Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Biochemistry

Supervisor

Turley, Eva

Affiliation

London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada

Abstract

Basal cell carcinoma (BCC), a keratinocyte cancer, is the most common human neoplasm worldwide. Although rarely metastatic, BCC is associated with high morbidity rates with globally rising incidence rates. Accompanying the increase in newly diagnosed cases, the societal cost for BCC treatment in Canada is also expected to inflate, exceeding over $900 million/year by 2031. Chronic UVB exposure has been identified as the primary carcinogen that causes activating mutations in the hedgehog signaling pathway. However, there are no effective preventative methods against BCC, since meta-analyses report sunscreen application does not reduce BCC in compliant patients. The native high molecular-weight hyaluronan (HMW-HA) was recently reported to confer tumor resistance to carcinogens including UVB in naked mole-rats (Heterocephalus glaber). We therefore prepared phosphatidylethanolamine-linked HMW-HA polymers (HA-PE) for topical application in UVB-induced, BCC susceptible Ptch+/LacZ/Hr-/- mice. HA-PE formed detectable HA coats around epidermal and hair follicle keratinocytes, and prevented histologically-detectable keratinocyte tumor formation, verified by reduced Ptch1 promoter activity indicating oncogenic hedgehog pathway shutdown. Further evidence of signaling inactivation by HA-PE includes strong suppression of the expression of hedgehog pathway gene targets in both the epidermis and hair follicles. Surprisingly, HA-PE did not prevent UVB/ROS-induced DNA damage. However, HA-PE promoted quiescence in the hair follicle bulge and selective apoptosis of K15+ stem cells that are BCC initiating in the Ptch1+/LacZ/Hr-/- susceptibility model. Consistent with this finding, the K15+ stem cells population decreased from hair follicles between 4-26 weeks of treatment. These results provide evidence of a novel mechanism for HA-mediated tumor resistance and implicate HA-PE as a promising BCC prophylactic. This knowledge will also provide a model for probing the interplay between the microenvironment and oncogenic mutations that permit or restrain tumor initiation.

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