Abstract
BackgroundBone 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.MethodsGC-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.ResultsGC-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.ConclusionTumor-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.
Highlights
Bone marrow mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with tumor growth and progression
(See figure on previous page.) Fig. 1 Characterization of human gastric cancer-derived MSCs. (A) Spindle-shaped cells migrated from gastric cancer tissues after 7–10 days of primary culture and fibroblast-like cells appeared at passage 4 of GC-MSCs culture with the morphology similar to GCN-MSCs or BM-MSCs (×40). (B) Representative photographs of GC-MSCs differentiated into mineralizing cells with alizarin red S staining and adipogenic cells with Oil red O staining (×200, ×400). (C) Surface antigens expressed on GC-MSCs analyzed by flow cytometry. (D) Surface antigens expressed on GCN-MSCs analyzed by flow cytometry which were similar to GCN-MSCs or BM-MSCs (Fig.1A)
The results showed that BGC-823 and MKN-28 cells were both stimulated to grow faster when incubated with 10 % GC-MSC-conditioned medium (CM), which displayed a more potent tumor-promoting ability than GCN-MSC-CM or BM-MSC-CM
Summary
Bone marrow mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with tumor growth and progression. 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. Deficiency of targeted agents seems to restrict the therapeutic strategy for gastric cancer and a thorough understanding of the mechanism is urgently needed. Tumor microenvironment (TME) has been indicated to play a critical role in both the initiation and progression of tumors [5,6,7]. Better understanding of the association between gastric cancer cells and components in TME could be directory for elucidating the underlying mechanisms of gastric cancer
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