Two sides to cilia in cancer

Rune Toftgård is at the Karolinska Institutet Center for Biosciences, Department of Biosciences and Nutrition, NOVUM, Huddinge, Sweden.
Nature medicine (Impact Factor: 27.36). 10/2009; 15(9):994-6. DOI: 10.1038/nm0909-994
Source: PubMed


The primary cilium can keep cancer at bay, or it can instigate tumor development, according to studies in mice (pages 1055–1061 and 1062–1065). The outcome depends on the nature of the initiating event, which involves signaling through the Hedgehog pathway.

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    • "If integrin binding and adhesion to the matrix is blocked, cells lose their mechanosensing properties leading to less aggressive disease.7 Reorganization of integrin binding sites due to IFs is a hypothesized mechanism by which cells sense and respond to fluid flow.64 Lastly, cancer cells have been shown to have a primary cila that can act as a sensor of the mechanical and chemical microenvironment around each cell.65 These cilia are vital to tissue development and homeostasis due to their involvement in cell signaling and may have similar signaling pathway effects in cancer.66 "
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    ABSTRACT: As cancer progresses, a dynamic microenvironment develops that creates and responds to cellular and biophysical cues. Increased intratumoral pressure and corresponding increases in interstitial flow from the tumor bulk to the healthy stroma is an observational hallmark of progressing cancers. Until recently, the role of interstitial flow was thought to be mostly passive in the transport and dissemination of cancer cells to metastatic sites. With research spanning the past decade, we have seen that interstitial flow has a promigratory effect on cancer cell invasion in multiple cancer types. This invasion is one mechanism by which cancers can resist therapeutics and recur, but the role of interstitial flow in cancer therapy is limited to the understanding of transport of therapeutics. Here we outline the current understanding of the role of interstitial flow in cancer and the tumor microenvironment through cancer progression and therapy. We also discuss the current role of fluid flow in the treatment of cancer, including drug transport and therapeutic strategies. By stating the current understanding of interstitial flow in cancer progression, we can begin exploring its role in therapeutic failure and treatment resistance.
    Cancer Management and Research 08/2014; 6:317-28. DOI:10.2147/CMAR.S65444
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    • "The Gli family of transcription factors regulates the expression of cell-type specific genes that control cell proliferation, migration and differentiation (Briscoe and Therond, 2013). In vertebrates , Hh binds to Patched at the primary cilium (Nozawa et al., 2013), and it has been demonstrated that Hh cannot activate signaling activity in cells without this appendage (Toftgard, 2009). "
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    ABSTRACT: Glypicans (GPCs) are a family of proteoglycans that are bound to the cell surface by a glycosylphosphatidylinositol anchor. Six glypicans have been found in the mammalian genome (GPC1 to GPC6). GPCs regulate several signaling pathways, including the pathway triggered by Hedgehogs (Hhs). This regulation, which could be stimulatory or inhibitory, occurs at the signal reception level. In addition, GPCs have been shown to be involved in the formation of Hh gradients in the imaginal wing discs in Drosophila. In this review we will discuss the role of various glypicans in specific developmental events in the embryo that are regulated by Hh signaling. In addition, we will discuss the mechanism by which loss-of-function GPC3 mutations alter Hh signaling in the Simpson-Golabi-Behmel overgrowth syndrome, and the molecular basis of the GPC5-induced stimulation of Hh signaling and tumor progression in rhabdomyosarcomas.
    Matrix biology: journal of the International Society for Matrix Biology 01/2014; 35. DOI:10.1016/j.matbio.2013.12.007 · 5.07 Impact Factor
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    ABSTRACT: Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists.
    PLoS ONE 06/2011; 6(6):e19904. DOI:10.1371/journal.pone.0019904 · 3.23 Impact Factor
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