This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite extensive study of human and rodent liver cancer, liver cancer stem cells remain difficult to identify. Increasingly, evidence supports a model where tumor stem cells arise from normal stem cells during the aging process through genetic mutations that contribute to dysregulation of normal cell processes. The resulting cancer stem cell in turn acquires a unique set of characteristics including the ability to self-renew and give rise to heterogeneous populations of daughter cells, properties needed for tumor survival and propagation. In previous studies, we have shown that with continued passage (p), rat bile duct epithelial cells (BDEC) accumulated neoplastic characteristics, some or all of which were required for the induction of anchorage independent growth and tumorigenicity by activated ErbB-2/Neu. Briefly, by mid-passage (p31-84), BDEC showed alterations in morphology, onset of aneuploidy, increased growth rate with growth factor independence, decreased cell adhesion and loss of cholangiocyte markers expressed at low passage (p85), an increasing number of BDEC expressed activated, tyrosine phosphorylated ErbB-2/Neu and exhibited anchorage independent growth on soft agar. Based on data generated in our laboratory using the BDEC and PEC models, we hypothesize that the soft agar invasion assay selects for a subpopulation of chemoresistant cells with high self-renewal, a characteristic that enables these cells to sustain and expand solid tumor progression. To accomplish this goal we will examine these cells for chemoresistance, tumorigenicity, and the ability to differentiate along an endodermal lineage when transplanted into rat liver. We will also investigate the role of soft agar invasive-derived microvesicle shedding, as horizontal transfer of microvesicle cargo (e.g., proteins, microRNA) to neighboring cells may impart a selective survival advantage to the originating tumor.
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