Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high risk of distant metastasis, in which the intercellular communication between tumor cells also plays a role. Exosomes can be released by tumor cells and promote distant metastasis through intercellular communication or changes in tumor microenvironment, it is an optimized transportation facility for biologically active payloads. This was a hypothesis-generating research on role of exosomal payload in TNBC distant metastasis. Exosomes isolated from supernatant of MDA-MB-231 and MDA-MB-231-HM (a highly pulmonary metastatic variant of parental MDA-MB-231 cells) were characterized. MMP-1 level was detected using mass spectrometry and western blot. Transwell assay, wound healing and CCK-8 assay were employed to explore the effect of exosomal MMP-1 on the metastatic capability of TNBC cells in vitro. Human breast cancer lung metastasis model in nude mice was established to observe the effect of exosomal MMP-1 in vivo. Tissue microarray and blood samples of TNBC patients were applied to analyze the relevance between MMP-1 with metastasis. MDA-MB-231-HM cells secrete exosomes enriched MMP-1, which can be taken up and enhance invasion and migration activities of TNBC cells, including MDA-MB-231, MDA-MB-468 and BT549. After ingesting exosomes enriched with MMP-1, cells secret more MMP-1, which may interact with membrane G protein receptor protease activated receptor 1 (PAR1), thereby initiating epithelial-mesenchymal transition (EMT) to enhance capability of migration and invasion. The lung colonization model shows that the expressions of MMP-1 and PAR1 in the metastases of the 231-HM-exo treated mice were both upregulated. Clinically, the enrichment of MMP-1 can be detected in exosomes extracted from serum of patients with metastasis at higher concentration than that in pre-operative patients. Moreover, in patients with multiple distant metastases, the level of MMP-1 in exosomes is also higher than that in patients with single lesion. MMP-1 from TNBC cells of high metastasis potential can promote the distant metastasis of transform those with low metastasis potential through PAR1-mediated EMT and is likely to be a potential molecular marker.
Highlights
Breast cancer is the most commonly diagnosed malignant tumor and the sixth cause of cancer-related deaths in women[1]
After ingesting exosomes enriched with matrix metalloproteinase-1 (MMP-1), cells secrete more matrix metalloproteinase (MMP)-1, which may interact with membrane G protein receptor protease activated receptor 1 (PAR1), thereby initiating epithelial-mesenchymal transition (EMT) to enhance capability of migration and invasion
The exosomal MMP-1 can be detected from serum of patients with metastasis at higher concentration than that in pre-operative patients
Summary
Breast cancer is the most commonly diagnosed malignant tumor and the sixth cause of cancer-related deaths in women[1]. In China, breast cancer is usually diagnosed at 45 to 55 years old, 15-20% of which is triple-negative breast cancer (TNBC)[2]. TNBC is a subtype of breast cancer with high malignancy, referring to negativity of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC is characterized by a high risk of recurrence and metastasis, a short progression-free survival (PFS) and overall survival (OS)[3]. Regarding the mechanism of breast cancer metastasis, most prior studies have focused on the process of metastasis. The interaction between cancer cell clones was less to be explored in terms of teamwork in the formation of distant metastasis
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