Department of Pathology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Department of Pathology, Women's Cancer Research Program, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Institute, Northwestern University, Chicago, IL, USA.
Breast Cancer Res Treat. 2019 Nov;178(1):35-49. doi: 10.1007/s10549-019-05347-0. Epub 2019 Jul 20.
Although survival rates for patients with localized breast cancer have increased, patients with metastatic breast cancer still have poor prognosis. Understanding key factors involved in promoting breast cancer metastasis is imperative for better treatments. In this study, we investigated the role of syndecan-1 (Sdc1) in breast cancer metastasis.
To assess the role of Sdc1 in breast cancer metastasis, we silenced Sdc1 expression in the triple-negative breast cancer human MDA-MB-231 cell line and overexpressed it in the mouse mammary carcinoma 4T1 cell line. Intracardiac injections were performed in an experimental mouse metastasis model using both cell lines. In vitro transwell blood-brain barrier (BBB) and brain section adhesion assays were utilized to specifically investigate how Sdc1 facilitates brain metastasis. A cytokine array was performed to evaluate differences in the breast cancer cell secretome when Sdc1 is silenced.
Silencing expression of Sdc1 in breast cancer cells significantly reduced metastasis to the brain. Conversely, overexpression of Sdc1 increased metastasis to the brain. We found that silencing of Sdc1 expression had no effect on attachment of breast cancer cells to brain endothelial cells or astrocytes, but migration across the BBB was reduced as well as adhesion to the perivascular regions of the brain. Loss of Sdc1 also led to changes in breast cancer cell-secreted cytokines/chemokines, which may influence the BBB.
Taken together, our study demonstrates a role for Sdc1 in promoting breast cancer metastasis to the brain. These findings suggest that Sdc1 supports breast cancer cell migration across the BBB through regulation of cytokines, which may modulate the BBB. Further elucidating this mechanism will allow for the development of therapeutic strategies to combat brain metastasis.
尽管局部乳腺癌患者的生存率有所提高，但转移性乳腺癌患者的预后仍然较差。了解促进乳腺癌转移的关键因素对于更好的治疗至关重要。在这项研究中，我们研究了 syndecan-1（Sdc1）在乳腺癌转移中的作用。
为了评估 Sdc1 在乳腺癌转移中的作用，我们在三阴性乳腺癌人 MDA-MB-231 细胞系中沉默 Sdc1 的表达，并在鼠乳腺肿瘤 4T1 细胞系中过表达 Sdc1。使用这两种细胞系在实验性小鼠转移模型中进行了心脏内注射。我们利用体外 transwell 血脑屏障（BBB）和脑切片黏附实验，专门研究 Sdc1 如何促进脑转移。进行细胞因子阵列实验以评估当 Sdc1 被沉默时乳腺癌细胞分泌组的差异。
沉默乳腺癌细胞中 Sdc1 的表达显著降低了脑转移。相反，过表达 Sdc1 增加了脑转移。我们发现，沉默 Sdc1 的表达对乳腺癌细胞与脑内皮细胞或星形胶质细胞的黏附没有影响，但迁移穿过 BBB 以及与脑血管周围区域的黏附都减少了。Sdc1 的缺失也导致了乳腺癌细胞分泌的细胞因子/趋化因子的变化，这可能影响 BBB。
综上所述，我们的研究表明 Sdc1 在促进乳腺癌向大脑转移中起作用。这些发现表明，Sdc1 通过调节细胞因子支持乳腺癌细胞穿过 BBB 的迁移，这可能调节 BBB。进一步阐明这一机制将为开发治疗脑转移的策略提供依据。
