non - melanoma skin cancer ( nmsc ) is the most commonly diagnosed type of cancer . over 2 million patients are treated for these cancers each year in the usa alone , resulting in nearly $ 1.5 billion total direct costs annually . unlike many other types of cancer , the rates of nmsc continue to rise , indicating the need to increase research and identify new , more effective therapies . nmscs are primarily caused by chronic exposure to ultraviolet ( uv ) light from the sun , although chemical exposure , chronic wounds , and viral infection can be risk factors as well [ 1 , 4 ] . there are two main types of nmsc : basal cell carcinoma ( bcc ) and squamous cell carcinoma ( scc ) . and although these tumors are rarely metastatic , patients have a high risk of developing additional tumors within 5 years of diagnosis . sccs make up roughly 16% of all skin cancers   and are typically more aggressive than bccs , posing a higher risk for metastasis and leading to approximately 2,500 deaths annually . the risk of developing skin cancer is very high in the general population , as one in five people will develop skin cancer in their lifetimes ; however , certain populations such as transplant patients are at an even greater risk [ 7 , 8 ] . angiogenesis , the growth and expansion of the vasculature , is an important process in the growth and metastasis of many cancers , including nmsc . vascular endothelial growth factor ( vegf ) is a potent pro - angiogenic factor and several studies have established a critical role for vegf in skin cancer . vegf transgenic and conditional knockout mice subjected to skin carcinogenesis protocols , such as the well - established two - stage chemical carcinogenesis model [ 11 , 12 ] , have demonstrated that vegf promotes skin carcinogenesis through the induction of angiogenesis [ 13 , 14 ] . additionally , several recent studies have now uncovered direct effects of vegf on keratinocytes and skin tumor cells . these studies have suggested that in addition to enhancing angiogenesis , vegf may promote skin carcinogenesis by altering the survival , proliferation , or stemness of keratinocytes and tumor cells in an autocrine manner [ 1518 ] . furthermore , immune cells such as macrophages can respond to directly vegf [ 19 , 20 ] and recent studies indicate that vegf recruits macrophages to skin tumors . this review will highlight our current knowledge of the angiogenic and newly discovered non - angiogenic activities of vegf that contribute to non - melanoma skin cancer , which are summarized in figure 1 . angiogenesis is a key process in the growth and spread of many cancers , including skin cancer . typically , angiogenesis is required for tumors to grow beyond 1 - 2  mm in size and offers a route for tumor cells to disseminate to secondary sites . because of this , tumor angiogenesis has been an attractive and promising therapeutic target . to induce angiogenesis , tumor cells and cells within the tumor microenvironment must alter the balance of pro- and anti - angiogenic factors , favoring an  angiogenic switch  . when pro - angiogenic signals outweigh anti - angiogenic signals , it allows for capillary sprouting through the proliferation and migration of endothelial cells . eventually , the newly formed vessels supply the tumor with oxygen and nutrients required for continued growth . many pro - angiogenic factors have been identified and characterized , including basic fibroblast growth factor ( bfgf ) , interleukin-8 ( il-8 ) , platelet - derived growth factor ( pdgf ) , placental growth factor ( plgf ) , transforming growth factor- ( tgf- ) , and vascular endothelial growth factor ( vegf ) . vegf - a ( referred to as vegf throughout this article ) is a 45  kda heterodimeric heparin - binding protein belonging to the family of vascular endothelial growth factors . at least 5 splice variants of vegf have been identified in humans , including vegf121 , vegf145 , vegf165 , vegf189 , and vegf206 [ 25 , 26 ] . vegf binds to three known receptors : vegf receptor-1 ( vegfr-1 ) , vegf receptor-2 ( vegfr-2 ) , and neuropilin-1 ( nrp-1 ) [ 2729 ] . vegfr-1 and vegfr-2 are tyrosine kinase receptors characterized by a seven immunoglobulin - like extracellular domain , a single transmembrane region , and an intracellular tyrosine kinase domain . nrp-1 is a single pass transmembrane protein that binds semaphorins as well as some isoforms of vegf . nrp-1 functions as a coreceptor for the vegfrs , enhancing their activity ; however , nrp-1 may be able to signal independently of vegfrs in response to vegf , particularly in tumor cells . vegf is well characterized as a potent inducer of angiogenesis and functions as a survival factor and mitogen for endothelial cells [ 34 , 35 ] . in general , vegf is expressed at low levels by epidermal keratinocytes and is upregulated during many pathological processes such as wound healing , psoriasis , and skin carcinogenesis [ 3638 ] . vegf production by keratinocytes can be induced by many stimuli including hypoxia , transforming growth factor- , keratinocyte growth factor , uv radiation , and the tumor promoter 