Adult Stem Cells Suppress Cancerous Growth While Dormant


William Lowry and his postdoctoral fellow Andrew White at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have discovered the means by which particular adult stem cells suppress their ability to trigger skin cancer during their dormant phase. A better understanding of this mechanism could provide the foundation to better cancer-prevention strategies.

This study was published online Dec. 15 in the journal Nature Cell Biology. William Lowry, Ph.D. is an associate professor of molecular, cell and developmental biology in the UCLA College of Letters and Science.

Hair follicle stem cells are those tissue-specific adult stem cells that generate the hair follicles. Unfortunately, they also are the cell population from which cutaneous squamous cell carcinoma, a common skin cancer, begins. However, these stem cells cycle between active periods, when they grow, and dormant periods, when they do not grow.

Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).
Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).

White and Lowry used transgenic mouse models for their work, and they inserted cancer-causing genes into these mice that were only expressed in their hair follicle stem cells. During the dormant phase, the hair follicle stem cells were not able to initiate skin cancer, but once they transitioned into their active period, they began growing cancer.

Dr. White explained it this way: “We found that this tumor suppression via adult stem cell quiescence was mediated by PTEN (phosphatase and tensin homolog), a gene important in regulating the cell’s response to signaling pathways. Therefore, stem cell quiescence is a novel form of tumor suppression in hair follicle stem cells, and PTEN must be present for the suppression to work.”

Retinoids are used to treat certain types of leukemias because they drive the cancer cells to differentiate and cease dividing. Likewise, understanding cancer suppression by inducing quiescence could, potentially, better inform preventative strategies for certain patients who are at higher risk for cancers. For example, organ transplant recipients are particularly susceptible to squamous cell carcinoma, as are those patients who are taking the drug vemurafenib (Zelboraf) for melanoma (another type of skin cancer). This study also might reveal parallels between squamous cell carcinoma and other cancers in which stem cells have a quiescent phase.

How Stem Cells Maintain Skin


Professor Kim Jensen from BRIC, University of Copenhagen and Cambridge University has used careful mapping studies to challenge current ideas of how the skin renews itself.

Skin is a rather complex organ system that consists of many cell types and structures. Skin includes proliferating cells in the stratum germanitivum, differentiating cells in the upper layers of the epidermis, hair cells, fat, sensory neurons, Langerhans cells, and sweat and sebaceous glands.

Jensen explained, “Until now, the belief was that the skin’s stem cells were organized in a strict hierarchy with a primitive stem cells type at the top of the hierarchy, and that this cell gave rise to all other cell types of the skin. However, our results show that there are differentiated levels of stem cells and that it is their close micro-environment that determines whether they make hair follicles, fat- or sweat glands.”

Jensen’s work completes what was a “stem cell puzzle.” As Jensen put it, “our data complete what is already known about the skin and its maintenance. Researchers have until now tried to fit their results into the old model for skin maintenance. However, the results give much more meaning when we relate them to the new model that our research purposes.”

To give an example of what Jensen is talking about, over-proliferation of skin cells can initiate skin cancer, but the stem cells of the skin that help maintain the integrity of the skin will lack any detectable genetic changes. According to Jensen, the reason these stem cells lack detectable genetic changes in that they do not take part in over-proliferation.

To demonstrate this, Jensen used a unique technique to label skin cells. They made a mouse strain that expresses a glowing protein from the control region of the Lrig1 gene. The Lrig1 gene is expressed in all proliferating skin stem cell populations. Therefore, making a mouse strain in which all cells expressing Lrig1 also express a glowing protein is a sure-fire way to label the skin stem cell populations.

Jensen and his cohorts used several experimental strategies. First, they simply mapped out the glowing cells in the skin. Jensen and his colleagues discovered that the skin contains several stem cell populations that reside in distinct compartments.  These different compartmentalized skin stem cells contributed to specific tissues and their domains did not over lap.

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When the mice were wounded, the proliferating stem cells freely crossed over into each other’s domains and helped heal and remake structures that they normally would not make.  This shows that upon wounding, the stem cells compartment boundaries break down as the stem cells proliferate to recreate the compartments that might have been lost as a result of wounding.  Therefore, Jensen’s work shows that Lrig1 marks stem cells in the epidermis, and that these stem cells have a unique lineage potential.  Secondly, the epidermis is maintained in discrete compartments by these multiple stem cell populations.  These stem cell populations largely keep to themselves and do not invade other compartments.  Therefore, stem cell compartmentalization underlies maintenance of the tissue complexity of the skin and not “hierarchy.”  This simply means that where the stem cells live is far more important to skin stem cell function than who their parents were.  Finally, wounding alters stem cell fate and break down the boundaries.

Wounding does more than that.  When Jensen and his colleagues made a mouse with an activated form of the ras gene that was expressed in skin, the skin showed no signs of tumor formation.  This is odd, since activating mutations in ras are extremely common in human and mouse tumors and cultured cells with activated ras mutations grow like cancer cells.  However, if the skin of these mice with the activated ras gene in their skin is wounded, then tumors form.  Therefore, wounding not only breaks down the compartments in which stem cells reside, it also potentiates cancer formation.

Jensen said of his results, “Our research will now take two directions.  We will establish mathematical models for organ maintenance in order to measure what stem cells are doing in the skin.  Also, we will expand our investigations in cancer initiation, hoping for results that can contribute to cancer diagnostics and improved treatment.”