Scherzed A, Hackenberg S, Froelich K, Rak K, Schendzielorz P, Gehrke T, Hagen R, Kleinsasser N
Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
Oncol Rep. 2016 Jan;35(1):219-26. doi: 10.3892/or.2015.4383. Epub 2015 Nov 3.
Human mesenchymal stem cells (hMSCs) have been applied therapeutically in numerous clinical trials. The pro-angiogenic effects of hMSCs, as well as their strong tumor tropism, have been shown both in vitro and in vivo. Some studies suggest using hMSCs as potential drug-carriers for tumor therapy. In previous investigations by our group, the pro-tumorigenic effects of hMSCs on head and neck squamous cell carcinoma (HNSCC) were shown. However, the influence of hMSCs on tumor vascularization as well as the possibility of its inhibition are yet to be elucidated. The cytokine patterns of the HNSCC cell line FaDu, native hMSCs (hMSCs-nat), hMSCs differentiated into adipocytes (hMSCs-adip) and osteocytes (hMSCs-ost) were evaluated. Human umbilical vein endothelial cells (HUVECs) were co-cultured with FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost. The capillary tube formation assay was applied. Furthermore, the migration capability of hMSCs-nat, hMSCs-adip and hMSCs-ost towards FaDu cells was measured in a Transwell system. Spheroids were cultured from hMSCs-nat, FaDu cells and DiI-labeled HUVECs. FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost released a wide range of cytokines and growth factors, e.g., IL-6, IL-8, IL-10, GRO and MCP. In the capillary tube formation assay, HUVECs generated significantly longer tubes after co-cultivation with hMSCs-nat as compared to HUVECs alone and FaDu. Differentiation into adipocytes and osteocytes counteracted the tube formation. The adipogenic differentiation did not alter hMSC motility, whereas osteogenic differentiation significantly inhibited hMSC migration. Generation of multi-cellular spheroids from hMSCs-nat, FaDu cells and DiI-labeled HUVECs was possible. Florescence microscopy revealed that all HUVECs were present in the spheroid core. Taken together, hMSCs-nat have a pro-angiogenic effect. The effects are counteracted by the differentiation of hMSCs towards osteogenic and adipogenic lineages. The differentiation of stem cells into different lineages may be a promising solution to generating carriers for cancer therapy without pro-tumorigenic properties.
人间充质干细胞（hMSCs）已在众多临床试验中得到治疗应用。hMSCs的促血管生成作用及其强大的肿瘤嗜性已在体外和体内得到证实。一些研究建议将hMSCs用作肿瘤治疗的潜在药物载体。在我们小组之前的研究中，已显示hMSCs对头颈部鳞状细胞癌（HNSCC）具有促肿瘤作用。然而，hMSCs对肿瘤血管生成的影响及其抑制可能性尚待阐明。评估了HNSCC细胞系FaDu、天然hMSCs（hMSCs-nat）、分化为脂肪细胞的hMSCs（hMSCs-adip）和成骨细胞的hMSCs（hMSCs-ost）的细胞因子模式。将人脐静脉内皮细胞（HUVECs）与FaDu细胞、hMSCs-nat、hMSCs-adip和hMSCs-ost共培养。应用毛细管形成试验。此外，在Transwell系统中测量了hMSCs-nat、hMSCs-adip和hMSCs-ost向FaDu细胞的迁移能力。从hMSCs-nat、FaDu细胞和DiI标记的HUVECs培养球体。FaDu细胞、hMSCs-nat、hMSCs-adip和hMSCs-ost释放了多种细胞因子和生长因子，例如IL-6、IL-8、IL-10、GRO和MCP。在毛细管形成试验中，与单独的HUVECs和FaDu相比，HUVECs与hMSCs-nat共培养后生成的管明显更长。分化为脂肪细胞和成骨细胞可抵消管的形成。脂肪生成分化未改变hMSC的运动性，而成骨分化显著抑制hMSC的迁移。可以从hMSCs-nat、FaDu细胞和DiI标记的HUVECs生成多细胞球体。荧光显微镜检查显示所有HUVECs都存在于球体核心。综上所述，hMSCs-nat具有促血管生成作用。hMSCs向成骨和脂肪谱系的分化可抵消这些作用。干细胞向不同谱系的分化可能是生成无促肿瘤特性的癌症治疗载体的一种有前景的解决方案。
