Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Proceedings of the National Academy of Sciences

Choi YJ, Ingram PN, Yang K, Coffman L, Iyengar M, Bai S, Thomas DG, Yoon E, Buckanovich RJ. Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2. Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6882-8. doi: 10.1073/pnas.1507899112. Epub 2015 Nov 30. Erratum in: Proc Natl Acad Sci U S A. 2021 Nov 16;118(46): PMID: 26621735; PMCID: PMC4687560.

Although there is evidence for the cancer stem cell theory, not much was known about the ovarian cancer stem cell system and how it operated. This paper characterized the stem cell hierarchy, showing the different cell identities and demonstrating that it was, in fact, a hierarchy and not just stochastically driven.

They confirmed that ALDH and CD133 are good markers for the stem cells that separate them into

distinct heterogeneous populations of ovarian cancer stem cells.

These markers could also identify a population of normal ovarian stem cells suggesting ALDH⁺CD133⁺ cells may be involved in the cell of cancer origin.

Both the ALDH⁺CD133⁺ cells and ALDH⁺CD133^- could engraft into mice, but the double positives generated tumors faster. ALDH^-CD133^- cells could not form tumors or produce any of the other cells in the heirarchy, while the double positives could produce all the cells in the hierarchy. Both ALDH⁺CD133^- and ALDH^-CD133⁺ cells could self-renew and produce double negatives.

Their study involved modulating BMP2 levels to perturb the hierarchy and force cells in one direction or the other. Both BMP2 and its inhibitor Noggin restrict cancer growth in vitro. One of the goals of the study was to reconcile the differences seen between in vivo and in vitro studies using BMP2: in vivo increases in BMP2 resulted in increased tumor growth and chemotherapy resistance but, in vitro, bulk cell proliferation is suppressed. Treatment with cisplatin and BMP2 increased the absolute number of double-positives, but treatment with Noggin and cisplatin decreased absolute CSC numbers. In tumor initiation tests, cisplatin and Noggin together decrease tumor initiation capacity compared to cisplatin alone and were smaller than tumors treated with BMP2 and cisplatin.

The double negative cells have the highest expression of BMP2, producing it to stimulate the self-renewal of the double-positives while inhibiting the proliferation of the middle progenitor groups. They believe this twofold purpose is key to the complexity underlying the discrepancy they see. In vitro, BMP2 treatment reduced the absolute cell numbers by limiting proliferation of the double negative population, but in vitro growth from BMP2 treatment has more to do with the increase in stem cells. Ovarian cancer shows upregulation of BMP2 and patient prognosis is correlated with BMP2 expression. Fully reconciling the contrasting results will require studies on the receptors involved in BMP2 pathways. They did see one rare stoachastic even where an ALDH⁺CD133^- cell produced a double positive cell.