12-o - tetradecanoylphorbol-13 acetate ( tpa ) , while vegf production is inhibited by the transcription factor fra-1 [ 3946 ] . strong evidence has demonstrated that vegf plays an important role in skin carcinogenesis . in human skin , vegf is expressed at low levels in normal epidermis , with more differentiated epidermal cell layers generally expressing more vegf than less differentiated epidermal cells [ 4749 ] . several studies have confirmed that vegf levels are elevated in tumor cells compared to normal epidermal cells using immunohistochemistry and in situ hybridization techniques [ 4749 ] . tumor cells of human bccs tend to show weak vegf expression [ 47 , 48 , 50 ] with positive tumor cells predominantly localized to the invading margin . in contrast , sccs , which are typically more aggressive than bccs , display more intense and widespread staining , with higher expression in tumor cells localized near infiltrating inflammatory cells [ 47 , 50 ] . furthermore vessel density is also high in sccs , especially in late - stage sccs , compared to normal skin , actinic keratoses , bccs , or early - stage sccs [ 48 , 49 ] . in mice , acute exposure to tumor promoters such as tpa or uv light causes upregulation of vegf and induction of angiogenesis in the skin [ 38 , 5153 ] . vegf expression patterns in murine models of skin carcinogenesis mimic what is observed in human tumors . a functional role for vegf in skin tumor angiogenesis has been demonstrated through the use of transgenic and conditional knockout mice . both k6-vegf and k14-vegf transgenic mice which overexpress vegf in epidermal keratinocytes show elevated blood vessel density in the skin and in skin tumors compared to controls [ 13 , 14 , 54 ] . vegf transgenic mice are also more susceptible to two - step chemical carcinogenesis [ 13 , 14 ] . in addition to containing a larger number of blood and lymphatic vessels both within and surrounding skin tumors , k14-vegf mice develop chemically - induced tumors more rapidly and also have a dramatically higher incidence of metastasis than controls . conversely , conditional k14-vegf knockout mice have reduced blood vessel density in tumors and are much more resistant to chemical carcinogenesis in addition to inducing papillomas and sccs , uv exposure increases vegf levels and neovascularization in the skin [ 52 , 53 , 56 ] . inhibition of vegf in the skin with compounds such as epigallocatechin-3-gallate ( ecgc ) and myricetin leads to a decrease in angiogenesis and a reduction in the number of uv - induced skin tumors [ 5658 ] . evidence from orthotopic skin tumor models has also shown a link between vegf , angiogenesis , and tumor development [ 59 , 60 ] . scc-13 cells transfected with vegf form invasive , highly vascularized tumors when injected subcutaneously or intradermally into nude mice . similarly , tumors arising from a malignant hacat cell line , which produce large amounts of vegf , initiate angiogenesis more quickly and to a larger degree than hacat cell lines which form benign tumors . furthermore , treatment with vegfr-2 blocking antibodies reduces endothelial cell proliferation and vessel density in tumors derived from the malignant cell lines to levels comparable to benign cell lines . in addition , vegfr-2 antibody treatments reduce tumor growth and invasiveness , suggesting that vegf promotes tumor growth by inducing angiogenesis . taken together , the evidence from human tumors and animal models demonstrate that vegf is critical for the development , growth , and spread of skin tumors , and these findings have been largely attributed to the promotion of angiogenesis by vegf . although dermal cells such as macrophages , fibroblasts , and other cell types are known to produce vegf , epidermal keratinocytes are believed to be the principle source of vegf in the skin [ 36 , 45 , 55 , 61 ] . in addition to stimulating angiogenesis through its actions on endothelial cells , recent evidence has demonstrated that vegf can have direct effects on keratinocytes . several groups have now identified vegf receptors on keratinocytes , suggesting the possibility of autocrine vegf signaling . currently , there is some disparity in the exact receptor profiles that have been described . some studies have identified vegfr-1 , vegfr-2 , and nrp-1 on keratinocytes [ 18 , 62 ] ; however , others do not detect vegfr-2 [ 1517 ] . our lab has shown that vegf induces the proliferation of cultured primary human keratinocytes through vegfr-1   and this finding has been confirmed by others in murine keratinocytes . additionally , vegfr-1 is expressed in mouse and human skin tumor cells and in squamous cell carcinoma cell lines , suggesting that vegf could affect tumor cells directly . autocrine functions for vegf in keratinocytes and skin tumor cells have also been suggested by recent functional studies performed in vivo [ 16 , 17 ] . lichtenberger et al . utilized various conditional knockout mice to uncover a direct role of vegf in skin carcinogenesis using the k5-sos model , in which the ras activator son of sevenless is constitutively activated in