CXCR3 signaling effects on the development and immunoregulation of basal cell carcinoma and related neoplasias

• Main Author: Lo, Blanche Ka Ki
• Language: English
• Published: University of British Columbia 2012
• Online Access: http://hdl.handle.net/2429/41381

Increasing evidence has revealed that the chemokines CXCL9, CXCL10, CXCL11, and their common receptor CXCR3, are associated with tumorigenesis. Basal cell carcinoma (BCC) is a type of non-melanoma skin cancer (NMSC) and is the most common malignancy encountered. In this thesis, I hypothesized that CXCR3 signaling provides a novel marker for the growth and putative immune privilege of BCC as well as for the development of other NMSCs, such as cutaneous squamous cell carcinoma (SCC). Increased expression of chemokines CXCL10, 11 and CXCR3 was detected in cytokeratin 17 (K17)⁺ BCC cells. CXCR3/CXCL11 signaling was found to support the proliferation and survival of primary K17⁺ BCC cells derived from patient samples. Also, human BCC cells migrated in response to CXCL11 peptide in a dose-dependent manner. These findings suggest that CXCR3 signaling may be an important autocrine and/or paracrine mediator in BCC tumorigenesis. To further support the role of CXCR3 signaling in NMSC, expression of CXCR3 and its ligands were found to be significantly upregulated in cutaneous SCC and its precancerous forms (greatest in SCC). Neutralization of CXCR3 bioactivity demonstrated that CXCR3/CXCL11 signaling supported the proliferation and survival of HaCaT neoplastic keratinocyte cell cultures. Moreover, HaCaT cells transmigrated in response to CXCL11 in a dose-dependent manner. Taken together, CXCR3/ligand signaling may be important for neoplastic keratinocyte proliferation and migration, especially in cutaneous SCCs. Studies suggest BCCs exhibit immune privilege (IP), though the mechanisms have not been defined. Upregulation of a panel of IP-related genes, including IDO1, IDO2, CD200 and CD200R was identified in BCC tissues with IDO2 being expressed at the highest level. Notably, the expression and enzymatic activity of indoleamine 2,3-dioxygenase (IDO) was increased in human K17⁺ BCC cells in vitro with increased CXCR3/CXCL11 signaling. These results suggest that functional IDO is synthesized by human BCCs and may confer immunoprotection to the tumor cells, which may be enhanced by CXCR3 signaling. This thesis has revealed novel roles of CXCR3 signaling as part of the mechanism of BCC and related neoplasia development. The data may improve our understanding of NMSC pathogenesis as well as enable invention and/or modification of treatment modalities.