Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, UK.
Breast Cancer Res. 2018 Nov 20;20(1):137. doi: 10.1186/s13058-018-1060-5.
Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types.
Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin.
In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ERα-negative breast cancer as well as in ERα-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin.
The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences.
癌症的进展不仅受到癌细胞群体中的遗传异常的影响，还受到肿瘤内微环境等其他因素的影响。各种细胞类型之间的直接相互作用以及通过分泌细胞因子进行的细胞信号转导可以驱动与疾病进展和治疗耐药性相关的关键肿瘤发生特性。此外，癌症干细胞功能受微环境影响。这一具有挑战性的细胞亚群与恶性特性有关。在一个筛选实验中，我们采用类似于体内的生长条件，发现颗粒蛋白前体（progranulin）是一种高度分泌的细胞因子，可影响乳腺癌中的癌症干细胞。该细胞因子已知在许多生物学和肿瘤相关过程中发挥作用，包括多种癌症类型的治疗耐药性。
使用不同的体外和体内相关条件来验证颗粒蛋白前体及其受体分选酶（sortilin）介导的乳腺癌干细胞的扩增。使用小干扰核糖核酸（siRNA）和分选酶的药理学抑制来阐明分选酶作为颗粒蛋白前体诱导的乳腺癌干细胞增殖过程中的功能性受体的作用，包括在体外和体内使用乳腺癌异种移植模型。此外，使用单细胞基因表达谱分析和 Sox2 报告基因乳腺癌细胞系来验证颗粒蛋白前体介导的去分化作用。
在各种类似于体内的筛选实验中，颗粒蛋白前体被鉴定为一种有效的癌症干细胞激活剂，在 ERα 阴性乳腺癌中高度分泌，在缺氧适应的 ERα 阳性乳腺癌中也是如此。颗粒蛋白前体的暴露导致去分化以及癌症干细胞池的增殖增加，这一过程被证明依赖于其受体分选酶。颗粒蛋白前体或其活性域（GRN A）的皮下注射会在乳腺癌异种移植模型中诱导肺转移，支持颗粒蛋白前体在癌症进展中的主要作用。重要的是，一种针对分选酶的口服生物可利用小分子（AF38469）可阻断 GRN A 诱导的肺转移，并防止癌细胞浸润皮肤。
综上所述，分选酶靶向治疗可能成为一种新的乳腺癌治疗方法，可抑制由分泌和微环境影响驱动的肿瘤进展。
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