Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, breast and prostate cancers. For this reason the Hh pathway is a flourishing area for development of anti-cancer drugs such as Hh ligand antagonists (e.g. 5E1, robotnikinin), Smo inhibitors (e.g. GDC-0449, IPI-926) and Gli transcriptional activity inhibitors (e.g. GANT58, GANT61). In vertebrate cells it is now clear that primary cilia are required for activation of the Hh pathway in normal cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by post-translational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs are developed that inhibit different steps of the Hh pathway, it is important to consider how these drugs will function in the context of primary cilia in the tumor environment. We will discuss why some of the Hh inhibitors may be ineffective if primary cilia are lost on cancer cells. Understanding the relationships between clinical inhibitors of the Hh pathway and the presence or absence of primary cilia may turn out to be critical for targeting these therapeutics to the correct population of patients and for improving their efficacy. Future work is needed in this area to maximize the potential of these exciting therapeutic targets.
BackgroundPrimary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Recent mouse models have also linked ciliary dysfunction to cancer. However, little is known about the role of primary cilia in breast cancer development. Primary cilia expression was characterized in cancer cells as well as their surrounding stromal cells from 86 breast cancer patients by counting cilia and measuring cilia length. In addition, we examined cilia expression in normal epithelial and stromal cells from reduction mammoplasties as well as histologically normal adjacent tissue for comparison.ResultsWe observed a statistically significant decrease in the percentage of ciliated cells on both premalignant lesions as well as in invasive cancers. This loss of cilia does not correlate with increased proliferative index (Ki67-positive cells). However, we did detect rare ciliated cancer cells present in patients with invasive breast cancer and found that these express a marker of basaloid cancers that is associated with poor prognosis (Cytokeratin 5). Interestingly, the percentage of ciliated stromal cells associated with both premalignant and invasive cancers decreased when compared to stromal cells associated with normal tissue. To understand how cilia may be lost during cancer development we analyzed the expression of genes required for ciliogenesis and/or ciliary function and compared their expression in normal versus breast cancer samples. We found that expression of ciliary genes were frequently downregulated in human breast cancers.ConclusionsThese data suggest that primary cilia are lost early in breast cancer development on both the cancer cells and their surrounding stromal cells.
Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.
contributed equally to experimental design, data collection and analysis, and manuscript writing. Yi Huang and Ellen M. Beauchamp helped with data collection and analysis. Samuel S. Freeman and Chandra Sekhar Pedamallu helped with bioinformatics. Shohei Koyama, Sunil Martin, Nicholas Souders, Kwok-Kin Wong and Glenn Dranoff aided with experimental design and provided reagents. Peter S. Hammerman and Esra A. Akbay helped with experimental design, data collection, providing reagents, and manuscript writing and editing.
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