Abstract
Resident macrophages in the tumor microenvironment exert a dual role in tumor progression. So far, the mechanism of intratumoral macrophage generation is still largely unknown. In the present study, the importance of macrophages in the pro-tumor role of gastric cancer-derived mesenchymal stromal cells (GC-MSCs) was observed in a mouse xenograft model with macrophage depletion. In gastric cancer tissues, high expression levels of Ym-1, Fizz-1, arginase-1, and CCR-2, as well as a low expression level of iNOS, were verified, and co-localization of GC-MSCs and tumor-associated macrophages (TAMs) was observed by dual immunofluorescence histochemistry. TAMs isolated from gastric cancer tissues predominantly displayed an M2 phenotype. In a co-culture system, the contribution of GC-MSCs to M2 polarization of macrophages was confirmed by the M2-related protein expression, M2-like immunophenotype and cytokine profile of GC-MSC-primed macrophages in vitro. Blockade of IL-6/IL-8 by neutralizing antibodies significantly attenuated the promoting effect of GC-MSCs on M2-like macrophage polarization via the JAK2/STAT3 signaling pathway. In addition, GC-MSC-primed macrophages promoted the migration and invasion of gastric cancer cells, and the process of EMT in gastric cancer cells was significantly enhanced by GC-MSC-primed macrophage treatment. Our study showed that tumor-promoting GC-MSCs contribute to M2 macrophage polarization within the gastric cancer niche through considerable secretion of IL-6 and IL-8. These GC-MSC-primed macrophages can subsequently prompt gastric cancer metastasis via EMT promotion in gastric cancer cells.
Highlights
Gastric cancer is the second most prevalent malignant tumors worldwide[1]
We reported for the first time that the polarization and generation of pro-tumor M2-like macrophages was strikingly triggered by gastric cancer-derived mesenchymal stromal cells (GC-mesenchymal stromal cells (MSCs)) in gastric cancer through activation of the JAK2/STAT3 signaling pathway via high secretion of IL-6/IL-8
Macrophages are essential for the tumor-promoting effect of GC-MSCs in vivo GC-MSCs were characterized by their pluripotent differentiation potential and immunophenotype
Summary
Gastric cancer is the second most prevalent malignant tumors worldwide[1]. Advancement in treatment has resulted in a decrease in mortality, the 5-year survival rate of patients after surgical resection remains low[2]. A high rate of metastasis is a major obstacle in improving long-term survival after curative resection[3]. Elucidation of a unique pathological mechanism for gastric cancer progression is urgently. Tumor-associated macrophages (TAMs) have high plasticity and predominantly present as an M2 phenotype, which is associated with cancer metastasis and worse prognosis in patients[7,8]. The underlying mechanism for M2-like TAM generation within the tumor microenvironment is largely unknown. The effects of cancer cells on the M2 polarization of macrophages have become a research focus.
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