Associate editor: Beverly TeicherOverlapping activities of TGF-β and Hedgehog signaling in cancer: Therapeutic targets for cancer treatment☆
Introduction
Cancer represents one of the leading causes of mortality in developed countries. Despite the encouraging development of cancer therapies over the past decades, the number of cancer-related deaths keeps rising. Deregulated cellular processes in tumors, including proliferation, invasion, angiogenesis, epithelial–mesenchymal transition (EMT) and tumor immune evasion, all occur as a consequence of aberrant activation of, or abnormal response to, signaling pathways such as those driving Transforming Growth Factor (TGF-β) and Hedgehog (HH) responses. TGF-β signaling is involved in the maintenance of normal tissue homeostasis and exerts tumor-suppressive roles in healthy and pre-malignant tissues (reviewed in Javelaud et al., 2008, Massague, 2008). However, malignant cells may take advantage of TGF-β signaling which promotes tumor growth, invasion and metastasis in advanced tumor stages, as it is the case in various malignancies including breast, lung, colon, prostate cancers and melanoma. The HH signaling cascade is critical as morphogen during embryonic development, and in the adult for tissue homeostasis and repair. Consistent with its role as a regulator of cell proliferation, differentiation and apoptosis, aberrant HH signaling is involved in a variety of cancer types, including basal cell carcinoma (BCC) of the skin, medulloblastoma, rhabdomyosarcoma, glioma, lung and pancreas cancers (reviewed in Varjosalo and Taipale, 2008, Javelaud et al., 2012). In this review, we focused our attention on the overlapping activities of these two pathways in cancer and cancer stem cell biology, with a particular interest for GLI transcription factors, effectors of the canonical HH cascade and direct target genes of the TGF-β/SMAD pathway. We then describe the pharmacological and therapeutic strategies targeting either pathways, to provide an update on the specificity and toxicity of the inhibitors assessed in preclinical and clinical studies. Preliminary and promising results obtained in ongoing trials are exposed for the most relevant molecules, as they represent major advances for the treatment of specific tumors, exemplified by the recent FDA approval of an HH inhibitor for the treatment of BCC (Dlugosz et al., 2012).
Section snippets
TGF-β superfamily members and functions
Mammalian Transforming Growth Factor-β (TGF-β) family members include more than 35 structurally related secreted proteins, including TGF-βs stricto sensu, activins and inhibins, Bone Morphogenetic Proteins (BMPs), Growth Differentiation Factors (GDFs) such as myostatin (GDF8), Glial-Derived Neurotrophic Factors (GDNFs), Nodal, Lefty and the Müllerian Inhibitory Substance/Anti-Müllerian Hormone (MIS/AMH) (reviewed in Zi et al., 2012). Members of the TGF-β family play fundamental roles during
Hedgehog signaling and effector molecules
The HH signaling pathway plays a major role during embryonic development where it controls processes such as cell proliferation, differentiation and tissue patterning. In adult tissue, HH signaling is involved in the maintenance of stem cells, tissue repair and regeneration. Alterations in HH pathway components leading to constitutively active signaling have been identified in several types of human cancers, such as basal cell carcinomas (BCCs) and medulloblastomas (reviewed in Rubin & de
Reciprocal regulation of the Hedgehog and TGF-β pathways
In normal and malignant tissues, the HH and TGF-β pathways have been shown to regulate key components of each other. During Drosophila development, Ci can either suppress or induce the transcription of Dpp (the fly homolog of BMP) in the wing imaginal disc, depending on the availability of HH ligand (Hepker et al., 1999). In zebrafish (Danio rerio), Dorsalin-1, a BMP family member, has been shown to compete with HH and repress the development of muscle pioneer cells (Du et al., 1997). In
The current concept of cancer stem cells
Conventional therapy against cancer, including chemotherapy and radiation therapy, has demonstrated efficacy in decreasing bulk tumor size when cancer is diagnosed in its early stages. However, tumor recurrence often occurs years later. Numerous studies have undertaken researches in order to identify a subpopulation of tumor-initiating cells that may be critical to early tumorigenesis and subsequent recurrence. These cells, called cancer stem cells (CSCs), possess properties of self-renewal,
Small-molecule inhibitors of the Hedgehog signaling pathway
In human cancers, aberrant HH signaling may be consecutive to genetic alterations of the pathway components, namely loss-of function mutations in PTCH and SUFU or gain-of-function mutation in SMO, as it is observed in BCC, medulloblastoma and rhabdomyosarcoma. Moreover, up-regulated expression of HH ligands by tumor cells or deregulated GLI expression may drive numerous other cancers. GLI1 gene amplification has been reported in glioblastoma, while HH ligands are abundantly secreted by a
Conclusion and perspectives
In this review, we have highlighted the pro-oncogenic roles of both the HH and TGF-β pathways, together with their broad overlapping activities. While various strategies have been followed to target these pathways for cancer treatment, numerous hurdles remain. Regarding TGF-β targeting, a critical issue consists in understanding the proper timing at which inhibitors should be administered during cancer progression. This is particularly important, as the tumor suppressor functions of TGF-β
Conflict of interest
We (AM DJ and CYP) herein declare that we have no potential conflict of interest including any financial, personal or other relationships with individuals or organizations within three years of initiating the work that could inappropriately influence, or be perceived to influence, the study design or data interpretation.
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Supported by Ligue Nationale Contre le Cancer (Equipe Labellisée LIGUE EL2011-AM), INCa (PLBIO08-126) and a donation from Emile and Henriette Goutière (to AM), Fondation ARC pour la recherche contre le Cancer (to DJ), and institutional funding from Institut Curie, INSERM and CNRS. CP is recipient of a doctoral studentship from the Ministère de l'Enseignement Supérieur et de la Recherche (France).