From Normal Skin to Squamous Cell Carcinoma: A Quest for Novel Biomarkers

Abstract

Squamous cells carcinoma (SCC) is the second most frequent of the keratinocyte-derived malignancies after basal cell carcinoma and is associated with a significant psychosocial and economic burden for both the patient himself and society. Reported risk factors for the malignant transformation of keratinocytes and development of SCC include ultraviolet light exposure, followed by chronic scarring and inflammation, exposure to chemical compounds (arsenic, insecticides, and pesticides), and immune-suppression. Despite various available treatment methods and recent advances in noninvasive or minimal invasive diagnostic techniques, the risk recurrence and metastasis are far from being negligible, even in patients with negative histological margins and lymph nodes. Analyzing normal, dysplastic, and malignant keratinocyte proteome holds special promise for novel biomarker discovery in SCC that could be used in the future for early detection, risk assessment, tumor monitoring, and development of targeted therapeutic strategies.

Figure 1

UV-induced skin carcinogenesis. UV radiation alters the normal immune responses, induces DNA damage and oxidative stress, and may lead to development of skin cancer.

Figure 2

Dysregulation of cellular signalling in SCC. Aberrant activation of EGFR induces phosphorylation of β-catenin and GSK-3β, leading to uncoupling of β-catenin from both destruction complex (β-catenin/GSK-3β/APC/CK1/Axin) and E-cadherin/p120/α-catenin complex and translocation to the nucleus. Once translocated to the nucleus it influences gene transcription, including Cyclin D1, c-Myc, MMP-1, and MMP-7 (viable biomarkers for SCC) which have important roles in proliferation, cell cycle, migration, and invasion. The figure also shows one of the first events in SCC carcinogenesis, namely, the induction of tumor suppressor p53 mutations. ^∗EGFR: epidermal growth factor receptor; GSK-3β: glycogen synthase kinase 3 beta; APC: adenomatous polyposis coli; CK1: casein kinase 1; MMP-1: matrix metalloproteinase 1; MMP-7: matrix metalloproteinase 7.