The Role of Cytokines and Chemokines in the Development of Basal Cell Carcinoma

The immune system plays an important role in surveillance against tumor development, and it is widely known that cancer cells protect themselves against the host's anti-tumor immune defense. Cancer cells have several means of evading the antitumor immunity, one of which is the production of immune modulators such as cytokines and chemokines. These factors can either promote or block immune responses. Many of these molecules are used by cancer cells to promote tumor progression including cell proliferation, cell migration, matrix remodeling, immune suppression and angiogenesis. On the other hand, some molecules are involved in immunotherapeutics for the purpose of enhancing and modifying antitumor immune responses.


Introduction
The immune system plays an important role in surveillance against tumor development, and it is widely known that cancer cells protect themselves against the host's anti-tumor immune defense. Cancer cells have several means of evading the antitumor immunity, one of which is the production of immune modulators such as cytokines and chemokines. These factors can either promote or block immune responses. Many of these molecules are used by cancer cells to promote tumor progression including cell proliferation, cell migration, matrix remodeling, immune suppression and angiogenesis. On the other hand, some molecules are involved in immunotherapeutics for the purpose of enhancing and modifying antitumor immune responses.
In basal cell carcinoma (BCC), several cytokines and chemokines and their receptors are associated with the development of this cutaneous cancer. There are varying degrees of inflammation in BCC. The majority of peritumor inflammatory cells are lymphocytes and most are T cells (1). It has been proposed that the tumor microenvironment of BCC is generally Th2 dominant. T regulatory cells and immature dendritic cells mediated by Th2 cytokines cause immunosuppression and decreased immunity to BCC (2). Tumor-associated macrophages (TAM), which are polarized to M2 type, are associated with tumor invasion and angiogenesis in BCC (3). In this chapter, we focus on cytokines and chemokines which may influence and enhance these immunosuppressive networks.

IL-6
Interleukin-6 (IL-6) is a pro-inflammatory cytokine, which can induce tumor progression by manipulating immune responses in the tumor microenvironment. IL-6 is directly related to epidermal hyperproliferation in psoriasis (4). There are many experimental evidences that IL-6 is associated with BCC. Overexpression of IL-6 in BCC cell lines increases anti-apoptotic activity and tumorigenic potency (5). The phosphotidyl inositol 3-kinase (PI3K)/Akt signal pathway is involved in such anti-apoptosis (6). On the other hand, IL-6 induces bFGFdependent angiogenesis in BCC cell line via JAK/STAT3 and PI3k/Akt pathways (7). IL-6 is also involved in CXCL-12 (SDF-1)-enhanced angiogenesis via activating ERK1/2 and NF-κB (8). IL-6 expression is associated with a significant increase of IL-8 (CXCL8) expression in www.intechopen.com BCC (9, 10), one of which functions is tumor angiogenesis. The expression of these two cytokines shows a significant positive correlation (10).
A single nucleotide polymorphism (SNP) in the promoter regions of IL-6 gene (IL6) is associated with the risk of BCC. The promoter region of IL6 contains several SNPs, including -634G>C, -597G>A and -174G>C. It has been reported that IL6 -597 G>A is significantly associated with BCC risk (11). However, others reported that there was no difference for genotype distributions of SNPs in the promoter region of IL6 between the BCC cases and controls, while linkage disequilibrium was observed between the -174 and -597 alleles in the IL6 (12).

IL-10
Interleukin-10 (IL-10) is a major immunosuppressive cytokine that plays a critical regulatory role in several areas of the immune system. It contributes to immunosuppression in the tumor microenvironment and may render it permissive for infiltration of cancer cells. IL-10 is upregulated in both melanoma (13)(14)(15) and non-melanoma skin cancer including BCC (2,16,17). The presence of IL-10 in BCC is associated with the lack of expression of HLA-DR, ICAM-1, CD40 and CD80 and the inconsistent expression of HLA-ABC in BCC (17). BCC is regarded as an indolent (slow growing) cancer with limited metastatic potential. While IL-10 expression by melanoma cells correlates with melanoma progression and development of metastatic competence (18), there is no clear correlation between IL-10 expression and tumor invasiveness of BCC. IL-10 can be detected by both aggressive BCC and nonaggressive BCC such as superficial BCC. However, there are discrepant results regarding IL-10 expression in superficial BCC. Urosevic et al. found that superficial BCC cells were uniformly negative for IL-10 expression at baseline and showed little change after imiquimod treatment (19). www.intechopen.com SNP in the promoter regions of IL-10 gene (IL10) is associated with the risk of BCC. IL10 -1082G>A is detected in BCC (12), and this polymorphism, as well as tumor necrosis factor-alpha (TNF-α) gene TNF -308G>A polymorphism, is more prevalent in aggressive BCC (20). However, others reported that there was no significant association between BCC and IL10 -1082 (11).

CXCL9, CXCL10, CXCL11 and CXCR3
CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC) are chemokines that are induced by interferon during inflammatory responses. These chemokines bind to a common receptor, CXCR3. They can promote chemotaxis of activated T cells and NK cells through binding to CXCR3. The most recent attention has been given to the role of these chemokines in tumorigenesis of BCC. It has been reported that CXCL9, CXCL10, CXCL11, and their receptor CXCR3 are significantly upregulated in BCC. CXCR3, CXCL10, and CXCL11, but not CXCL9, colocalize with keratin 17, which is a BCC keratinocyte marker. Exposure of BCC cells to CXCL11 in vitro enhances keratinocyte cell proliferation (23). CXCL9, CXCL10 and CXCL11 promote expression of functional indoleamine 2,3-dioxygenase (IDO), which also colocalizes with keratin 17 (24). Thus, CXCR3 and its ligands may be important in tumorigenesis of BCC.

