Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer.
揭示癌细胞与其肿瘤微环境之间复杂的相互作用网络具有重要的临床意义，因为这可能有助于发现新的癌症治疗靶点。肿瘤微环境中多种细胞分泌的细胞因子和生长因子，能够影响具有治疗抵抗性和侵袭性特征的癌症干细胞亚群。通过多种模型系统，我们研究了乳腺癌干细胞启动生长因子颗粒体蛋白前体如何影响癌症相关蛋白的分泌。在单层细胞培养中，颗粒体蛋白前体通过分拣蛋白依赖性方式诱导了多种炎症相关细胞因子（如白细胞介素-6和-8）的分泌。进一步研究发现，在乳腺癌细胞系MCF7和MDA-MB-231中，通过替代性乳腺球形成实验监测发现，白细胞介素-6与颗粒体蛋白前体相似，均能增加癌症干细胞比例。在63例患者来源的支架培养模型（与乳腺癌细胞共培养）队列中，我们观察到白细胞介素-6与颗粒体蛋白前体分泌量之间存在显著相关性，这明确验证了在人类来源的微环境中两者也存在关联。总之，颗粒体蛋白前体与白细胞介素-6之间的相互作用通过分拣蛋白介导了双重乳腺癌干细胞促进功能，进一步支持分拣蛋白作为侵袭性乳腺癌的重要治疗靶点。
肿瘤(癌症)患者之家