Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Sci Adv. 2021 Jul 30;7(31). doi: 10.1126/sciadv.abg5982. Print 2021 Jul.
Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically engineered Pten mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analog with reported anticancer activities. We show that this analog induces apoptosis in senescent PINs, normalizes extracellular matrix remodeling by stromal fibroblasts, and reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal cells expressing Krt8, Krt4, and Tacstd2 (termed luminal-C cells) is lost by such a treatment, antiapoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of PINs and the microenvironment to Gemini-72, and shed light on mechanisms that limit treatment's efficacy.
流行病学数据将维生素 D 缺乏与各种癌症（包括前列腺癌）的发病和严重程度联系起来，尽管体外研究已经证明了维生素 D 的抗癌活性，但临床试验得出了相互矛盾的结果。为了确定维生素 D 信号对前列腺癌前病变的影响，我们用 Gemini-72 治疗携带前列腺上皮内瘤变（PIN）的基因工程 Pten 小鼠，这是一种具有报道的抗癌活性的维生素 D 类似物。我们表明，这种类似物可诱导衰老的 PIN 细胞凋亡，通过基质成纤维细胞使细胞外基质重塑正常化，并减少免疫抑制性髓源性抑制细胞在前列腺中的浸润。此外，单细胞 RNA 测序分析表明，虽然一组表达 Krt8、Krt4 和 Tacstd2 的腔细胞（称为腔细胞-C）会因这种治疗而丢失，但在持续的腔细胞-C 中会诱导抗凋亡途径。因此，我们的发现描绘了 PIN 和微环境对 Gemini-72 的不同反应，并揭示了限制治疗效果的机制。
