Pituitary tumors contain a side population with tumor stem cell-associated characteristics

MERTENS, FREYA; GREMEAUX LIES ; CHEN, JIANGHAI; FU, QIULI; WILLEMS, CHRISTOPHE; ROOSE, HELEEN; GOVAERE, OLIVIER; ROSKAMS, TANIA; CRISTINA, CAROLINA; BECU VILLALOBOS, DAMASIA; JORISEEN, MARK; BEX, MARIE; VAN LOON, JOHANNES; VANKELECOM, HUGO

ENDOCRINE - RELATED CANCER

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2015 vol. 22 p. 481 - 504

1351-0088

Pituitary adenomas cause significant endocrine and mass-related morbidity. Only little is known about mechanisms underlying pituitary tumor pathogenesis. We searched for a side population (SP) in pituitary tumor, representing cells with high efflux capacity and potentially enriching for tumor stem cells (TSC). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) depleted from endothelial and immune cells, enriches for cells that express ?tumor stemness? markers and signaling pathways, including epithelial mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self renewing sphere-forming cells, considered a property of TSC. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it more tumorigenic than the non-SP ?main population?. Of the two EMT regulatory pathways tested, inhibition of C-X-C chemokine receptor type 4 (Cxcr4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas activation of TGFβ had no effect. The adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2-/-) mice bearing prolactinomas, contain more pSP, Sox2+ and colony-forming cells than wildtype glands. In conclusion, we detected a SP in pituitary tumor and identified TSC-associated characteristics. Our study adds new elements to the unravelment of pituitary tumor pathogenesis and may lead to new therapeutic targets.