TY - JOUR
T1 - Stromal-derived extracellular vesicles suppress proliferation of bone metastatic cancer cells mediated by ERK2
AU - Shupp, Alison B.
AU - Neupane, Manish
AU - Agostini, Lebaron C.
AU - Ning, Gang
AU - Brody, Jonathan R.
AU - Bussard, Karen M.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.
PY - 2021/10
Y1 - 2021/10
N2 - Bone is a common site of cancer metastasis, including cancers such as breast, prostate, and multiple myeloma. Disseminated tumor cells (DTCs) shed from a primary tumor may travel to bone and can survive undetected for years before proliferating to form overt metastatic lesions. This period of time can be defined as metastatic latency. Once in the metastatic microenvironment, DTCs engage in intercellular communication with surrounding stromal cells, which can influence cancer cell survival, proliferation, and ultimately disease progression. The role of the surrounding tumor microenvironment in regulating DTC fate is becoming increasingly recognized. We have previously shown that in the bone microenvironment, osteoblasts are “educated” by interactions with breast cancer cells, and these “educated” osteoblasts (EOs) produce soluble factors that regulate cancer cell proliferation. In this study, we provide evidence indicating that EOs produce small extracellular vesicles (sEVs) that suppress breast cancer proliferation, in part through regulation of ERK1/2 signaling. Additionally, using EdU-incorporation assays and propidium iodide staining we demonstrate that exposure to EO-derived sEVs decreases breast cancer cell entry to S-phase of cell cycle. We also have evidence that particular microRNAs, including miR-148a-3p, are enriched in EO-derived sEVs, and that miR-148a-3p is capable of regulating breast cancer proliferation.
AB - Bone is a common site of cancer metastasis, including cancers such as breast, prostate, and multiple myeloma. Disseminated tumor cells (DTCs) shed from a primary tumor may travel to bone and can survive undetected for years before proliferating to form overt metastatic lesions. This period of time can be defined as metastatic latency. Once in the metastatic microenvironment, DTCs engage in intercellular communication with surrounding stromal cells, which can influence cancer cell survival, proliferation, and ultimately disease progression. The role of the surrounding tumor microenvironment in regulating DTC fate is becoming increasingly recognized. We have previously shown that in the bone microenvironment, osteoblasts are “educated” by interactions with breast cancer cells, and these “educated” osteoblasts (EOs) produce soluble factors that regulate cancer cell proliferation. In this study, we provide evidence indicating that EOs produce small extracellular vesicles (sEVs) that suppress breast cancer proliferation, in part through regulation of ERK1/2 signaling. Additionally, using EdU-incorporation assays and propidium iodide staining we demonstrate that exposure to EO-derived sEVs decreases breast cancer cell entry to S-phase of cell cycle. We also have evidence that particular microRNAs, including miR-148a-3p, are enriched in EO-derived sEVs, and that miR-148a-3p is capable of regulating breast cancer proliferation.
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U2 - 10.1158/1541-7786.MCR-20-0981
DO - 10.1158/1541-7786.MCR-20-0981
M3 - Article
C2 - 34021072
AN - SCOPUS:85117827725
SN - 1541-7786
VL - 19
SP - 1763
EP - 1777
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 10
ER -