form a new microenvironment by secreting various cytokines such as inflammatory factors, chemokines, and adhesion molecules to the extracellular matrix. The cells will continue to proliferate in this tumor microenvironment, which in turn will form tumor associated inflammation; and tumor associated inflammation can in turn promote the continuous renewal and proliferation of tumor cells, and induce tumor development and metastasis. Inflammation in the tumor microenvironment has a variety of promoting effects on tumors, including: 1 promoting the proliferation and development of tumor cells; 2 promoting new angiogenesis and metabolism, increasing vascular permeability; 3 destroying adaptive immune response; 4 changing the reaction of hormones and chemotherapeutic drugs for tumors; 5 inducing the production of matrix metalloproteinases to promote the infiltration and metastasis of tumor cells. Therefore, inflammation plays a critical role in tumor growth and metastasis. Inflammatory cells induced by injury and pathogen invasion are important components of tumor stroma. It includes tumor-associated macrophages (TAM), dendritic cells, lymphocytes and mast cells. Among them, TAM is the largest number of inflammatory cells in the tumor stroma, accounting for 30% to 50% of the total number of inflammatory cells. TAM plays a key role in tumor formation, development and metastasis. Activated macrophages have been considered to have anti-tumor effects in the past, such as antigen presenting cells (APC), can induce anti-tumor responses. However, recent studies have shown that TAM is different in phenotype and function with macrophages in other tissues of the body. It inhibits immune function by reducing the expression of proteins such as MHC II, and induces angiogenesis and the expression of tumor growth media such as vascular endothelial growth factor (VEGF). Another study found that epidermal growth factor (EGF) and colony-stimulating factor (CSF-1) produced by TAM cooperate with EGF receptor and CSF-1 receptor expressed by tumor cells to promote tumor metastasis.
From the previous introduction, we can know that the inflammatory cells in the tumor microenvironment secrete a variety of cytokines, chemokines, and cytotoxic mediators such as TNF-α, ROS, CSF-1, and matrix metalloproteinases. They can induce early cell carcinogenesis, and promote the infiltration and metastasis of tumor cells. For example, growth factors and cytokines produced by inflammatory cells can activate downstream transcription factors such as NF-κB, AP-1, STAT, SMAD, etc., and induce the expression of anti-apoptotic gene and activation of cyclins, thereby promoting tumor cell survival and proliferation. Activated inflammatory cells release a large amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which cause oxidative stress in the body, leading to DNA damage in proliferating cells. Mutations in the cells gradually accumulate, leading to oncogene activation and inactivation of tumor suppressor genes. Continuous stimulation of chronic inflammation also causes the body to develop immune tolerance, losing the ability to recognize and clear mutant cells. The accumulation of the above numerous factors ultimately lead to the occurrence of tumors.
Anti-inflammatory Drugs in Cancer Treatment
Studying the interaction between tumor and inflammation is not only clarify the pathogenesis of tumors, but also provide new ideas for the prevention and treatment of tumors. Anti-inflammatory drugs, such as COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), etc., can be used as chemopreventive drugs to reduce the incidence of tumors. NSAIDs mainly include salicylic acid, pyrazolone and acetic acid and so on. To varying degrees, they inhibit tumor growth in preclinical and clinical trials. The advantage of drugs targeting the inflammatory microenvironment in tumor therapy is that it does not cause mutations of drug-resistant in the normal genomes of inflammatory cells, and less frequent gastrointestinal complications. Despite this, anti-inflammatory drugs have certain limitations in the treatment and prevention of tumors. In most cases, anti-inflammatory treatment cannot kill tumor cells, and it is necessary to combine the conventional treatment of killing tumor cells. Moreover, NSAIDs are not specific and cause side effects during long-term treatment, which brings certain difficulties for tumor treatment.