Actinic keratoses (AK) are regarded as early in situ carcinomas and bear the potential to progress into an invasive cutaneous squamous cell carcinoma (cSCC). In industrial countries, increasing incidence of keratinocyte cancers and AKs in particular has been observed. AKs are considered as chronic diseases with increasing costs to the health service as the prevalence continues to rise.
Clinically, AKs present as macules, papules, or hyperkeratotic plaques with an erythematous background on photoexposed areas.
Single AK was found to have HPVs in healthy looking and lesional skin of affected patients. AK patients express in their skin HPV5,-38,-76,-110,-120,-4 and SD2, some of which are oncogenic in vitro and in animal models.
The microRNA (miRNA) profile of AK samples showed that several miRNAs regulating specific gene expression involved in cancer progression are modulated in AK compared to healthy skin.
Extracellular membrane vesicles (EVs), as a vehicle-like device, appear to be an important multifaceted regulator of tumor progression. EVs derived from cancer cells, released in greater numbers than from normal proliferative cells, can modulate immune responses, transfer oncogenic proteins and nucleic acids, reprogram stromal cells and transfer the drug-resistance phenotype. There is little mechanistic knowledge of EV-related events in cancer i.e. the mechanism(s) of cargo selection and release, and their molecular target(s) in cytoplasm and nuclear compartment of host cells.
This project will analyze the features of AK and cSCC clinical samples focusing on the detection of selected ß and y-HPVs in a liquid biopsy approach to identify virus-associated biomarkers of cancer progression useful to develop both diagnostic tests and targeted therapies. In addition, cell free circulating- and EV-associated miRNAs, will be assessed on blood samples of cSCC patients admitted to anti-PD-1 treatment, to identify possible therapeutic outcome predictive biomarkers.
Actinic keratoses are regarded as early in situ carcinomas and bear the potential to progress into an invasive cutaneous squamous cell carcinoma (Ackerman & Mones, Br J Dermatol 155:9, 2006). Due to a change in leisure activities in the past few decades and a demographic change in industrial countries, increasing incidence of keratinocyte cancers and AKs in particular has been observed. AKs are considered as chronic diseases, and as the prevalence continues to rise, this has led to an increasing number of episodes of treatment and the options available, resulting in increasing costs to the health service. (Rosen & Lebwohl, J Am Acad Dermatol 68:S2, 2013; Schmitz et al., J Eur Acad Dermatol Venereol 32:752, 2018). Clinically, actinic keratoses present as macules, papules, or hyperkeratotic plaques with an erythematous background that occur on photoexposed areas.
A higher progression rate of 0.53% per lesion per year was estimated if the patient already had cSCC elsewhere. At the same time, however, single AK was found to have HPVs in healthy looking (HS) and lesional skin of affected patients. The majority of the AK patients had in their skin HPV5, 38, 76, 110, 120, 4 and SD2, some of which known to be oncogenic in vitro and in animal models.
The miRNA profile of AK samples showed that several miRNAs involved in cancer progression are modulated in AK compared to healthy skin.
This project will analyze in AK and cSCC clinical samples the transcriptional activity of selected ß and y-HPVs in a liquid biopsy approach, with the goal to identify biomarkers of cancer progression useful to develop both diagnostic tests and targeted therapies. In addition, cfc-DNA, cfc- and EV-associated miRNAs as well as cytokines and immune cellular subset, will be assessed on blood samples of cSCC patients admitted to anti-PD-1 treatment, to identify possible therapeutic outcome predictive biomarkers.
The proposal, following clinical and epidemiological interests, aims at studying specific profiles of AK and cSCC with respect to cancer progression and at evaluating in clinical practice the efficacy of new diagnostic and therapeutic approaches.
Therefore, the identification of biomarkers of disease progression is a priority for the public health. Our results will allow us to identify a panel of putative molecules, HPV mRNAs and cellular miRNAs, useful to be targeted for the development of novel diagnostic assays and innovative chemo- and immunotherapies.