Dr. Yingqun Huang, Assistant Professor of Obstetrics and Gynecology at the Yale School of Medicine, recently published a study that identified cancer stem cells in ovarian cancer and showed implications for a cure. Ovarian cancer, currently the fourth highest cause of cancer death in women, is especially lethal because its early stages are difficult to detect. Even after detection and treatment, ovarian cancer has developed a high frequency of resistance to drug therapy. To explain the biology of similar cancers, a model of cancer stem cells has emerged.
“To prove the existence of ovarian cancer stem cells,” Huang emphasized, “several vigorous studies are needed.” To qualify as cancer stem cells, cells must have the ability to self-renew and differentiate, driving the growth of malignant tumors. This model possibly explains how cancers like ovarian cancer develop resistance to drugs with such high frequencies. Previous research had already identified the presence of cancer stem cells in breast and colon cancers, but Huang’s recent publication identified two key proteins, Lin28 and Oct4, that contribute to cancer stem cell properties in ovarian cancer. Lin28 and Oct4 are stem cell factors, the expression of which preserves the stem cells’ ability to self-renew and differentiate into different tissue cells. They are also factors in reprogramming human somatic cells to stem cell-like cells.
To determine Lin28 and Oct4’s roles in epithelial ovarian cancer (EOC) cells, Huang’s research team conducted immunohistochemistry tests on small-scaled tissue microarrays. The small-scaled tissue microarrays contained EOC cells at varying stages of differentiation into cancer cells. The tests revealed that the least differentiated EOC cells correlated to an expression of both Lin28 and Oct4 proteins, while the most differentiated cancer cells correlated to a lack of expression of either protein, the former possibly exhibiting cancer stem cell-like behavior. Since Lin28 and Oct4 maintain pluropotency in healthy human stem cells, these proteins potentially preserve stem cell characteristics in cancer cells. Additionally, Lin28 has been found to regulate the expression of Oct4, specifically by binding to Oct4 mRNA to promote translation of Oct4 protein. Because of this relationship, the expression of both proteins more strongly preserves stem cell-like properties than the expression of either protein alone.
Huang and her research team continue to conduct further tests to confirm the presence of cancer stem cells in ovarian cancer. They aim to isolate cancer stem cell candidates and prove that cell transplantation of these cells could result in malignant tumors that retain the properties of original tumors. If these are truly cancer stem cells, then gene therapy presents a possible cure.
One possible form of gene therapy involves adding small interfering RNA (siRNA) to both Lin28 and Oct4 sites to effectively block the expression of these genes. Lin28 inhibits the let-7 microRNAs, which in turn block cell cycle progression. Repressing Lin28 allows let-7 microRNA expression to cease cell proliferation. Oct4 maintains cell survival by inhibiting the apoptosis pathway; without Oct4, a cell more easily undergoes programmed cell death. More importantly, gene therapy specific to Lin28 and Oct4 avoids non-specific targeting. Since Lin28 and Oct4 are expressed in very few somatic cells, the chance that the siRNA would disrupt other body cells is very small.
This gene therapy is only possible, Huang cautioned, if “we can determine whether the expression of Lin28 and Oct4 correlates with the severity of ovarian cancer in the patient.” Even though more tests must be performed before Huang’s research can be translated into therapeutic applications, her findings provide us with a better understanding of the role of cancer stem cells.
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