Chronic Inflammation in Skin Malignancies

Introduction Inflammation is characterized by the infiltration of plasma and leukocytes to tissues that undergo disrupted homeostasis [1]. The causes of inflammation range from pathogenic infection, tissue injury to tissue stress and malfunction [1]. Inflammatory process is critical for normal physiological responses against infection and tissue damage, and promotes the clearance of invading pathogens and the regeneration of damaged host tissues. Inflammation is also important for maintaining homeostasis and monitoring stress signals that arise with tissue malfunction [1, 2]. However, the process of inflammation may bring detrimental side effects to the host, depending on the nature, duration and magnitude of inflammatory response elicited during infections and diseases. Examples of such side effects include allergies, autoimmune diseases, and life-threatening immune responses induced by viral and bacterial infection in humans [3–6]. Inflammation is also recognized as one important player in the entire course of carcinogenesis [7, 8]. Different myeloid and lymphoid cells infiltrate into tumor stroma and exert divergent, even contradicting effects on the growth, progression and metastatic spread of cancers [7, 8]. In this review we will summarize our current understanding on the nature of immune-cancer interaction, focusing primarily on skin malignancies. There are four major types of skin malignancies: basal cell carcinoma, squamous cell carcinoma, melanoma and nonepithelial skin cancers [9]. Among them, melanoma is the most deadly form of skin cancer and contributes to 10,000 deaths per year in the United States [10]. About 132,000 new cases of melanoma arise globally each year, leading to vast majority of skin cancer-related deaths [11]. Risk factors of skin carcinogenesis include chronic cutaneous inflammation, viral infection, ultraviolet radiation (UVR), and other inflammation-inducing agents and traumas [12, 13]. UVR promotes the transformation of skin cells by damaging cellular DNA. The major DNA damage products generated through UVR exposure are cyclobutane pyrimidine dimers and pyrimidine [4–6] pyrimidone [14]. Damaged DNA is typically repaired by the nucleotide excision repair pathway, whereas defective repair of the damaged DNA results in cancer predisposition [15]. UVR also serves as a link between skin cancer and inflammation, as its exposure alters immunological functions in the skin [16]. For example, exposure to UV light results in the upregulation of COX-2 protein in keratinocytes and increased production of prostaglandin E2 (PGE2), which leads to cutaneous tissue inflammation [17]. UV exposure also adversely affects skin immune system by suppressing the function of antigen-presenting cells, inducing the expression of immune-suppressive cytokines and modulating contact and delayed-type hypersensitivity reactions [18]. The suppression on adaptive immunity by UVR REVIEW