Editorial [Hot Topic: Inflammation as Target for Pharmaceutical Intervention in Cancer (Executive Editors: R.M. Schiffelers and K.E. de Visser)]

Inflammation and cancer are closely associated. Crosstalk between both disease processes starts at the level of carcinogenesis but is also implicated in tumor growth, progression and metastasis [1-4]. Although the inflammatory response can play a role in tumor suppression by stimulating an antitumor immune response, support of tumor development is more dominant. This makes a variety of anti-inflammatory pharmaceuticals interesting candidates for therapeutic intervention in cancer [5-8]. At the same time, it is not completely understood how cancer-associated inflammation is regulated and how pro- and anti inflammatory pathways can optimally be manipulated to maximize anticancer effects. Improving insight into the cells and mediators that play a role in the crosstalk between inflammation and cancer is the aim of this issue. In some cancer types, inflammation is present before a malignant change occurs. This so-called tumor-initiating inflammatory response can be caused by infectious agents, chronic irritation or chemical damage [9-11]. For example persistent bacterial infections, like Helicobacter pylori, predispose for gastric cancer, and Crohn's disease is associated with colon cancer. In addition, chronic inflammation caused by reflux esophagitis or asbestosis is clearly linked with esophageal adenocarcinoma and mesothelioma respectively. In many other types of cancer, however, inflammation is not the initiating trigger. Instead, oncogenic changes in these cancers frequently elicit an inflammatory tumor microenvironment that facilitates further tumor development and progression, i.e. cancer-associated inflammation [12]. For example, human breast cancer is frequently characterized by abundant presence of infiltrating immune cells, whereas breast cancer has not been directly linked with infectious conditions. Thus, also malignancies not directly linked to bacterial or viral infections are often associated with inflammation. Inflammation may develop into a chronic process when the cause for the inflammatory response is not eliminated or when the normal mechanisms that terminate the process fail. As a result, the balance between pro-and anti-inflammatory mediators is not restored and inflammation continues. It is believed that carcinogenesis is promoted by chronic inflammation as a result of local activation of stromal cells that release a variety of pro-inflammatory molecules that activate endothelium and attract circulatory inflammatory cells [13, 14]. The ensuing inflammatory reaction can promote tumor progression via direct and indirect mechanisms. For example, macrophages may be a source of reactive oxygen and nitrogen species which can cause direct damage to DNA by forming single or double-stranded breaks and stimulate recombination [15, 16]. Central enzyme in the damage by free radicals is cyclooxygenase 2 (COX-2) [17]. Consequently, drugs that inhibit this enzyme have been under investigation for their prophylactic activity. Apart from damage by reactive molecules, inflammatory cells also release cytokines that favor cell proliferation and survival, thereby increasing the number of cells that are at risk for mutations [18]. At the same time, angiogenic factors are released that stimulate new blood vessel growth [19, 20]. All in all, these pathways create a microenvironment that is susceptible to cancer development. It is important to recognize that the relation between proinflammatory stimuli and cancer is more subtle than suggested by the previous examples. There are also cases where infiltration of immune cells protects against cancer and examples of anti-inflammatory therapies that promote tumorigenesis [21, 22]. It is particularly the balance between anti and pro-inflammatory stimuli which needs to be repaired, requiring a pharmaceutical strategy that reflects this dual approach.