Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in theDrosophila melanogasteraccessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer.
流行病学研究指出，胆固醇可能是前列腺癌发病和进展的关键因素。作为可靶向的代谢物，胆固醇在最具侵袭性的肿瘤中似乎也对旨在降低高胆固醇血症的疗法（如他汀类药物）敏感。然而，胆固醇是否以及如何通过其膳食摄入和代谢在早期肿瘤发生中发挥重要作用，目前尚不清楚。通过果蝇副腺中的癌基因克隆诱导，我们能够模拟从起始到早期进展的肿瘤发生过程，其中肿瘤细胞经历基底挤出形成上皮外肿瘤。本研究表明，这些肿瘤会积累脂质，尤其是酯化胆固醇，这与人类晚期癌变过程相似。有趣的是，高胆固醇饮食对副腺肿瘤发生的影响有限。相反，胆固醇摄取、细胞内运输或代谢反应的细胞特异性下调会阻碍此类肿瘤的形成。此外，在此背景下，高胆固醇饮食能够抑制这种阻碍作用。值得注意的是，原发性前列腺癌组织的表达数据显示，早期存在从胆固醇从头合成转向摄取的特征。综上所述，这些结果揭示了在早期肿瘤发生过程中，肿瘤细胞显著增加对膳食胆固醇的摄取和利用，以特异性促进基底挤出步骤。因此，这些结果提示了减少膳食胆固醇摄入可能降低前列腺癌风险并延缓其进展的作用机制。
肿瘤(癌症)患者之家