Abstract C93: Liver nonparenchymal cells drive metastatic breast cancer survival but fail to initiate mesenchymal to epithelial reversion

Abstract

Abstract Nearly half of breast cancer metastases will become clinically evident 5 or more years after the cancer was seemingly ablated. This implies that metastatic cancer cells survived over this extended timeframe without emerging as detectable nodules. Breast cancer metastatic dormancy has yet to be universally defined, and is not well understood as a potential means by which clinically evident metastases emerge after being undetected for years (or decades) from the primary tumor diagnosis. Various mechanistic and microenvironmental factors may work independently, collaboratively (or both) in order to allow a dormant metastatic breast cancer cell (or small cluster) to survive long term. At least one tumor dormancy hallmark is likely required: that of E-cadherin re-expression in order to form heterotypic connections between the carcinoma cells and the liver parenchyma. This re-expression is known as the mesenchymal-to-epithelial-reverting-transition (MErT). This re-expression provides not only survival signals to the breast cancer cells but may also establish cell polarity and protection from autocrine signaling (or extracellular factors) that otherwise may prompt the breast cancer cells to initiate metastatic outgrowth. The purpose of this study was to determine whether non-parenchymal liver cells (NPC) contribute to metastatic competency, initiate mesenchymal to epithelial reverting transition (MErT), and trigger metastatic dormancy. We co-cultured human or rat hepatic isolations with highly metastatic human immortalized breast cancer cells (MDA-MB-231). The hepatocytes, non-parenchymal hepatic supernatant, and liver sinusoidal endothelial cell enriched populations were independently cultured with the breast cancer cells in standard monolayer cultures. Because MDA-MB-231 cells do not survive in the hepatocyte culture media alone, we were able to assess the unique properties imparted by the experimental cultures. Confocal immunofluorescent imaging for proliferation and epithelial markers revealed a mesenchymal phenotypic transition only in the hepatocyte/breast cancer cultures. Interestingly the NPC/breast cancer co-cultures promoted cancer cell proliferation (but lower than with hepatocytes included) but did not impart carcinoma epithelial reversion. The liver sinusoidal endothelial cell (LSEC)-enriched co-cultures exhibited much lower breast cancer cell proliferation hinting toward a possible dormancy, though E-cadherin reversion was not detected. These data suggest that perturbations of the parenchymal and non-parenchymal cell ratios in the liver metastatic microenvironment may contribute to metastatic dormancy initiation or stability. Citation Format: Donald P. Taylor, Alan Wells. Liver nonparenchymal cells drive metastatic breast cancer survival but fail to initiate mesenchymal to epithelial reversion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C93.