Roles for Aberrant CXCR3 Signaling in Basal Cell Carcinoma

Abstract

Cellular growth and proliferation are normally regulated by extracellular stimulation through receptor-ligand interactions at the cell surface. Depending on the cell type, a cell can either express a cell-surface receptor, secrete its cognate ligand, or in some cases both. Cells bearing a specific cell-surface receptor can respond to its cognate ligand secreted by a neighboring cell (paracrine signaling) or a more distant cell (endocrine signaling). If a cell expresses a receptor as well as its ligand, a positive feedback loop is generated (autocrine signaling). Through orchestration of the multitude of heterotypic and homotypic signaling elements, homeostasis of normal cellular proliferation is maintained.Cancer cells are frequently characterized by aberrant, deregulated receptor signaling, either through prevalent (dominant) autocrine signaling loops or nonautocrine singaling loops, which can drive tumor cell proliferation, angiogenesis, motility, migration, and invasion as well as metastasis.1,2 This can involve a number of cell-surface receptor tyrosine kinases (RTKs), several types of extracellular matrix receptors (such as integrins), and different kinds of G protein-coupled cell surface receptors (such as chemokine receptors). In the current issue of The American Journal of Pathology, Lo and colleagues describe a role for CXCR3/ligands through autocrine and paracrine-signaling loop in proliferation and tumorigenesis of basal cell carcinoma (BCC). 3BCC develops from the basal layer of the epidermis or from the pilosebaceous adnexa, accounting for 75% of all cases of non-melanoma skin cancer in the United States. Unlike melanoma, BCC is rarely metastatic and is typically characterized by low mortality and highly successful surgical excision. However, BCC commonly causes cosmetic disfigurement because it usually affects sun-exposed skin of the head, neck, and face. BCC has a very high incidence rate and is the most common type of skin cancer. More than one-fifth of the population of the United States develops BCC. Moreover, the incidence frequency is rising by 2% to 19% per year. 3 Aberrant CXCR3 Signaling in Proliferation and Survival of BCCCXCR3 is a chemokine receptor belonging to the G protein-coupled cell surface receptor family. CXCR3 can bind with high affinity to the interferon-␥-induced chemokines CXCL9, CXCL10, and CXCL11. 4 Moreover, CXCR3 exists as three alternatively-spliced forms: CXCR3-A, CXCR3-B, and CXCR3-alt. 4,5 CXCR3-A is the predominant form in activated T cells, natural killer cells, dendritic cells, and B cells, 4 whereas CXCR3-B has been detected on human microvascular endothelial cells. CXCR3-alt is characterized by a truncated C terminus with loss of the intact second and third extracellular loop, and coexpresses with CXCR3-A. Recent studies have found that CXCR3 is expressed in several types of tumors, including melanoma, breast cancer, and colon cancer.6 -8 The work of Lo et al now provides new evidence linking CXCR3 to BCC. 3Based on microarray data and qRT-PCR, Lo and colleagues...

Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12

“…Therefore, CXCR3-mediated homing of immune cells as well as its strong angiostatic response classically represents a potential target for tumor therapy. However, emerging evidence now suggests that the CXCR3 signaling network can positively influence tumor cell growth, survival, and migration [70,77–83]. It is noteworthy that determination of the role of CXCR3 in tumorigenesis is complicated by the fact that many cells in the tumor microenvironment potentially express CXCR3 splice variants and their ligands.…”

“…It is noteworthy that determination of the role of CXCR3 in tumorigenesis is complicated by the fact that many cells in the tumor microenvironment potentially express CXCR3 splice variants and their ligands. CXCR3 and its ligand CXCL10 are expressed in many human glioma cell lines, and CXCL10 treatment activates MAPK, stimulating cell proliferation [83]. Several breast cancer cell lines, such as, MCF-7, and MDA-MB-435 harbor CXCR3/ligand autocrine loops that influence cell proliferation [70].…”

“…Furthermore, CXCL10/CXCR3 signaling has been reported to promote invasion-related properties as well as metastasis in human colorectal carcinoma cells [81]. Recent findings by Lo et al suggest that aberrant CXCR3/ligand signaling promotes proliferative receptor isotypes [82,83]. Indeed, it has been reported that forced overexpression of CXCR3-A induces enhanced survival of human microvascular endothelial cells, whereas CXCR3-B overexpression dramatically reduces DNA synthesis and stimulates apoptosis in these cells [15].…”