Trends in Cell Biology
ReviewThe Gli code: an information nexus regulating cell fate, stemness and cancer
Introduction
How organs develop to attain specific adult sizes and shapes and then maintain them throughout life is not fully understood. Similarly, how closely related species can vary in size is not clear. These evolutionarily plastic mechanisms are thought to have a basis in the control of cell behavior and much effort has been devoted over the last three decades to elucidating them. Interestingly, pathological changes in cell number, such as in cancer, seem to result from abnormal tissue and organ patterning, indicating that morphogenesis, homeostasis and cancer are intimately interconnected.
A handful of intercellular signaling pathways are known to operate in most instances of animal patterning. They include the Hedgehog (Hh)–Gli, Notch, Wnt, epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF) and bone morphogenetic protein/transforming growth factor β (BMP/TGFβ) pathways as well as other peptide growth factor–tyrosine kinase receptor intracellular signaling cascades. Of these, Hh–Gli signaling has crucial roles in development, as well as in stemness and cancer [1] and is the focus of this review. Secreted Hh ligands act on responding cells by turning on an intracellular signaling pathway (Figure 1) that ultimately induces activating and inhibits repressive activities of the Gli transcription factors. Hh signaling thus regulates the combinatorial and cooperative function of the Gli proteins, which together form the Gli code 2, 3.
Section snippets
Gli proteins: context-dependent transcriptional regulators acting in a combinatorial and cooperative fashion
The three Gli proteins are zinc-finger transcription factors of >1000 amino acids that encode both activator and repressor functions. In frogs, fish, mice and humans, Gli1 is a strong transcriptional activator; Gli2 has both activator and repressor functions; and Gli3 is mostly a repressor, although it can also have positive effects 4, 5, 6, 7, 8, 9, 10. The fly Gli protein, Cubitus interruptus (Ci), is also both an activator and a repressor 11, 12. Full-length Gli proteins, possibly modified,
The Gli code in vertebrate tissue patterning acts through gradients of repressor and activator functions in time and space
During normal development, Hh ligands have been proposed to act as morphogens in developmental fields, although they also act as mitogens (Figure 1b). In the vertebrate neural plate and neural tube, a ventral gradient of Hh contributes to the patterning of this tissue. It induces a double Gli gradient with opposite polarities of activators (high to low from ventral or medial to dorsal or lateral) and repressors (high to low from dorsal or lateral to ventral or medial) 2, 4, 7, 9, 27, 28. A
The Gli code is targeted by oncogenes: implications for senescence and tumor progression
With this developmental background, how are we to view cancer? We think cancer is a disease of patterning [38] and not of single cells gone amok as a result of the disregulation of the cell cycle, for instance. In this context Hh–Gli signaling is taking center stage in the understanding and possible treatment of many kinds of human sporadic cancers, including those of skin, brain, lung, prostate, pancreas and stomach (39, 40, 41, 42, 43, 44, 45, 46, 47, 48; reviewed in Ref. [1]).
GLI1 was
The Gli code controls the behavior of activated stem cells and cancer stem cells
Hh–Gli signaling regulates the behavior of a variety of precursors in different tissues, including the cerebellum (see earlier), cerebral cortex and colliculi [39]. It also regulates the behavior of stem cells, notably of neural stem cells in neurogenic niches of the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle of the forebrain 56, 57, 62, 63, 64, as well as other stem-cell types [65]. Quiescent epithelial stem cells seem to have little or no Gli1
The GLI code and metastasis
Metastatic founder or pioneer cells are likely to be cancer stem cells that undergo selection to perform organ-specific colonization. Recent data involve the HH–GLI pathway and the GLI code in metastasis. Human malignant melanoma, pancreas and prostate cells grow metastatically into the lungs of nude mice and this is prevented by systemic treatment with cyclopamine 45, 46, 48 (Figure 4). Cyclopamine treatment changes the GLI code from a locked hyperactivating state to a repressive one [48].
Combinatorial cancer therapies and the GLI code
The fact that all gliomas, medulloblastomas, prostate cancers and melanomas that we have tested require SMO and/or GLI1 function is striking 39, 44, 47, 48. It is even more striking that this is the case for many kinds of unrelated human sporadic cancers. Indeed, although some authors have tried to divide tumors based on transcriptome profiles or levels of expression of GLI1 or PTCH1, these evaluations remain artificial at best because expression of GLI1 per se is an indicator of an active
Concluding remarks
Work over the last decade has provided multiple lines of support for the Gli code hypothesis and has crucially extended it to stemness and cancer. Although our focus on the GLI code might seem narrow at first and many other genes and pathways play important roles in stemness, tumorigenesis and tumor progression, the evaluation of current data strongly indicates a central role of the GLI code in human cancer. We envision a unified therapy for many human cancers of different grades, including
Acknowledgements
We thank present and previous lab members, collaborators and colleagues for discussion. Work in the authors’ laboratory is supported currently by grants from the Swiss National Foundation, the National Institutes of Health, the Swiss Cancer League, the Louis-Jeantet and Leenaards Foundations and the State of Geneva. We apologize to colleagues whose work could not be referenced owing to space restrictions.
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