Women with late-stage
ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the
tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple
ovarian cancer cell lines an
ovarian cancer stem cell-enriched population marked by CD44, CD24, and
Epcam (3+) and by negative selection for Ecadherin (Ecad-) that comprises less than 1% of
cancer cells and has increased colony formation and shorter
tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as
doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad- cells. Similarly, proliferation of the 3+Ecad- cells in monolayer increased with treatment, by either
doxorubicin or
cisplatin, compared with the unseparated or cancer stem cell-depleted 3-Ecad+ cells. However, these cells are sensitive to
Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits
ovarian cancer cells by inducing G1 arrest of the 3+Ecad- subpopulation through the induction of
cyclin-dependent kinase inhibitors. 3+Ecad- cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian
carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of
ovarian cancer and in other human
ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of
therapeutics.