Editors' ChoiceCancer

BMP2 decides cancer cell fate

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Sci. Signal.  22 Dec 2015:
Vol. 8, Issue 408, pp. ec379
DOI: 10.1126/scisignal.aaf1131

Subpopulations of cells referred to as cancer stem cells (CSCs) may contribute to drug resistance and cancer relapse. Choi et al. used a microfluidic device to culture four heterogeneous ovarian cancer cell populations, identified from three primary patient samples and three ovarian cancer cell lines. The cells were classified on the basis of differences in the abundance of two proteins, aldehyde dehydrogenase (ALDH) and CD133; increased abundance of these two proteins is considered a marker for ovarian cancer stem cells. The four heterogeneous cell types were identified as ALDH+CD133+, ALDH-CD133+, ALDH+CD133-, and ALDH-CD133-. Immunofluorescence microscopy analysis of these cell subpopulations grown in microfluidic chambers revealed that ALDH+CD133+ cells gave rise to all four cell types, ALDH-CD133+ and ALDH+CD133- cells gave rise to ALDH-CD133- cells, and ALDH-CD133- did not give rise to any other cell type. This indicated that the ovarian cancer subpopulations of cells arose from cells organized in a hierarchy based on their stem cell characteristics. The abundance of bone morphogenetic protein (BMP2), a protein also associated with “stemness” in ovarian cancer cells, was unexpectedly low in ALDH+CD133+ and high in ALDH-CD133- cells. Unexpectedly adding BMP2 or inhibiting BMP2 activity by adding the inhibitor noggin decreased the proliferation of the primary cancer cells and one of the cells lines. However, when tested on the ALDH-CD133 subpopulations using a tumor sphere assay, only ALDH+CD133+ cells responded to BMP2 with an increase in proliferation, and noggin inhibited proliferation of these cells. BMP2 decreased the proliferation of ALDH+CD133-, ALDH-CD133+, and ALDH-CD133- cells. When injected into mice, primary ovarian cancer cells that had been previously exposed to noggin exhibited decreased tumor initiation compared with cells that had not been exposed to noggin before injection. ALDH+CD133+ cells showed increased proliferation when grown in the presence of ALDH-CD133- cells compared with proliferation when grown in the presence of ALDH-CD133- cells with BMP2 knockdown, which indicated that BMP2 produced by ALDH-CD133- cells stimulated the proliferation of ALDH+CD133+ cells. Exposure of ovarian cancer cell lines to cisplatin, a cell cycle inhibitor, and noggin reduced the number of ALDH+CD133+ cells in the populations. Treatment of mice with both noggin and cisplatin, compared with cisplatin treatment alone, resulted in smaller xenografted ovarian cancer cell tumors. Thus, the differential production of BMP2 by subpopulations of ovarian cancer cells preferentially stimulates the proliferation of ALDH+CD133+, which may function as CSCs, and blocking this pathway may be beneficial in cancer treatment.

Y.-J. Choi, P. N. Ingram, K. Yang, L. Coffman, M. Iyengar, S. Bai, D. G. Thomas, E. Yoon, R. J. Buckanovich, Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2. Proc. Natl. Acad. Sci. U.S.A. 112, 6882–6888 (2015). [PubMed]