Novel Hedgehog pathway targets against basal cell carcinoma

Abstract

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastro-intestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence. Epidemiology of Basal cell carcinoma (BCC)Basal cell carcinoma (BCC), the most common of all human cancers, affects close to 1 million Americans a year. Over the past 40 years there has been a dramatic increase in the incidence of BCC, and it is estimated that nearly 30% of Caucasians living in areas of high ambient sun exposure will develop a BCC (Miller and Weinstock, 1994). Furthermore, the incidence of BCC is rising in younger populations, especially among women (Christenson et al., 2005). Although the case fatality rate of BCCs is low, the high incidence and frequent occurrence of multiple primary tumors in affected individuals leads to significant morbidity. BCCs characteristically arise in sun-exposed body areas, most commonly on the head and neck, but also occur on the trunk and extremities. There are three accepted environmental insults for BCC development: ultraviolet radiation (UV), ionizing radiation (IR), and arsenic. Interindividual differences in the susceptibility to BCC development have been recognized for many years. Epidemiologic studies have identified phenotypic features such as fair skin and freckling tendency that are associated with an increased susceptibility to BCCs (Rubin et al., 2005).It is generally accepted that BCC can be caused by UV exposure from the sun. While the risk of squamous cell carcinoma is strongly related to cumulative sun exposure, sunlight's exact role in BCC development remains less clear (Armstrong and Kricker, 2001). Thus, epidemiologic studies have shown that BCC risk correlates better with intermittent sun exposure (i.e. childhood sunburns, weekend sun exposure) than with cumulative lifetime sun exposure (Corona et al., 2001). Hence, the timing, dose, and duration of UV exposure are critical to carcinogenesis, but UV seems to have a different role in SCC versus BCC carcinogenesis development. Consistent with this, a randomized clinical trial of daily sunscreen use showed that sunscreen reduced the incidence of SCC but not BCC. The daily application of an SPF 15 sunscreen to the head, neck, arms, and hands over a 4-5 year period had no e...

Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

“…48 Tumor progression, including BCC development, usually depends on inappropriate cell proliferation, impaired apoptosis and cell senescence, and some degree of dedifferentiation. 7,49 Our data show a significant decrease in Ki-67(ϩ) presumptively proliferative cells in pTT-versus vehicle-treated BCC nests, as well as an increase in the number of TUNEL(ϩ) cells, consistent with anti-proliferative and proapoptotic effects of T-oligos that we have previously reported for several malignant cell lines. 20,26,27,50 UV exposure induces Cox-2 expression in murine skin 49 and Cox-2 is known to be anti-apoptotic and proangiogenetic in BCCs and other tumors.…”

“…4,5 By contrast, murine SCC photocarcinogenesis is inhibited poorly by topical retinoids and quite well by oral NSAIDs or green tea. 4,6 These differing effects of UV radiation and chemopreventive agents on BCC versus SCC, in combination with the large socioeconomic burden of BCCs, 7 stimulated us to test thymidine dinucleotide (pTT), an agent already demonstrated to prevent SCCs in UV-irradiated mice 8 for its ability to reduce BCC development.…”

“…They include topical retinoids such as tazarotene, ornithine decarboxylase, cyclopamine, and a synthetic Smo antagonist, CUR61414. 5,7,32 It has also been suggested that cholesterol reduction using statins may decrease signaling through Shh pathway. 7 The ability of T-oligos to act via multiple relevant signaling pathways, as well as to decrease causative UV mutations, makes pTT an attractive addition to this list.…”

Sonic hedgehog pathway dysregulation in skin basal-cell carcinoma of a Polish population

“…Recent data indicates the role of cyclopamine in blocking the growth of UV-induced BCCs in mice. Additionally, it is known that this molecule may also inhibit the proliferation of BCC murine cell lines [2]. One clinical report concerning four patients with BCC described the rapid clinical regression of the cancer in response to topical cyclopamine versus placebo [29].…”

“…Recently, there has been a significant increase in the incidence of BCC, especially among women [1]. BCC is generally a disorder of white individuals, arising particularly in sun-exposed body areas, most commonly on the head and neck, but also on the trunk and extremities [2].…”