BioProject

Metastasis is considered to be the final and fatal stage of cancer progression. More...

Metastasis is considered to be the final and fatal stage of cancer progression. However, some evidence seems to indicate that tumor cell dissemination could occur early in the natural history of cancer progression. Early disseminated tumor cells (DTC) have been described in the bone marrow (BM) of patients suffering from diverse types of solid tumors as well as in experimental models. The presence of early DTC - which share many features of dormant tumor cells - was found to correlate with later development of metastasis in several cancer types. However, little is known about the tumorigenic features of DTC obtained at different time points along tumor progression. Here, we investigated the actual tumorigenic capacities of DTC. We found that early DTC obtained from BM of 15-17 week-old Her2-neu transgenic (BALB-neuT) mice were not tumorigenic in immunodeficient mice. In contrast, DTC-derived tumors were easily obtained (44 % frequency) when DTC from 19-22 week-old BALB-neuT mice (late DTC) were injected. Angiogenesis, which can contribute to regulate tumor dormancy in other systems, appeared dispensable to reactivate late DTC, although it accelerated growth of secondary DTC tumors. Gene expression profiling disclosed a distinctive transcriptional signature of late DTC tumors compared with that of mammary tumors, which was enriched for hypoxia-related transcripts and appeared to be maintained in cell culture ex-vivo. Immunohistochemical analysis confirmed high HIF-1α expression in DTC tumors, which was maintained in tumor-derived in vitro cultures. Altogether, these findings highlight a different tumorigenic potential of early and late DTC in the BALB-neuT model and describe a HIF-1α-related transcriptional signature in DTC tumors, which may render DTC angiogenesis-competent, when placed in a favourable environment. Overall design: Four tumors derived from Early disseminated tumor cells (DTC) against four mammary tumors Less...