INFLAMMATION AND IMMUNE RESPONSE IN THE CANCER MICROENVIRONMENT

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In the nineteenth century Rudolf Virchow observed that cancer grows in conditions of chronic inflammation and described the presence of leukocytes in tumor tissues (1,2). Immune system cells and their mediators are present within the cancer microenvironments of all types of malignant tumors (3). The development of the tumor is accompanied by chronic inflammation. Such inflammation induces carcinogenesis in some situations while in others it exerts an anti-cancer effect (3). Cancer-related inflammation is predominantly linked with non-specific innate immune response (4). The acquired, specific immune response also participates in the cancer-associated inflammation; on animal models it was observed that B lymphocytes also participated in carcinogenesis and in the anti-tumor immune response. In patients with cancer, specific anti-tumor antibodies (antibodies against tumor antigens) were observed (5,6). Moreover, it has been observed that the cancer microenvironment can restrict the activity of tumor-infiltrating lymphocytes (7). Both types of immune-response participate in inducing carcinogenesis and in inhibiting tumor growth. It has further been observed that congenital and acquired immune deficits are related to an increased incidence of malignant neoplasms, and this indicates that the immune system plays an important role in fighting cancer (8,9). Additionally, the relationship between cancer and the immune system seems to constitute a dynamic process. Initially, the immune system controls and eliminates the pre-neoplastic lesions and early malignant tumors (10). As the tumor grows, however, the cancer cells, following the exposure to the anti-tumor immune response, become resistant to the immune attack and acquire a new phenotype able to manipulate and alter immune system cell activity through the secretion of cytokines and chemokines (11). At this point, tumor-associated macrophages and B lymphocytes might interact, promoting tumor growth through the secretion of factors that activate cancer microenvironment remodeling, including angiogenesis.

There are two types of inflammation that occur in the human body; one is acute inflammation; which is short-lived and carries positive therapeutic consequences. The other is chronic inflammation which lasts for a long time and has destructive consequences that support cancer development and initiate metastases. Chronic inflammation is therefore a risk factor for developing many types of malignant neoplasms (e.g., cigarette smoking in cases of lung cancer, Helicobacter pylori infection and chronic gastritis in cases of gastric cancer, HPV virus infection and chronic cervicitis in cases of cervical cancer, HPV virus infection and chronic mucositis in cases of oral and pharyngeal cancer, HBV and HCV infections and chronic hepatitis in cases of hepatic cancer, etc.) (12). 

The development of chronic inflammation is associated with hypoxia. Hypoxia is commonly found in solid tumors of various types and is connected with a decreased response to anti-cancer treatment, malignant progression, local invasion, and distant metastases. Hypoxia-inducible factor (HIF-1) is a transcription factor commonly induced by inflammatory mediators, including cytokines, hormones (insulin and insulin like growth factor 1 and 2 (IGF-1, IGF-2), and vasoactive peptides (angiotensin II) (13,14). Cytokines, such as IL-b and TNF-a, induce HIF-1a activity in the hepatocellular cancer cell line. Additionally, HIF-1 stimulates the expression of genes controlling inflammation, including erythropoietin, VEGF, VEGF-receptor, iNOS (inducible NO synthase), COX-2, glycolytic enzymes, and others in order to induce oxidative stress (15). HIF-1 is a main regulator of the adaptation of cells to oxidative stress, controlling the alteration from aerobic to anaerobic metabolism, inducing the glycolytic phenotype in cancer cells and enabling the access to energy and survival (15). The activation of HIF-1 in cancer cells induces various types of mechanisms that activate angiogenesis, glycolysis, secretion of growth factors (PDGF- platelet derived growth factor  and EGF- epidermal growth factor) (platelet derived growth factor, epidermal growth factor), TGF-β (transforming growth factor), IGF-2, and proteins that participate in tumor invasion. Moreover, hypoxia inhibits the expression of adhesion proteins enabling the detachment of single cells and their migration(16,17). Macrophages typically accumulate in the hypoxemic region of a tumor. This microenvironment induces the adaptation of cells to hypoxemia and the change in their phenotype; for instance, the experimental removal of HIF-1 from these cells increased their cytotoxicity. Hypoxia selectively induces the expression of CXCR4 receptor (chemokine receptor CXC), influencing the migration of the cancer cells (18).

Chronic inflammation also induces the reactive oxygen and nitrogen species, thus generating oxidative stress in the cancer microenvironment. Oxidative stress is a condition of disturbed tissue homeostasis between the activity of reactive oxygen and nitrogen species and the processes of detoxification and tissue repair. Reactive oxygen species develop in all cells during the physiological process of respiration and react with the most important structures and molecules in the cell changing their biological function. The disturbance of homeostasis between the reactive oxygen species and the mechanisms of cell repair and detoxification lead to tissue destruction and the development of a malignant tumor and its progression (19).