Origin of tumor-derived endothelial cells

Description of projects available to graduate students:

The growth of a tumor past a certain size demands that it establish an independent blood supply. In addition to providing nourishment, this “neovasculature” serves as a portal for metastases. Anti-angiogenic therapies are predicated on the assumption that the stroma comprising the neovasculature is genetically stable and less prone to developing therapy resistance. We have obtained evidence from several human cancer cell lines that the tumor neovasculature contains a variable fraction of endothelial cells (ECs) derived directly from the tumor cells. This conclusion is based on the observation that multiple genetic tags, stably introduced into the starting tumor population, are expressed in subpopulations of tumor-associated ECs (TAECs). These cells harbor only human chromosomes with the same markers as the tumor cells and can be isolated from tumors derived from single cell clones. These “tumor-derived ECs” (TDECs) are similar to normal ECs and reside within the tumor vasculature. TDECs can also be serially passaged in vivo and home to the tumor neo-vasculature. The incomplete nature of the TDEC phenotype may be a consequence of the genomic instability of the parental tumor cells. We are extending these findings to other established tumor cells and primary human cancers. We are also determining whether TDECs can out-compete their murine counterparts for establishment within the neo-vasculature and whether they are more adept at repopulating the tumor from which they derive than heterologous tumors. We are also determining whether TDECs, like the tumor cells from which they arise, are genetically unstable and alter their genetic profiles during adaptation to serial in vivo passage. We are also exploring whether TDECs are actually needed for optimal tumor xenograft growth and maintenance. Finally, we are refining an in vitro model for early TDEC development by establishing the time course of this process and by characterizing the factors that promote the tumor cell→TDEC transition. These studies should provide new insights into the genesis of TDECs, how they differ both functionally and molecularly from murine ECs, and whether TDEC genomic instability might explain the limited success of anti-angiogenic therapies.

Techniques graduate student will learn:
Standard in vitro and in vivo manipulation of tumor cells and tumor xenografts; confocal microscopy; Genome-wide SNP analysis and transcriptional profiling to genetic differences among various TDEC populations.