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Breast Cancer Emergence from Dormancy can be Activated by Hepatic Stellate Cells
Author(s) -
Khazali Ahmad Suhail,
Clark Amanda,
Wheeler Sarah,
Wells Alan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.698.8
Subject(s) - hepatic stellate cell , breast cancer , metastasis , cancer , ca 15 3 , medicine , liver cancer , cancer research , cancer cell , ca15 3 , chemokine , pathology , inflammation , oncology
Tumor dormancy is a well‐known clinical phenomenon. Studies have shown that in breast cancer survivors, the cancer recurs within 5–10 years (up to 20%) and more than 10 years (up to 11%) post initial treatment. Liver is one of the main metastatic sites for breast cancer recurrence as 60% of breast cancer patients had liver metastases at autopsy and 5–14% of the patients had liver metastases 4–10 years after radical mastectomy suggesting tumor dormancy. The factors and mechanisms for tumor outgrowth in the liver still remain unclear. Inflammation may increase the risk of breast cancer recurrence as increased levels of inflammation markers have been correlated with poor disease‐free and overall survival. We hypothesized that inflammatory signals from activated liver non‐parenchymal cells (NPC) can stimulate dormant micrometastatic cancer cells to grow and form macrometastases. In this study, we performed co‐culture experiments of breast cancer cell lines with hepatic stellate cell lines. Transwell assay was performed to determine whether soluble factors contribute to tumor growth. Protein array and luminex assays were conducted to determine the soluble factors secreted by the stellate cells. Finally, induction of breast cancer growth by these chemokines was validated in both in‐vitro and ex‐vivo. Human and rat hepatic stellate cell lines promoted significant breast cancer cells (MCF‐7) growth in‐vitro. Transwell assay indicated that MCF‐7 growth was due to soluble factors. IL‐8 and MCP‐1 were highly secreted by the stellate cells in‐vitro as well as by primary human NPC in a 3D ex‐vivo microphysiologic system, Liverchip. In‐vitro and ex‐vivo assays verified that IL‐8, but not MCP‐1, could directly stimulate breast cancer cell proliferation. These data suggest that activated NPC may mediate breast cancer escape from dormancy in the liver by secreting inflammatory signals. Disrupting inflammation might be an ideal therapeutic alternative to prevent tumor escape from dormancy in the liver. Support or Funding Information Joint support by the NIH (UH3TR000496), NCATS and NCI