Gastric cancer-derived mesenchymal stem cells_prompt gastric cancer progression through_secretion of interleukin-8
Li W1,2, Zhou Y3, Yang J4, Zhang X5, Zhang H6, Zhang T7, Zhao S8, Zheng P9, Huo J10, Wu H11
Bone marrow mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with tumor growth and progression. However, the roles of tumor-resident MSCs in cancer have not been thoroughly clarified. This study was to investigate the regulating effect of gastric cancer-derived MSCs (GC-MSCs) on gastric cancer and elucidate the underlying mechanism.
GC-MSCs were isolated from primary human gastric cancer tissues and characterized. The effect of GC-MSCs on gastric cancer cell proliferation was analyzed by MTT assay and colony formation assay. Transwell migration assay was performed to evaluate the influence of GC-MSCs in gastric cancer cell migration. The regulating effects of interactions between gastric cancer cells and GC-MSCs on their pro-angiogenic abilities were analyzed in a co-culture system, with the expression, and secretion of pro-angiogenic factors detected by RT-PCR and Luminex assay. Tube formation assay was used to further validate the angiogenic capability of gastric cancer cells or GC-MSCs. Cytokine profiles in the supernatant of GC-MSCs were screened by Luminex assay and neutralizing antibody was used to identify the key effective cytokines. The activations of Akt and Erk1/2 in gastric caner cells were detected by Western blot.
GC-MSC treatment enhanced the proliferation and migration of BGC-823 and MKN-28 cells, which was more potently than MSCs from adjacent non-cancerous tissues (GCN-MSCs) or bone marrow (BM-MSCs). Higher expression levels of pro-angiogenic factors were detected in GC-MSCs than GCN-MSCs or BM-MSCs. After 10 % GC-MSC-CM treatment, BGC-823, and MKN-28 cells expressed increased levels of pro-angiogenic factors and facilitated tube formation more potently than cancer cells alone. Furthermore, GC-MSCs produced an extremely higher level of interleukin-8 (IL-8) than GCN-MSCs or BM-MSCs. Blockade of IL-8 by neutralizing antibody significantly attenuated the tumor-promoting effect of GC-MSCs. In addition, 10 % CM of IL-8-secreted GC-MSCs induced the activations of Akt or Erk1/2 pathway in BGC-823 and MKN-28 cells.
Tumor-resident GC-MSCs promote gastric cancer growth and progression more efficiently than GCN-MSCs or BM-MSCs through a considerable secretion of IL-8, which could be a possible target for gastric cancer therapy.