Researchers have found a genetic switch belonging to a class of molecules called microRNAs that regulate the cancer stem cells in mice.
Tumor stem cells, which live indefinitely and cause subsequent tumors, are suspected to cause many cancers. However, these cells remain unaffected to chemotherapy or other existing treatments, their survival might explain the reason of the recurrence of tumors after treatment.
So, researchers aim at getting rid of these bad seeds as the effective way in treating cancer. But, their rarity, even in large tumors, makes it difficult to study them.
The scientists have devised a way to generate large numbers of human breast cancer stem cells in mice and have discovered a genetic switch that regulates critical properties of the cells.
The regulator, which belongs to a class of molecules called microRNAs (microRNAs), pushes the stem cells to become more differentiated and less tumorigenic through its ability to switch off particular genes.
The research was led by Fengyan Yu, Judy Lieberman, an investigator at the Immune Disease Institute and Harvard Medical School professor of pediatrics at Children's Hospital Boston and Erwei Song, a former postdoc in her lab now working as a breast cancer surgeon at Sun Yat-Sen University in Guangzhou, China.
"People know that microRNAs are important regulators of cell differentiation, but nobody has shown that they regulate the critical properties of cancer stem cells, or any kind of stem cells," said Lieberman.
Through demonstrating that microRNAs can rein in tumor stem cells, the work suggests a unique way to target these cells to treat cancer with therapeutic RNAs, a promising new class of medicine under development for many diseases.
The researchers first started working in China to isolate breast cancer stem cells from freshly removed tumors.
As cancer stem cells resist chemotherapy, the researchers predicted that breast tumors from women who had received such treatment before surgery might be enriched with stem-like cells, and their experiments confirmed this idea.
In tumors from untreated women, less than 1 in 250 cells had the cell surface markers and growth characteristics of stem cells; in treated tumors, the number rose to 1 in 17.
This discovery gave the scientists the idea of trying to generate larger quantities of tumor stem cells by growing human breast cancer cells in immunosuppressed mice dosed with a chemotherapeutic agent.
Almost 75 percent of the cells in the retrieved tumors displayed the properties of stem cells, after three months of such a regimen: they had the expected cell surface markers, were highly tumorigenic and metastatic in mice, were relatively drug resistant, and could be induced to differentiate into multiple kinds of breast tissue cells.
Constant supply of cancer stem cells enabled the researchers to measure levels of microRNAs.
It was discovered that cancer stem cells contained low amounts of several microRNAs compared to more mature tumor cells or stem cells that had differentiated in culture.
The researchers concentrated on a tumor-supressing microRNA called let-7which when in the stem cells, lost their ability to self-renew and began to differentiate. The cells became unable to form tumors in mice or to metastasize.
Further studies revealed that let-7 did this by switching off two cancer-related genes: the oncogene Ras, and HMG2A, which when switched off caused the cells to differentiate.
Let-7 may offer a unique opportunity to attack tumor stem cells using therapeutic RNA, if this finding applies to other tumor types. Delivery of the let-7 RNA to tumors could potentially deplete stem cells by pushing them down the path of differentiation.
The study is published in the recent issue of Cell.