A Stem Cell-Based Therapy for Colon Cancer

Colorectal cancer is the third leading cause of death in the Western World. Like many other types of cancer, colorectal cancer spreads and is propagated by cancer stem cells. Therefore, understanding how to inhibit the growth of cancer stem cells provides a key to treating the cancer itself.

By inactivating a gene that drives stem cell renewal in cancer stem cells, scientists and surgeons at the Princess Margaret Cancer Centre in Toronto, Canada, have discovered a promising new approach to treating colorectal cancer.

John Dick, a senior scientist at the Princess Margaret Cancer Centre, said, “This is the first step toward clinically applying the principles of cancer stem cell biology to control cancer growth and advance the development of durable cures.”

In preclinical experiments with laboratory rodents, Dick and his team identified a gene called BMI-1 as a pivotal regulator of colon cancer stem cell proliferation. With this knowledge in hand, Dick’s laboratory dedicated many hours to finding small molecules that disarm BMI-1. Then Dick and his co-workers replicated human colorectal cancer in mice, and used their BMI-1-inhibiting small molecules to treat these cancer-stricken mice.

According to lead author of this work, Antonija Kreso: “Inhibiting a recognized regulator of self-renewal is an effective approach to control tumor growth, providing strong evidence for the clinical relevance of self-renewal as a biological process for therapeutic targeting.”

Dr. Dick explained: “When we blocked the BMI-1 pathway, the stem cells were unable to self-renew, which resulted in long-term and irreversible impairment of tumor growth. In other words, the cancer was permanently shut down.”

The clinical potential of this approach is significant, since it provides a viable treatment that specifically targets colon cancer. About 65% of all colorectal cancers have an activated BMI-1 pathway. Since physicians now have techniques for identifying the presence of BMI-1 and the tools to inhibit it, this strategy could translate into a clinical treatment that might radically transform the treatment of aggressive, advanced colorectal cancers. Such a treatment would be specific, personal, and specific. May the phase 1 trials begin soon!!!

Expanding Blood-Making Stem Cells for Use in Patients

John Dick is a senior scientist at the University Health Network’s McEwen Centre for Regenerative Medicine and a professor at the University of Toronto. He is also the senior investigator for a study that includes a collaboration between Canadian and Italian stem cell scientists that examined ways to expand human blood stem cells for human use.

A new master control gene was identified in this study that, when manipulated, could increase stem cell production.

In the words of Dick, “For the first time in human blood stem cells, we have established that a new class of non-coding RNA called miRNA represents a new tactic for manipulating these cells, which opens the door to expanding them for therapeutic uses.”

In 2011, Dick’s research group published a landmark paper in which he and his colleagues succeeded in isolating “CD49f+” cells. Just one of these CD49f+ cells could reconstitute an entire blood-cell making system in bone marrow. It has been known for some time that the population of blood cell-making stem cells in bone marrow is rather heterogeneous, and some cells have tremendous regenerative capacities, but others shown only slight regenerative abilities. DIck’s group isolated bone marrow stem cells that could replenish the whole blood-making system of a laboratory animal (see Notta, et al., Science 333, 218-221).

Dick has also pioneered the field of cancer stem cells when his lab identified leukemia stem cells in 1994 (Lapidot T, et al., Nature. 367, 645-8.) and colon cancer cells in 2007 (O’Brien CA, et al. Nature. 445, 106-10).

The lead author of this study, Eric Lechman, recounted his laboratory work with a master control gene known as microRNA 126 or miR-126. THis small RNA normally silences the expression of many genes, and thus keeps stem cells in a quiescent, dormant state. His strategy in working with miR-126 was to introduce new binding sites into the cell for miR-126 in order to lower the concentration of free miR-126 inside the cell. To do this, he infected stem cells with a genetically engineered virus that was loaded with miR-126 binding sites. The results were remarkable.

According to Lechman, “The virus acted like a sponge and mopped up the specific miRNA in the cells. This enabled the expression of normally expressed genes to become prominent, after which we observed a long-term expansion of the blood stem cells without exhaustion or malignant transformation.”

Given the difficult many labs have has growing sufficient quantities of blood stem cells in the laboratory, this finding could completely revolutionize blood stem cell research and clinical treatments with these stem cells.

According to Dick, “We’ve shown that if you remove the miRNA you can expand the stem cells while keeping their identity intact. That’s the key to long-term stem cell expansion for use in patients.”