Cytochromes p450 and skin cancer: role of local endocrine pathways

Abstract

Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7- steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.

Fig. (1)

Basal cell carcinoma (low magnification: A, high magnification: B) and squamous cell carcinoma (low magnification: C, high magnification: D). Basal cell carcinoma is characterized by basaloid islands with prominent cleft artifact and abnormal surrounding stroma. Squamous cell carcinoma is characterized by keratin pearls, atypia of keratinocytes and infiltrative features. Pictures were taken and processed with an Aperio Imaging System.

Fig. (2)

Melanoma. Melanoma in situ (A). This is a proliferation of atypical melanocytes along dermal-epidermal junction in sun damaged skin. Melanoma in radial and vertical phases of growth (superficial spreading type; high magnification: B, low magnification: C). This is a proliferation of nested atypical melanocytes with dusty melanin centered primarily along the dermal-epidermal junction with some melanocytes extending to the papillary dermis. Melanoma in the vertical phase of growth (nodular type, D). This is a dermal proliferation of nested atypical melanocytes. Pictures were taken and processed with an Aperio Imaging System.

Fig. (3)

Vascular and pseudovascular lesions. Lobular capillary hemangioma (A). This lesion is composed of vessels in benign stroma surrounded by epidermal collarette. Angiokeratoma (B). This lesion has prominent acanthosis and hyperkeratosis. Hemorrhagic dermatofibroma (C). This lesion is composed primarily of dermal dendrocytes and has some extravasated blood within its boundaries. Kaposi’s sarcoma (D). This tumor is characterized by vessels lined by atypical endothelial cells dissecting collagen fibers. Pictures were taken and processed with an Aperio Imaging System.

Fig. (4)

Soft tissue lesions. Solitary fibrous tumor (low magnification: A, high magnification: C). This is relatively well delineated tumor that consists of spindle cells in “patternless” pattern. Fibrosarcoma (low magnification: B, high magnification: D). This is also a relatively well delineated tumor that consists of spindle cells in herringbone pattern. Pictures were taken and processed with an Aperio Imaging System.

Fig. (5)

CYP11A1 mediated metabolism of cholesterol 22R-hydroxylation changes stereochemical descriptors at C-20 (see recommendations of IUPAC-IUBHy on vitamin D nomenclature [256]).

Fig. (6)

CYP11A1 mediated metabolism of 7-dehydrocholesterol. 22R-Hydroxylation changes stereochemical descriptors at C-20 (see recommendations of IUPAC-IUB [256]).

Fig. (7)

RT-PCR of the cytochrome gene products in human cell lines: A) CYP17A; B) CYP21A2 C) CYP7A1; D) CYP7B1; E) CYP39A1. RT-PCR was performed using primers listed in Table 1 following methodology described before [81, 257]. Briefly, the following program was used: initial heating at 95°C for 3 min, followed by 30 cycles of 94°C for 30s, 55°C for 40s, 72°C for 40s. Products of CYP7B1, CYP39A1 and CYP17A amplification were visualized by agarose gel electrophoresis. Products of CYP7A1 and CYP21A2 amplification were diluted 40 times with water and used as the templates for the nested round of amplification using same program and also visualized on anagarose gel. The products were sequenced and they showed 100% homology with the corresponding genes. Location of samples on gels A and B: DNA ladder (M), immortalized epidermal keratinocytes (HaCaT) (1), normal human epidermal keratinocytes (HeKa) (2), immortalized human epidermal melanocytes (Pig1) (3), primary human epidermal melanocytes (HeM) (4), dermal fibroblasts (5), squamous cell carcinoma (C1–4) (6), and SKMELl188 (7), SBCE2 (8), WM35 (9), WM98 (10), WM164 (11), WM1341 (12) melanoma lines, subcutaneous adipose tissue (13). Location of samples on the gels C, D and E: DNA ladder (M), HeM melanocytes (1), fibroblasts (2), C1–4 cells (3), SKEMEL188 (4), SBCE2 (5), WM35 (6), WM98 (7), WM164 (8), WM1341 (9), HaCaT keratinocytes (10), HeKa keratinocytes (11).

Fig. (8)

Classical (upper portion) and non-classical (CYP11A1-initiated) pathways of vitamin D activation and metabolism.

Fig. (9)

UVB-induced production of pregna- or androsta-secosteroids with short or absent side chain.

Fig. (10)

Cytochromes P450 are the guardians of the key metabolic pathways, including: steroidogenesis, secosteroidogenesis, melatonin synthesis. The loss of their proper function by genetic and epigenetic factors results in destabilisation of internal homeostasis that eventually leads to cancer progression.