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Direct Effects of VEGF on Keratinocyte Function During Skin Carcinogenesis and Wound Healing

Johnson, Kelly Elizabeth
http://rave.ohiolink.edu/etdc/view?acc_num=osu1376662806

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Epidermal keratinocytes, the predominant cell type in the epidermis, play a crucial role in two processes in the skin: skin carcinogenesis and cutaneous wound healing. Non-melanoma skin cancer (NMSC) is the most prevalent type of cancer, with 3.5 million cases diagnosed each year in the US. These cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are primarily caused by exposure to ultraviolet (UV) light from the sun. Wound healing is a key process in many aspects of medicine. In addition to injury and trauma, millions of surgeries are performed each year. Chronic wounds, which do not heal properly, can lead to hospitalizations, amputations, death and affect 6.5 million patients every year at an estimated cost of $12 billion dollars. Therefore, it is critical to understand how keratinocytes function in both of these processes. Angiogenesis, the growth and expansion of new blood vessels, occurs during both NMSC and wound healing. Vascular endothelial growth factor (VEGF) promotes angiogenesis by causing the proliferation, migration and survival of vascular endothelial cells. VEGF is produced by the skin in response to UV and promotes NMSC indirectly through the induction of angiogenesis. Additionally, wounds contain high levels of VEGF. VEGF receptor 1 (VEGFR-1) has now been identified on epidermal keratinocytes, suggesting that VEGF can affect keratinocytes directly. Therefore, we hypothesize that VEGF may influence wound healing and skin carcinogenesis by directly affecting keratinocytes via VEGFR-1. To test this, a unique conditional knockout mouse with VEGFR-1-deficient keratinocytes (cKO) was developed and was utilized in acute and chronic UV-induced skin carcinogenesis studies as well as wound healing studies. Immunohistochemical analysis of human and murine NMSC samples revealed that VEGFR-1 is highly expressed in skin tumors. Furthermore, in vitro studies indicated that keratinocyte VEGF and VEGFR-1 expression is regulated by UV light. To examine the direct effects of VEGF on keratinocytes in skin carcinogenesis, cKO and control mice were exposed to acute and long term UV radiation. Keratinocytes in the epidermis of cKO mice showed a significant increase in apoptosis 24 hours following a single UV exposure compared to controls, suggesting that VEGF may function as a survival factor in UV-irradiated keratinocytes. Additionally, macrophage recruitment to UV damaged skin was reduced in cKO mice. Long term UV-induced skin carcinogenesis studies are ongoing and suggest that cKO mice are resistant to UV-induced skin carcinogenesis compared to controls. To examine the direct role of VEGF on keratinocytes in wound repair, excisional wounds were inflicted on cKO and control mice. A significant delay in reepithelialization was observed in cKO mice compared to controls 5 days after wounding. These results suggest that VEGF can stimulate epidermal keratinocytes directly to promote reepithelialization. Similar to acute UV studies, a significant decrease in the number of macrophages was observed in wounds from cKO mice compared to controls, indicating that VEGF can affect keratinocyte-mediated recruitment of macrophages. Overall, these studies have uncovered novel roles of VEGF in two important processes in the skin: wound healing and skin carcinogenesis.
Traci Wilgus, PhD (Advisor)
Tatiana Oberyszyn, PhD (Committee Member)
Gregory Lesinski, PhD (Committee Member)
Amanda Toland, PhD (Committee Member)
128 p.
Biomedical Research
skin; keratinocyte; VEGF; skin cancer; wound healing

Recommended Citations

Citations

  • Johnson, K. E. (2013). Direct Effects of VEGF on Keratinocyte Function During Skin Carcinogenesis and Wound Healing [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376662806

    APA Style (7th edition)

  • Johnson, Kelly. Direct Effects of VEGF on Keratinocyte Function During Skin Carcinogenesis and Wound Healing. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1376662806.

    MLA Style (8th edition)

  • Johnson, Kelly. "Direct Effects of VEGF on Keratinocyte Function During Skin Carcinogenesis and Wound Healing." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376662806

    Chicago Manual of Style (17th edition)

osu1376662806
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© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.