IL-8 (CXCL8)
Interleukin-8 (IL-8, CXCL8) is a chemokine produced by inflammatory cells and other cell types. This chemokine is one of the major mediators of the inflammatory response. It functions as a chemoattractant, but is also known as an angiogenic factor. IL-8 is associated with tumor angiogenesis in many solid tumors. It has been reported IL-8 is highly expressed in BCC (25). As described earlier in this chapter, IL-8 expression is associated with a significant increase of IL-6 expression in BCC (9, 10), and is positively correlated with IL-6 expression (10). However, the detailed mechanisms of IL-8 involved in the development of BCC are not fully understood.

CCL27
CCL27 is a chemokine that functions as a chemoattractant by interacting with its receptor, CCR10. This chemokine regulates T cell homing under homeostatic and inflammatory www.intechopen.com conditions, and plays a role in T cell-mediated inflammation of the skin. In BCC, the downregulating of CCL27 expression is associated with tumor immune escape. A significant decrease in CCL27 expression is also observed in squamous cell carcinoma and actinic keratosis. These skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways (26).

IFN-γ
Interferon-gamma (IFN-γ) is a cytokine that is critical for immune responses against cancer. IFN-γ binding to the receptor activates the JAK-STAT pathway. In BCC, The expression of IFN-γ receptor is significantly decreased on the cancer cells compared with the overlying epidermis. The absence or paucity of IFN-γ receptor and the absence of intercellular adhesion molecule-1 (ICAM-1) may explain the lack of tumor-infiltrating cells and the lack of an active cell-mediated immune response in BCC (27).
On the other hand, Th1 cytokines including IFN-γ play a role in spontaneously regressing BCC. Some cases of BCC may show spontaneous regression in the absence of therapy. Such spontaneous regression is mediated by activated CD4+ T cells, and IFN-γ is elevated in actively regressing BCC (28). There is a significantly increased number of CD4+ T cells infiltrating regressing tumors, and the expression of IL-2 receptor, which is an early activation marker for T cells is also increased (29). Abundant CD8+ T cells and interferon signal transduction is associated with partial host antitumor response (2).
Imiquimod has been shown to be efficacious as a topical treatment for BCC. Imiquimod is a Toll-like receptor 7 (TLR7) agonist, which induces interferon and other cytokines through the immune system and stimulates innate and adaptive cell-mediated immunity. Clinical studies have demonstrated clinical and histological clearance of superficial BCC after treatment with imiquimod 5% cream (30)(31)(32). Imiquimod treatment is associated with the early appearance of lymphocytes and macrophages. This early response tends to be a mixed cellular response of CD4 cells, activated dendritic cells and macrophages, with later infiltration by CD8 T cells (33). Application of imiquimod induces a cascade of Th1 cytokines including IFN-α, TNF-α, IL-1α, IL-12, and IFN-γ, with profound effects on innate and adaptive immunity and on immunologic memory and antigen presentation. IFN-γ is produced by CD4 and CD8 T cells. IFN-γ is associated with the enhanced expression of ICAM-1, promoting the influx of immune cells. Imiquimod treatment also induces a massive increase in macrophage peritumoral and intratumoral infiltration (19). Thus, the TLR7agonist plays an important role in inducing a lymphocytic infiltrate by promoting specific Th1 cellular immune response capable of eliminating cancer cells (34).

FasL (CD95L) and Fas (CD95)
Fas ligand (FasL, CD95L) belongs to the tumor necrosis factor (TNF) family. FasL binds to its receptor, Fas (CD95), and induces apoptosis. Apoptosis via FasL/Fas pathway plays an important role in the regulation of the immune system. FasL expressed by cacncer cells induces apoptosis of infiltrating lymphocytes and they can evade immune surveillance, contributing to cancer progression. BCC has been reported to lack Fas expression (19,35), while they commonly retain the expression of FasL (36). In normal skin, Fas is expressed by keratinocytes in the basal layer. Fas expression is up-regulated in chronically sun-damaged skin. Actinic keratosis does not express Fas. Squamous cell carcinoma focally expresses Fas at the sites of contact with lymphocytes (35).
It has been suggested that BCC can evade host immune surveillance by expressing FasL (37). However, different results were obtained for the FasL expression in BCC (19,38,39), and the issue of FasL expression in BCC is still debatable. After imiquimod treatment, the infiltrating cells demonstrate an increase in Fas/FasL expression, while Fas expression by BCC cells remains unaffected and FasL expression demonstrates either an increase or a decrease in different cases (19). After intralesional IFN-α treatment, BCC cells become Fas-positive with signs of tumor regression as a result of tumor cell apoptosis (36). Thus, Fas/FasL pathway may be associated with tumor regression by such treatments.

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Conclusions
There is much more work to be done in order to adequately characterize the clinical significance of cytokines, chemokines and related molecules in BCC. Studies thus far show that the factors described in this chapter play an integral role in BCC development and immunosuppression. A better understanding of these interactions may facilitate development of more potent immune-based treatment for BCC.