Abstract
In metastasis, circulating tumor cells penetrate the walls of blood vessels and enter the metastatic target tissue, thereby becoming exposed to novel and relatively unsupportive microenvironments. In the new microenvironments, the tumor cells often remain in a dormant state indefinitely and must adapt before they are able to successfully colonize the tissue. Very little is known about this adaptive process. We studied temporal changes in gene expression when breast cancer cells adapt to survive and grow on brain, bone marrow, and lung tissue maintained in an in vivo culture system, as models of the metastatic colonization of these tissues. We observed the transient activation of genes typically associated with homeostasis and stress during the initial stages of adaptation, followed by the activation of genes that mediate more advanced functions, such as elaboration of cell morphology and cell division, as the cells adapted to thrive in the host tissue microenvironment. We also observed the temporary induction of genes characteristic of the host tissue, which was particularly evident when tumor cells were grown on brain tissue. These early transient gene expression events suggest potential points of therapeutic intervention that are not evident in data from well-established tumors.
Highlights
Signals supplied by the local microenvironment control gene expression during development [1] and when cells are placed in novel tissue microenvironments for investigative purposes [2,3]
We explored the time-dependence of differential gene expression when cancer cells were directly embedded in different tissue microenvironments, as a model for the immediate events that occur during post-extravasation colonization in different metastasis microenvironments
These disseminated tumor cells reside in foreign tissue microenvironments as single cells until they acquire the ability to divide
Summary
Signals supplied by the local microenvironment control gene expression during development [1] and when cells are placed in novel tissue microenvironments for investigative purposes [2,3]. Gene expression in 4T1 cells, which metastasize to bone, lung, and lymph nodes, was compared to gene expression in 4TO7 cells, which were derived from the same primary tumor, and which extravasate into but fail to colonize the lung [10], to identify genes that mediate colonization of lung [11] In those experiments, cells introduced into the circulation were cultured from the target tissue, and this process was repeated, resulting in cell lines with progressively more aggressive ability to extravasate, survive, and colonize the target tissue. Events that ensure the survival of the cell immediately after extravasation are not understood
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