Overlapping activities of TGF-β and Hedgehog signaling in cancer: Therapeutic targets for cancer treatment

Abstract

Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings.

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).