Abstract
BackgroundThe origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior.MethodsER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC.ResultsThe presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ERα and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-β1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines.ConclusionsSpontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties and propensity to metastasize to brain, suggest that cell fusion can contribute to tumor heterogeneity.
Highlights
Breast cancer is the most frequent malignant disease in women, affecting 1 in 8 North American women throughout their lifetime and is the second leading cause of cancer-related deaths in U.S [1]
We show that the estrogen-independent cells, isolated from an estrogenindependent tumor, is a novel hybrid cell line generated spontaneously in a metastatic site, which has propensity to metastasize to brain in addition to lung and bone
Experimental evidence indicates that soluble factors produced by aggressive cancer cells may generate metastatic niches for less aggressive cancer cells, and we were interested to determine if growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line could affect the metastatic potential of a less aggressive ER-positive breast cancer cell line
Summary
Breast cancer is the most frequent malignant disease in women, affecting 1 in 8 North American women throughout their lifetime and is the second leading cause of cancer-related deaths in U.S [1]. Random mutational events and/or epigenetic changes of cancer cells followed by the selection of more malignant variants or acquisition of stem cell like properties has been believed to be the mechanism for tumor progression and for the generation of heterogeneous tumor cell population. Rapid acquisition of metastatic phenotypes has recently been shown through fusion between tumor cells [4] or between tumor cells and bone marrow derived cells [5] indicating a potentially important role of cell fusion in the progression and phenotypic diversity of cancer. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other’s metastatic behavior
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