A hypoxic signature marks tumors formed by disseminated tumor cells in the BALB-neuT mammary cancer model
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Aichi Msaki1, Anna Pastò1, Matteo Curtarello1, Maddalena Arigoni2, Giuseppina Barutello2, Raffaele Adolfo Calogero2, Marco Macagno2, Federica Cavallo2, Alberto Amadori1,3,*, Stefano Indraccolo1,*
1Istituto Oncologico Veneto - IRCCS, Padova, Italy
2Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
3Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
*These authors have contributed equally to this work
Stefano Indraccolo, email: [email protected]
Keywords: breast cancer, Her2/neu, hypoxia, DTC, tumorigenesis
Received: July 30, 2015 Accepted: March 31, 2016 Published: April 20, 2016
Metastasis is the final stage of cancer progression. Some evidence indicates that tumor cell dissemination occurs early in the natural history of cancer progression. Disseminated tumor cells (DTC) have been described in the bone marrow (BM) of cancer patients as well as in experimental models, where they correlate with later development of metastasis. However, little is known about the tumorigenic features of DTC obtained at different time points along tumor progression. Here, we found that early DTC isolated 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 detectable when late DTC obtained from 19-22 week-old BALB-neuT mice were injected. Angiogenesis, which contributes to regulate tumor dormancy, appeared dispensable to reactivate late DTC, although it accelerated growth of secondary DTC tumors. Compared with parental mammary tumors, gene expression profiling disclosed a distinctive transcriptional signature of late DTC tumors which was enriched for hypoxia-related transcripts and was maintained in ex-vivo cell culture. 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.
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