Keeping Stem Cells Stem Cells

Chengcheng Zhang is an assistant professor in the UT Southwestern Medical Center departments of physiology and developmental biology in Dallas, Texas. His lab has identified a receptor on the surface of cancer stem cells that, when activated, prevents them from differentiating.

Zhang explains his work this way: “Cancer cells grow rapidly in part because they fail to differentiate into mature cells. Drugs that induce differentiation can be used to treat cancers.” In his however has identified a new target for cancer: “Our research has identified a protein receptor on cancer cells that induces differentiation, and knowing the identity of this protein should facilitate the development of new drugs to treat cancers.”

The receptor to which Zhang is referring is a member of a family of proteins known as the “leukocyte immunoglobulin-like receptors.” These LIRs, as they are called, have bits located outside the cell and help regulate cells of the immune system. The LIR that Zhang’s lab found is called the subfamily B member 2 or LILRB2. LILRB2 is found on the surface of immune cells where it binds to molecules on the surface of cells that process antigens (foreign substances in the body) and prevents the initiation of an immune response. LILRB2 also has a newly-described role in stem cell biology.

Zhang again: “The receptor we identified turned out to be a protein called a classical immune inhibitory receptor, which is known to maintain stemness of normal adult stem cells and to be important in the development of leukemia.”

What does Zhang mean by “stemness?” He is referring to the potential of a bone marrow stem cell that makes blood cells to develop into different kinds of cells and replenish red blood cells lost to wear and tear or injury. Once stem cells differentiate into adult cells, they cannot return to their original stem cell state. The body seems to only have a finite number of stem cells and, therefore, depleting them is unwise.

Before Zhang’s study, there was no indication that LILRB2 could bind to anything but surface proteins on antigen-presenting cells, but Zhang and his team has discovered a new function for LILRB2. LILRB2 can bind to members of a poorly understood group of proteins known as angiopoietic-like proteins that support stem cell growth. By binding angiopoietic-like proteins, LILRB2 sends a signal to the interior of the stem cell to not differentiate. This inhibition keeps cancer stem cells from differentiating. By not differentiating, the stem cells divide furiously and never differentiate and make progeny cells that also divide many times and do not differentiate. This is the main mechanism that drives the progression of leukemia.

Zhang said that this inhibition does not cause cancer stem cells to make new stem cells but does not preserve their potential to do so. Also, making inhibitors that prevent the interaction between angiopoietin-like proteins and LILRB2 can force cancer stem cells to differentiate. Thus these new findings may give us a target for fighting leukemia.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).