# Promotion of photocarcinogenesis by the senescent field and mechanisms for field persistence

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

Exposure to the ultraviolet (UV) rays of sunlight is the primary cause of skin cancer, which kills greater than
20,000 U.S. individuals each year. Veterans are at increased risk for skin cancer development due to increased
sun exposure during training and deployment. UV exposure also causes photoaging that results in cells
acquiring a post-mitotic phenotype called senescence. In addition to sun exposure, age and treatment with
immunosuppressants are the most significant risk factors for skin cancer development. In this proposal, we will
examine our novel 2 component cancer field model of cutaneous carcinogenesis that links photoaging and
immunosuppression to skin cancer development. Historically, the cancer field refers to multifocal areas of
otherwise normal epithelium that are at increased risk for cancer development. This epithelial cancer field is
characterized by the stepwise accumulation of mutations that eventually lead to malignant conversion. We
have shown that UV induces a multifocal dermal senescent field that is characterized by inflammatory
angiogenesis that can be visualized and measured by imaging the dermal hemoglobin (Hb) content. This
dermal field persists & expands following cessation of UV treatments and predicts sites of overlying epidermal
clonal expansion & tumor formation. In this proposal, we propose that a dermal field also exists and that the
key characteristic of this dermal field is the presence of senescent cells. These senescent cells produce and
secrete specific pro-inflammatory, mitogenic and immunomodulatory mediators that we propose drive the
continued development of the overlying epithelial mutant field. However, the immune system can recognize
and clear senescent cells (senescence surveillance). We predict that this immune-mediated clearance acts to
suppress the effects of the senescent dermal field on tumor formation. We expect that treatment with
immunosuppressive drugs would promote tumorigenesis by blocking immune-mediated clearance of dermal
senescent cells. Transforming growth factor beta (TGF-β) is a cytokine that is necessary for UV-induced
senescence and is produced by senescent cells. This TGF-β production can in turn result in the induction of
senescence in nearby cells (bystander senescence). We propose that bystander senescence, in an
immunosuppressed setting, provides a self-perpetuating mechanism that drives senescent field persistence
AND expansion. Finally, not all immunosuppressive agents have the same capacity to promote skin cancer
development. Cyclosporine A promotes skin cancer development, TGF-β production, and induces senescence.
In contrast, sirolimus has a limited effect on skin cancer risk, is known to suppresses TGF-β production, and
suppresses senescent cell formation and secretory activity. In this proposal, we will determine whether the UV-
induced senescent field is necessary for skin cancer development, determine whether immunosuppressive
therapy promotes senescent field develo...

## Key facts

- **NIH application ID:** 10487791
- **Project number:** 1I01BX005816-01A1
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** RAYMOND L KONGER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487791

## Citation

> US National Institutes of Health, RePORTER application 10487791, Promotion of photocarcinogenesis by the senescent field and mechanisms for field persistence (1I01BX005816-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10487791. Licensed CC0.

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