Evidence for a non-stochastic two-field hypothesis for persistent skin cancer risk

Abstract

With recurring carcinogen exposures, individual tumors develop in a field of genetic mutations through a stepwise process of clonal expansion and evolution. Once established, this “cancer field” persists in the absence of continued carcinogen exposures, resulting in a sustained risk for cancer development. Using a bioimaging approach, we previously demonstrated that a dermal premalignant field characterized by inflammatory angiogenesis persists following the cessation of ultraviolet light exposures and accurately predicts future overlying epidermal tumor formation. Following ultraviolet light treatments, others have observed that patches of p53 immunopositive cells persist stochastically throughout the epidermal stem cell population. However, these studies were done by random biopsies, introducing sampling bias. We now show that, rather than being randomly distributed, p53+ epidermal cells are enriched only in areas overlying this multi-focal dermal field. Moreover, we also show that the dermal field is characterized by a senescent phenotype. We propose that persistence of the overlying epithelial cancerization field in the absence of exogenous carcinogens or promoters requires a two-field composite consisting of a dermal senescent field driving the persistence of the overlying epidermal cancer field. These observations challenge current models that suggest that persistence of cancer risk in the absence of continued carcinogen exposures is simply a function of stochastically arranged, long-lived but dormant epithelial clonal stem cells mutants. The model proposed here could provide new insights into how cancer risk persists following cessation of carcinogenic exposures.

Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro‐inflammation cues

“…28 In addition, dermal senescent cells produce senescence-associated secretory phenotype, which triggers angiogenesis and inflammation surrounding the cells, leading to the production of more dermal senescent cells and an environment suitable for continued carcinogenesis. 37 This could potentially explain the hyperemic expansion noted in the previous study. 28 Importantly, this also identifies a need for noninvasive imaging of subclinical lesions, as it has now been shown that tumorigenic expansion can continue in individuals no longer exposed to UV-B radiation.…”

“…The biological origins of carcinogenesis field expansion can be explained by multiple factors, including acquired mutations in p53 as discussed previously, the influence of dermal senescent cells within the hyperemic foci, and the tumour immune microenvironment associated with vasculature alterations and inflammation 12,34–36 . The influence of dermal senescence and genetic mutations plays an important role in the setting of continued tumorigenesis after the cessation of exogenous stimuli 37 . It was shown that p53 + clones were focused within the dermal hyperemic foci, suggesting that tumour growth following initial genetic mutations can continually expand after cessation of extrinsic carcinogenic treatment in areas of increased vascularity 28 .…”

“…12,[34][35][36] The influence of dermal senescence and genetic mutations plays an important role in the setting of continued tumorigenesis after the cessation of exogenous stimuli. 37 It was shown that p53 + clones were focused within the dermal hyperemic foci, suggesting that tumour growth following initial genetic mutations can continually expand after cessation of extrinsic carcinogenic treatment in areas of increased vascularity. 28 In addition, dermal senescent cells produce senescence-associated secretory phenotype, which triggers angiogenesis and inflammation surrounding the cells, leading to the production of more dermal senescent cells and an environment suitable for continued carcinogenesis.…”

“…Our team successfully applied hyperspectral imaging to determine spatiotemporal and carcinogenic changes following UV radiation in a mouse model. 28,37 This study focused on finding a correlation between UV-B exposure and cutaneous tumour production. Mice were exposed to UV-B light three times weekly for 10 weeks to induce experimental carcinogenesis.…”

“…It was shown that p53 + clones were focused within the dermal hyperemic foci, suggesting that tumour growth following initial genetic mutations can continually expand after cessation of extrinsic carcinogenic treatment in areas of increased vascularity 28 . In addition, dermal senescent cells produce senescence‐associated secretory phenotype, which triggers angiogenesis and inflammation surrounding the cells, leading to the production of more dermal senescent cells and an environment suitable for continued carcinogenesis 37 . This could potentially explain the hyperemic expansion noted in the previous study 28 .…”