the epidermis . in this model , k5-sos mice develop skin tumors spontaneously and tumors can be induced rapidly by wounding the skin [ 17 , 64 ] . keratinocytes were shown to overexpress vegf in the k5-sos model , and k5-specific deletion of vegf reduced tumor development in these mice . loss of keratinocyte vegf also lead to a decrease in vessel density and a decrease in tumor cell proliferation , and vegf was able to enhance keratinocyte proliferation in vitro . because vegfr-1 expression was detected in murine and human skin cells , epidermal vegfr-1 was deleted in k5-sos mice . a reduction in papilloma development and tumor cell proliferation was observed in conditional vegfr-1 knockout mice compared to controls , while blood vessel density was unaffected . together , these studies establish a direct role for vegf in skin carcinogenesis , wherein vegf stimulates tumor cell proliferation through vegfr-1 . interestingly , an autocrine loop between vegf and nrp-1 has also been discovered . using the two - stage chemical skin carcinogenesis model , beck et al . cd34 tumor cells were shown to express higher levels of vegf than cd34 tumor cells or normal keratinocytes . epidermal overexpression of vegf increased the pool of cd34 cscs , while inhibition of vegfr-2 activity with dc101 or conditional deletion of vegf in the epidermis reduced the csc pool and diminished csc proliferation , in addition to reducing the number of established tumors . conditional deletion of nrp-1 completely blocked tumor formation in the chemical carcinogenesis model compared to control mice which all developed papillomas . in addition , when conditional nrp-1 knockout mice were crossed with vegf transgenic mice , vegf was unable to promote tumor growth , even though efficient tumor angiogenesis was still observed . overall , the results suggest that epithelial cell - derived vegf regulates cscs in an autocrine manner .   in addition to affecting epithelial cell proliferation and stemness , a recent study suggested that vegf may also directly affect keratinocyte survival in vitro.zhu et al . showed that exposure to uv light , the primary causative agent of nmsc , increased the expression of vegfr-1 , vegfr-2 , and nrp-1 in primary normal human keratinocytes in vitro and in human epidermis in vivo . interestingly , vegf was able to protect keratinocytes from apoptosis following exposure to moderate ( 300  j / m ) but not high ( 700  j / m ) doses of uv . activation of vegfr-2 , but not vegfr-1 , was responsible for the observed increase in keratinocyte survival . although these results will need to be confirmed in vivo , they suggest that vegf could function as a survival factor for keratinocytes following uv exposure . in addition to endothelial cells , some immune cells also express vegf receptors , supporting the idea that vegf can have paracrine effects that are not related to its pro - angiogenic activity . for example , monocytes and macrophages express vegfr-1 and vegf has been shown to be a chemoattractant for these cells [ 19 , 20 ] . tumor - associated macrophages , particularly m2 macrophages , are believed to promote tumor growth and invasion and well as angiogenesis [ 65 , 66 ] . recently , linde et al . used an orthotopic tumor model in which control or vegf - transfected hacat cells were injected subcutaneously into mice . vegf - driven hacat tumors were larger , more vascular , more invasive , and had higher numbers of infiltrating m2 macrophages compared to control tumors . depletion of macrophages reversed the effects of vegf overexpression , indicating that vegf was influencing tumor development by affecting macrophages . in this model , vegf stimulated the recruitment of macrophages to the tumors but was not sufficient to polarize them . these studies indicate that in addition to promoting angiogenesis , vegf can influence skin carcinogenesis by recruiting immune cells . strong evidence has established a critical role for vegf in the development of non - melanoma skin cancers . vegf is produced by the skin in response to tumor - promoting agents such as tpa and uv light , and skin tumors are known to express elevated levels of vegf . in mouse studies , vegf increases angiogenesis and tumor growth , while the loss of vegf inhibits skin carcinogenesis . to date , these findings have been primarily attributed to the potent pro - angiogenic effects of vegf . however , the presence of vegf receptors on non - endothelial cell types , such as keratinocytes and macrophages , has expanded our view of the potential functions of vegf . indeed , new evidence suggests that vegf can impact skin carcinogenesis by directly affecting keratinocytes , tumor cells , and immune cells . while there is no doubt that vegf plays an important role in skin carcinogenesis , more work is required to characterize the various mechanisms by which vegf contributes to this process and to understand the relative importance of each of these pathways . further studies will have to be carried out to determine whether these newly described alternative functions of vegf can be targeted to treat nmsc .