title: Intravital microscopy through an abdominal imaging window reveals a pre-micrometastasis stage during liver metastasis.
abstract: Cell dynamics in subcutaneous and breast tumors can be studied through conventional imaging windows with intravital microscopy. By contrast, visualization of the formation of metastasis has been hampered by the lack of long-term imaging windows for metastasis-prone organs, such as the liver. We developed an abdominal imaging window (AIW) to visualize distinct biological processes in the spleen, kidney, small intestine, pancreas, and liver. The AIW can be used to visualize processes for up to 1 month, as we demonstrate with islet cell transplantation. Furthermore, we have used the AIW to image the single steps of metastasis formation in the liver over the course of 14 days. We observed that single extravasated tumor cells proliferated to form "pre-micrometastases," in which cells lacked contact with neighboring tumor cells and were active and motile within the confined region of the growing clone. The clones then condensed into micrometastases where cell migration was strongly diminished but proliferation continued. Moreover, the metastatic load was reduced by suppressing tumor cell migration in the pre-micrometastases. We suggest that tumor cell migration within pre-micrometastases is a contributing step that can be targeted therapeutically during liver metastasis formation.
authors.affiliation: Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht 3584 CT, Netherlands.
authors.forename: Laila
authors.initials: L
authors.lastname: Ritsma
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beerling
authors.forename: Cindy J M
authors.initials: CJ
authors.lastname: Loomans
authors.forename: Anoek
authors.initials: A
authors.lastname: Zomer
authors.forename: Carmen
authors.initials: C
authors.lastname: Gerlach
authors.forename: Nienke
authors.initials: N
authors.lastname: Vrisekoop
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Seinstra
authors.forename: Leon
authors.initials: L
authors.lastname: van Gurp
authors.forename: Ronny
authors.initials: R
authors.lastname: Schäfer
authors.forename: Daniëlle A
authors.initials: DA
authors.lastname: Raats
authors.forename: Anko
authors.initials: A
authors.lastname: de Graaff
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
authors.forename: Inne H Borel
authors.initials: IH
authors.lastname: Rinkes
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018715:Microscopy, Video / Q000379:methods*; D061206:Neoplasm Micrometastasis / Q000175:diagnosis*