Browsing by Subject "Hedgehog Proteins"

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    Defective TGFβ signaling in bone marrow-derived cells prevents Hedgehog-induced skin tumors
    (American Association for Cancer Research, 2014-01-15) Fan, Qipeng; Gu, Dongsheng; Liu, Hailan; Yang, Ling; Zhang, Xiaoli; Yoder, Mervin C.; Kaplan, Mark H.; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Hedgehog (Hh) signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here we report that Hh- driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immune suppressive tumor microenvironment. This change was associated with activated TGFβ signaling in several cell types in BCCs. We determined that TGFβ signaling in bone marrow (BM)-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the BM-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSC to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSC. Moreover, the CCR2 inhibitors prevented MDSC migration towards skin cells in vitro, reduced MDSC accumulation and Hh signaling-driven tumor development in mice. Our results reveal a signaling network critical for Hh signaling in cancer cells to establish an effective immune suppressive microenvironment during tumor development.
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    Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer
    (Springer, 2019-02) Carpenter, Richard L.; Ray, Haimanti; Biochemistry and Molecular Biology, School of Medicine
    The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with the development of several types of cancer, including basal cell carcinoma (BCC) and acute promyelocytic leukemia, among many others. Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, only three US FDA-approved drugs for cancers affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide, which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the safety and tolerability of these clinically approved drugs targeting the Shh pathway, along with a discussion on other Shh pathway inhibitors being developed.