Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

Abstract

Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression.

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

“…Relevantly, EVs derived from 8701-BC breast cancer cells and HT-1080 fibrosarcoma cells were reported to contain MMP9 in both pro-and mature forms with proteolytic activity [45,46]. Besides, MMP3 has been identified in/on EVs released from stromal cells, such as mesenchymal stromal cells (MSC) and adipocytes [47,48]. Moreover, it has been shown that cancer exosomes could trigger MSC differentiation into pro-angiogenic and pro-invasive myofibroblasts, secreting high levels of matrix-regulating factors (MMP-1, -3, and -13), VEGF-A, and HGF [49].…”

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

“…Exosomes are extracellular microvesicles (30 to 150 nm in diameter) derived from various cells, transferring different proteins, non-coding RNA and coding RNA, which have been looked as diseases biomarkers or cellcell communication factors [31,32]. Increasing studies have unveiled that exosomes derived from the insulinresistant adipocyte were implicated in the skeletal muscle insulin resistance, obesity-related liver disease, atherosclerosis, and lung cancer [33][34][35][36]. Given the broad spectrum of the discoveries of the function of these exosomes, it is not surprising that exosomes derived from insulin-resistant adipocytes, functioned as independent metabolic units, which might provide a promising therapeutic target on the insulin resistance, diabetes, and related metabolic disorders [37].…”

Exosomes play roles in sequential processes of tumor metastasis

“…These exosomes, either TDEs or non‐TDEs, are also heterogenetic, differing in size, morphology, composition or biogenic mechanisms; moreover, they are able to generate a complex network of interactions that are both tumor facilitative and inhibitive . For instance, non‐cancer cells, such as adipocytes, could transfer matrix metalloproteinase (MMP)3 proteins via exosomes, which fused with tumor cells enhance their invasive ability by activating MMP9 . Acute myeloid leukemia blasts remodel the bone marrow niche into a leukemia‐growth‐permissive and normal‐hematopoiesis‐suppressive microenvironment via TDEs, thus promoting leukemic cell proliferation and survival, while suppressing normal hematopoiesis .…”

“…2 For instance, noncancer cells, such as adipocytes, could transfer matrix metalloproteinase (MMP)3 proteins via exosomes, which fused with tumor cells enhance their invasive ability by activating MMP9. 15 Acute myeloid leukemia blasts remodel the bone marrow niche into a leukemia-growth-permissive and normalhematopoiesis-suppressive microenvironment via TDEs, thus promoting leukemic cell proliferation and survival, while suppressing normal hematopoiesis. 16 Here, we highlight five different crucial events in primary tumor sites, hoping to define the specific roles of exosomes in the initiation of metastasis.…”