Abstract
A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203, a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203-transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.
Highlights
Distant metastasis is the leading cause of mortality in cancer patients, including those with colorectal cancer (CRC) which is one of the most common malignant tumors worldwide [1] and has a poor prognosis despite recent advances in diagnosis and treatment [2]
We found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs)
We recently reported that increased production of C-C motif chemokine 2 (CCL2) due to downregulation of F-box and WD repeat domain containing 7 (FBXW7) in bone marrow (BM)-derived stromal cells promoted the formation of premetastatic niches through recruitment of myelo-monocytic cell-derived suppressor cells and TAMs, thereby promoting metastatic tumor growth [6]
Summary
Distant metastasis is the leading cause of mortality in cancer patients, including those with CRC which is one of the most common malignant tumors worldwide [1] and has a poor prognosis despite recent advances in diagnosis and treatment [2]. The ‘seed and soil hypothesis’ of malignancy proposed that the distribution of metastasis from cancers is not based on chance alone, and that the microenvironment of the potential metastatic ‘soil’ could either promote or prevent the primary ‘seed’ from growing [3, 4]. This “seed and soil” hypothesis is fundamental to the concept of the premetastatic niche whereby tumors prepare defined organs for metastasized cells [5]. Understanding this mechanism should open up a new field of cancer therapy through the targeting of tumorhost interaction
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