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Reciprocal communication between cancer cell and tumor microenvironment promotes breast cancer metastasis

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abstract
Metastasis is the principle cause of the deaths among breast cancer patients. Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism is poorly understood. One of critical steps of brain metastasis is the breaching of the BBB and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival followed by verification in brain metastatic cell lines and found that only MMP1 is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin that are key components of BBB. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, while ectopic expression of MMP1 significantly increased the brain metastatic ability of breast cancer cells. We also found that COX2 was up-regulated in brain metastatic cells and that COX2-induced prostaglandins promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release Chemokine CCL7 which in turn promoted self-renewal of tumor initiating cells in the brain. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis. One the other hand, bone is the most frequently affected organ in metastatic breast cancer. Prediction and early detection of bone metastasis is particularly important for the management of breast cancer progression. We checked the secreted microRNA profiles in breast cancer patients and breast cancer metastatic cells lines with distinct organ tropisms and found miR-19a is specifically up-regulated in the serum exosome of patients with bone metastases, as well as exosome from bone metastatic cell lines. MiR-19a in the exosome is able to induce osteoclast activity in vitro. Knockout of miR-19a significantly decreased the bone metastases in the MCF7BoM2 Xenograft mouse model, obliterating the osteoclast-promoting effect of the cancer cell derived exosomes. Overall, exosomal miR-19a is a key regulator involved in the formation of osteolytic niche, suggesting its potential as a novel biomarker and therapeutic target for breast cancer bone metastasis.
subject
BBB
Bone Metastasis
Brain Metastasis
Breast Cancer
Exosome
Osteoclast
contributor
Wu, Kerui (author)
Watabe, Kounosuke (committee chair)
Kucera, Greg (committee member)
Lo, Hui-Wen (committee member)
Metheny-Barlow, Linda (committee member)
Singh, Ravi (committee member)
date
2017-06-15T08:36:05Z (accessioned)
2018-06-14T08:30:11Z (available)
2017 (issued)
degree
Cancer Biology (discipline)
embargo
2018-06-14 (terms)
identifier
http://hdl.handle.net/10339/82221 (uri)
language
en (iso)
publisher
Wake Forest University
title
Reciprocal communication between cancer cell and tumor microenvironment promotes breast cancer metastasis
type
Dissertation

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