Lymphovascular Breast Carcinoma Tumoral Emboli Form through Stem Cell Initiated Self-Budding Histogenesis.
Sanford H Barsky, Yin Ye, Joseph D Tellez, Meagan Belcher, Fredika M Robertson. University of Nevada School of Medicine and Nevada Cancer Institute, Reno; University of Texas MD Anderson Cancer Center, Houston
Background: Florid lymphovascular tumoral emboli is the diagnostic signature of inflammatory breast cancer (IBC) and other aggressive metastasizing breast cancers but the genesis of the florid numbers of emboli observed in these cases is not readily explanable. It has been assumed that lymphovascular tumoral emboli form as a result of either direct lymphovascular invasion or the induction of encircling lymphovasculogenesis but both these events are thought to be rare events in tumor progression and therefore would not readily explain the large number of emboli which are observed in the human cases.
Design: We carried out both animal and in vitro imaging studies with our human xenograft model of inflammatory breast cancer, MARY-X, which exhibits florid lymphovascular tumoral emboli and in vitro spheroids. We also carried out morphometric studies on the density of the lymphovascular emboli in 10 IBC and 100 non-IBC cases. In addition we carried out laser capture microdissection of these emboli and compared the pooled emboli to non-embolic tumoral areas by RT-PCR and IHC studies.
Results: Animal and in vitro multicolor imaging studies using anti-E-cadherin and anti-podoplanin antibodies showed evidence of self-budding histogenesis within the lymphovascular spaces with one parent embolus giving rise to daughter emboli. Correspondingly, budding spheroidgenesis was observed in vitro. Density studies of the lymphovascular tumoral emboli in the human cases showed their numbers distributed over an exponential rather than linear range. By both RT-PCR and IHC studies, lymphovascular tumoral emboli compared to their respective non-embolic invasive carcinoma areas exhibited five-ten fold higher stem cell marker transcripts and proteins including Stellar, H19, Rex-1, Nestin, CD133 and Aldehyde Dehydrogenase 1 (ALDH1) as well as stem cell transcriptional determinants including OCT4, SOX2, and Nanog. In addition stem cell signaling pathways including Notch3, Bmi-1 and Hedgehog were activated selectively within the lymphovascular tumoral emboli.
Conclusions: These studies, while not addressing the genesis of the initial embolus, show conclusively that emboli beget emboli. This process of self-budding histogenesis is probably stem cell initiated. This phenomenon occurs exclusively within the lymphovascular spaces and explains the exponential increases in embolic number seen in human cases with florid lymphovascular tumoral emboli.
Tuesday, March 1, 2011 8:30 AM
Platform Session: Section C, Tuesday Morning