Genetic alterations of the HIF inhibitor Hedgehog pathway cause a subset of sporadic and familial, skin (basal cell carcinoma) and brain (medulloblastoma) tumors [53]. For example, inactivating mutations of the twelve-pass transmembrane Patched proteins or activating mutations of the seven-pass transmembrane protein Smoothened of the Hedgehog signaling pathway have been associated with those skin and brain cancers [53]. Oxysterols have been recently reported to interact with and activate Smoothened in vitro, thereby stimulating Hedgehog signaling and proliferation

of medulloblastoma cells [54]. The stimulatory effect of oxysterols on Smoothened was found to be stereo-selective, requiring the S-configuration of 20(S)-HC and

25(S)-HC. It is noteworthy to mention that the treatment of medulloblastoma cells with inhibitors of cholesterol synthesis is capable of blocking selleck kinase inhibitor their proliferation [55], suggesting the possibility of experimentally using oxysterol inhibitors to treat patients affected by medulloblastoma. A protumor effect has recently been reported for the oxysterol 27-HC. Indeed, 27-HC exerted a proliferative and tumorigenic effect in a spontaneous mouse breast tumor model. In this model, 27-HC participates in the tumorigenesis by interacting with and activating estrogen receptors [56]. Moreover, by activating LXRs, 27-HC promoted lung metastasis through the activation of genes involved in the epithelial–mesenchymal transition process [56] (Fig. 2B). Whether tumor formation and establishment in this tumor model is also dependent on the effect of oxysterols on immune cells infiltrating the tumor microenvironment is currently unknown and deserves a careful investigation. Oxysterols are therefore able to exert an inhibitory effect in the majority of tumor models investigated through an LXR-dependent manner. However, in a medulloblastoma cell line [55] and in a model of breast tumor [56], oxysterols are able to promote tumor growth by LXR-independent mechanisms, requiring Smoothened activation and estrogen receptor

activation, Cyclin-dependent kinase 3 respectively. Oxysterols may exert opposing effects in the control of tumor growth through both indirect and direct mechanisms. The former involve the establishment of immunosuppressive networks within the tumor microenvironment (protumor effects), whereas the latter engage cell cycle control, dysregulation of cholesterol catabolism, and oncogenic signaling (antitumor effects), with the exception of the stimulatory effect played by 20(S)-HC and 25(S)-HC on Smoothened in medulloblastoma cells [55], and of the recently identified protumor role exerted by 27-HC in a breast mouse tumor model [56]. In recent years, a variety of immune cell functions have been reported to be activated by LXRα and LXRβ.