Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
NET-IMPACT, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Front Immunol. 2020 Sep 10;11:1820. doi: 10.3389/fimmu.2020.01820. eCollection 2020.
Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential , as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.
半乳糖凝集素-3（Galectin-3）是一种细胞外基质糖结合蛋白，具有多种免疫抑制和促肿瘤功能。Galectin-3 在癌症干细胞样细胞（CSCs）中的作用尚未得到充分研究。在这里，我们表明，在转基因前列腺腺癌小鼠（TRAMP）的前列腺引流淋巴结中定植的前列腺 CSCs 也过度表达 Gal-3。Gal-3 有助于前列腺 CSC 介导的免疫抑制，因为在 CSCs 中沉默 Gal-3 或在 Gal-3 抑制剂 N-乙酰-D-乳酰胺存在下共培养 CSCs 和 T 细胞均可挽救 T 细胞增殖。N-乙酰-D-乳酰胺也挽救了受前列腺上皮内瘤变影响的 TRAMP 小鼠前列腺引流淋巴结中 T 细胞的增殖。此外，Gal-3 还影响前列腺 CSC 的致瘤和转移潜力，因为在前列腺 CSCs 中沉默 Gal-3 可降低原发性肿瘤生长和继发性侵袭。Gal-3 也在更分化的前列腺癌细胞中表达，但与 CSCs 相比，其细胞内分布不同，这表明 Gal-3 在这两种细胞群中的功能不同。事实上，与更分化的前列腺癌细胞相比，Gal-3 在前列腺 CSCs 中普遍存在核内和细胞质内分布，这使它们对凋亡的敏感性降低。最后，我们发现 Gal-3 在人源和鼠源前列腺上皮内瘤变病变以及转移性淋巴结中表达。综上所述，这些发现表明 Gal-3 是一个关键分子，也是一个潜在的治疗靶点，已经存在于前列腺癌进展和转移的早期阶段。
