A hypoxic signature marks tumors formed by disseminated tumor cells in the BALB-neuT mammary cancer model.
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.
Istituto Oncologico Veneto - IRCCS, Padova, Italy.
Aichi
A
Msaki
Istituto Oncologico Veneto - IRCCS, Padova, Italy.
Anna
A
Pastò
Istituto Oncologico Veneto - IRCCS, Padova, Italy.
Matteo
M
Curtarello
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Maddalena
M
Arigoni
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Giuseppina
G
Barutello
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Raffaele Adolfo
RA
Calogero
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Marco
M
Macagno
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Federica
F
Cavallo
Istituto Oncologico Veneto - IRCCS, Padova, Italy.|Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Alberto
A
Amadori
Istituto Oncologico Veneto - IRCCS, Padova, Italy.
Stefano
S
Indraccolo
D000818:Animals; D063646:Carcinogenesis; D015687:Cell Hypoxia / Q000502:physiology; D018450:Disease Progression; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic
DTC; Her2/neu; breast cancer; hypoxia; tumorigenesis