Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice

Abstract

Abstract. The present study revealed the effects of Lycopene enriched tomato extract (LycT) on chemically induced skin cancer in mice. Skin tumors were induced by topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) [500 nmol/100 ul of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7 nmol/100 ul of acetone, twice a week for eighteen weeks] and LycT (5 mg/kg b.w.) was administered orally. Male Balb/c mice were divided into four groups (n = 15 per group): control, DMBA/TPA, LycT and LycT + DMBA/TPA. The chemopreventive response of LycT to skin tumorigenesis was evident by inhibition in tumor incidence, number, size, burden and volume in LycT + DMBA/TPA group when compared to DMBA/TPA group. This was associated with inhibition of cell proliferation in LycT + DMBA/TPA group as observed by the decrease in epidermal morphometric parameters and mRNA and protein expression of proliferating cell nuclear antigen when compared to DMBA/TPA group (p ≤ 0.05). LycT decreased (p ≤ 0.05) the mRNA and protein expression of angiogenic genes (vascular endothelial growth factor, angiopoietin-2, basic fibroblast growth factor) in LycT + DMBA/TPA group, suggesting its anti-angiogenic effects. The increase (p ≤ 0.05) in protein expression of connexin-32 and 43 in LycT + DMBA/TPA group suggests improved inter cellular communication when compared to DMBA/TPA group. Histochemical studies demonstrated that the components of extracellular matrix (fibrous proteins and mucopolysaccharides) were also modulated during skin carcinogenesis and its chemoprevention by LycT. The decrease in cell proliferation parameters and expression of angiogenesis associated genes, modulation of ECM components and increase in expression of connexins suggest that LycT improved multiple dysregulated processes during chemoprevention of skin cancer.

Altered presence of extra cellular matrix components in murine skin cancer: Modulation by Azadirachta indica leaf extract

“… 24 The characteristic features of SCC including epidermal hyperproliferation and hyperkeratinisation, presence of keratin whorls/keratin pearls, squamous eddies and infiltrating cells in the dermis were observed and are in corroboration with other reports in literature. 23 , 24 , 44 , 45 , 46 , 47 , 48 The microscopically visible inflammation in the epidermis of AAILE group was not associated with any deleterious effects since all the skin layers were visibly intact and seems to be a non-specific response. The increase in epidermal thickness in AAILE group was not associated with any increase in cell number as determined by micrometry and cell count studies.…”

“…The tumors obtained in DMBA/TPA and AAILE + DMBA/TPA groups exhibited characteristic features of squamous cell carcinoma (SCC). 23 , 24 , 44 , 45 , 46 , 47 , 48 Hyperkeratosis (i.e. increased keratin formation), abnormally thickened and corrugated epidermis (infolds of epidermis) as a result of cellular hyperproliferation was prominent in tumors of DMBA/TPA group.…”

“… 59 A recent study from our laboratory has revealed that DMBA/TPA induced skin tumors in mice exhibited intense staining for collagen, suggesting enhanced production of collagen in skin tumors. 44 Remodelling of ECM by employing antifibrotic therapies is gaining attention for its anticancer effects and could be effective in both cancer prevention and therapy. Putative anti-cancer agents have been known to inhibit cancer metastasis by their ability to reduce hydroxyproline/collagen levels.…”

“…Studies have revealed that substantial amounts of mucopolysaccharides/GAGs are present in tumors 70 , 71 , 44 , 72 , 73 ; Histopathological studies have revealed that desmoplastic areas in carcinomas stain metachromatically with cationic dyes like alcian blue suggesting the increased presence of GAGS (hence PGs) in tumors. 74 Enhanced production of GAGs was evident in tumors of DMBA/TPA group and this decreased with the administration of AAILE.…”

“…PAS stain is used for histochemical detection of neutral mucopolysaccharides. 43 , 44 …”