PARENT SESSION
9:00 AM to 11:00 AM
Wednesday, April 24, 2002
Symposium 22
Tumor-Vascular Interaction
Room: Nevada 1-2
Chair: Dewhirst, Mark²²Rm 201 MSRB, Durham, NC
Speakers: Hill, Richard⁴; Muschel, Ruth⁵; Dewhirst, Mark⁶; Hendrix, Mary⁷⁴Rm 10-113, Toronto, Ontario, Canada⁵Rm 269 John Morgan Bld, Philadelphia, PA⁶Rm 210, Durham, NC⁷100 Bowen Science Bldg., Iowa City, Iowa

(S22-2) Fate of Circulating Tumor Cells.

Muschel, Ruth^*,1, Fu, Weili¹, Kim, Jay¹, Wong, Chris¹, Al-Mehdi, Abu¹, Zhou, Zenyi¹, Roos, Ed³, DiPersio, Mike², ¹ University of Pennsylvania, Philadelphia, PA³ Netherlands Cancer Institute, Amsterdam, Netherlands² Albany Medical College, Albany, NY

ABSTRACT-
Hematogenous metastasis results from circulating tumor cells lodgment and subsequent proliferation at distant sites. We have used fluorescent microscopy of isolated, perfused lungs to examine tumor cells within the lung after their entry into the circulation. These methods have revealed that tumor cells rapidly attach to the pulmonary endothelium. After attachment metastatic tumor cells proliferate, but unexpectedly this proliferation was found to first occur within the vascular channels. The vascular channels could be specifically delineated in this system using DiI-acetylated LDL that binds to endothelial LDL receptors. Although extravasation rarely occurred, the extravasated cells were rapidly cleared and did not result in early colony formation. Thus intravascular proliferation leads to early colony formation. At subsequent times as the colonies enlarge the integrity of the vasculature is destroyed and colony growth then escapes the vasculature. This alternative model of tumor metastasis has the implications that extravasation would be a poor target for therapy, but that tumor cells attachment might be a useful target. We have used this methodology to compare metastatic to non metastatic cells. We used melanoma as a model system. Both metastatic and non metastatic melanoma cells attached to the pulmonary endothelium. However after 2-3 days the non-metastatic cells did not survive while the metastatic cells had gone on to form intravascular colonies. We showed that apoptosis was the mode of death for these attached tumor cells. Interestingly inhibition of apoptosis by bcl-2 could enhance metastasis. Thus resistance to apoptosis appears to be a significant rate limiting step for metastasis.

KEYWORDS: metastasis