Trends in Molecular Medicine
ReviewHijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells
Introduction
From one perspective, quiescent cells, which include fibroblasts, lymphocytes, hepatocytes, stem cells and germ cells, are unarguably distinct from cancer cells. Whereas quiescent cells respond to antiproliferative signals from the environment by inducing cell cycle arrest, cancer cells fail to respond to such cues and continue to proliferate unabated [1]. From another perspective, however, cancer and quiescent cells actually share some similarities. Quiescent cells retain the capacity to re-enter the cell cycle upon receiving the appropriate cues and, therefore, must ensure that they do not commit to typically irreversible pathways such as senescence, differentiation or apoptosis (Figure 1). Similarly, a subset of cells within a tumor can also remain in a non-dividing state of tumor dormancy. These cells, which might represent cancer stem cells, have been reported to exist in a quiescent state and to be relatively resistant to traditional chemotherapeutic agents, which are generally designed to kill proliferating cells 2, 3. During dormancy, cancer cells endure conditions of low oxygen, acidic pH and nutrient deficiencies inside a tumor 4, 5. Then, for reasons that remain unclear, these cells can become activated, proliferate and can form a secondary tumor. For many tumor types, the presence of cells that might represent dormant tumor cells is closely associated with subsequent metastatic relapse [6]. Thus, an ability to survive in a reversible, out-of-cycle state is central to both quiescence and cancer.
Accumulating evidence suggests that quiescence, instead of being a passive default state, is actively maintained by specific molecular mechanisms 7, 8. Using DNA microarrays, molecular signatures of quiescence in hematopoietic stem cells [9], lymphocytes [8] and fibroblasts [10] have been identified. These studies have revealed that quiescence is associated with both the downregulation and upregulation of a large number of transcripts. Gene expression changes have also been monitored in human diploid fibroblasts that enter quiescence in response to one of three independent signals: loss of adhesion, contact inhibition and mitogen withdrawal [11]. With each of these antiproliferative signals, there is a major reprogramming of gene expression. Among the gene expression changes that occur are some that are likely to enforce the non-dividing state, for instance, the regulation of molecules that are involved in cell division itself. Other gene expression changes might ensure the reversibility of quiescence, for instance, by protecting cells from the damage induced by free radicals [11]. Yet other changes suggest the involvement of pathways that quiescent cells might utilize to protect themselves against senescence or differentiation. It has been hypothesized that these same pathways might be ‘co-opted’ by tumor cells to allow them to maintain their proliferative potential and avoid terminal cell fates [12].
The HES1 transcriptional repressor has been identified as one of the genes that might protect quiescent cells from a differentiated fate. Some tumor cells also rely on HES1 for protection against differentiation. Here we consider several pathways that activate HES1—the Notch and Hedgehog pathways—and an effector pathway of HES1—HDACs. Small molecule regulators of each of these pathways have shown promise as anticancer drugs and are being developed in clinical trials, as summarized in Table 1. We will show how these compounds, individually and in combination, might represent promising avenues for the treatment of multiple tumor types.
Section snippets
HES1 protects quiescent cells and tumors from differentiation
Recent studies have shown that quiescent cells actively resist a commitment to differentiation. To investigate this, the master regulator of muscle differentiation, the MyoD transcription factor, was introduced into quiescent or proliferating fibroblasts, and the induction of muscle genes was monitored [11]. Quiescent cells were less likely to induce muscle differentiation in response to MyoD in comparison with proliferating cells, indicating that quiescent cells employ active mechanisms to
The Notch signaling pathway
The Notch signaling pathway, the canonical pathway for the induction of HES1, facilitates the determination of cell fate during development and regulates differentiation in somatic stem cell populations [20]. The elimination of Notch pathway components in Drosophila results in the formation of embryos with excess neuroblasts at the expense of epidermal precursors [21]. Mice with Notch signaling defects exhibit a wide range of developmental abnormalities [22]. The aberrant upregulation of Notch
The Hedgehog signaling pathway
HES1 can also be induced by other signals besides the Notch pathway (Box 1), and here we focus on the regulation of HES1 by the Hedgehog pathway 43, 44. Hedgehog signaling is used to pattern organs during development, and is employed in adult tissue in the context of wound repair and tissue maintenance [45]. The Hedgehog pathway often results in an inhibition of differentiation, although in other conditions hedgehog signaling can activate cells towards a particular fate [46]. Mutations that
Histone deacetylases
In addition to the pathways that activate HES1, the mechanisms through which HES1 mediates its effects might also suggest promising strategies for anticancer therapy. HES1 can repress the transcription of its target genes through the sequestration of other transcription factors or recruitment of cofactors from the TLE family [66]. Based on analogy with Drosophila, it has been suggested that TLE family members recruit HDACs to aid in transcriptional repression [67]. By removing acetyl groups
Combinations of therapies
Inhibitors of the Notch pathway, the Hedgehog pathway and HDACs represent several therapeutic avenues that are available to reverse the anti-differentiation pathways activated in tumors, and thereby induce differentiation or apoptosis. It is possible that the use of combinations of these compounds might be even more effective. Depending on the tissue type or cellular context, multiple different pathways could contribute to an elevation of HES1 levels. For instance, both Notch and Hedgehog
Concluding remarks
Here, we have discussed one of the strategies used by quiescent cells to evade differentiation and how similar pathways are activated in tumors. There remain many avenues through which the insights described here can be translated into clinical treatments (Box 2). Of particular interest would be cancer therapies that specifically target HES1 itself. Because HES1 lies at the crossroads of multiple signaling pathways, and is closely associated with tumor outcome [97], it represents a potentially
References (104)
- et al.
The hallmarks of cancer
Cell
(2000) Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia
Blood
(1999)Regulation of quiescence in lymphocytes
Trends Immunol.
(2003)Roles of bHLH genes in neural stem cell differentiation
Exp. Cell Res.
(2005)The bHLH gene Hes1 regulates differentiation of multiple cell types
Mol. Cells
(2000)The Hairy and Enhancer of Split 1 is a negative regulator of the repressor element silencer transcription factor
FEBS Lett.
(2005)Cancer stem cell markers in common cancers – therapeutic implications
Trends Mol. Med.
(2008)Notch signaling in development and disease
Semin Cancer Biol.
(2004)Emerging role of Notch in stem cells and cancer
Cancer Lett.
(2009)Notch signaling: from the outside in
Dev. Biol.
(2000)