Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

O’Toole, Sandra A.; Machalek, Dorothy A; Shearer, Robert F.; Millar, Ewan K.A.; Nair, Radhika; Schofield, Peter R.; McLeod, Duncan; Cooper, Caroline; McNeil, Catriona M.; McFarland, Andrea; Nguyen, Akira; Ormandy, Christopher J.; Qiu, Min; Rabinovich, Brian A.; Martelotto, Luciano G.; Vu, Duc; Hannigan, Gregory E.; Musgrove, Elizabeth A.; Christ, Daniel; Sutherland, Robert L.; Watkins, D. Neil; Swarbrick, Alexander

doi:10.1158/0008-5472.can-10-3738

Cited by 152 publications

(179 citation statements)

References 34 publications

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“…Other solid tumor xenografts that we examined from colon, breast, and lung cancers demonstrated similar findings, in that Hh-responsive signaling was limited to the mouse stroma in the tumor microenvironment (Supplementary Table S1). This is consistent with recent data showing that in most solid epithelial-derived malignancies, tumor cell-derived Hh ligands do not stimulate the tumor cells themselves, but instead activate the Hh pathway in the surrounding stromal cells in a paracrine manner (31)(32)(33)(34)(35).…”

Section: Discussionsupporting

confidence: 93%

Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

Campbell

Nadesan

Ali

et al. 2014

Molecular Cancer Therapeutics

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Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and liganddependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is liganddependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI-926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926-treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma. Mol Cancer Ther; 13(5); 1259-69. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 93%

Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

Campbell

Nadesan

Ali

et al. 2014

Molecular Cancer Therapeutics

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“…Constitutive Hh signaling activation, as a result of overexpression of Hh components, including SHH, PTCH1, GLI1, and GLI2, has been linked to breast tumorigenesis and invasiveness (42,43). The mechanisms underlying the up-regulation of Hh components in tumors are still poorly characterized.…”

Section: Depletion Of P63 In Erbb2 Progenitors Attenuates Mammary Tumormentioning

confidence: 99%

p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

Memmi

Sanarico

Giacobbe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

145

131

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The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway. mammary stem cells | p53 family | breast cancer

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“…Mutations that inactivate PTCH or constitutively activate SMO have been described in basal cell carcinoma (BCC), medulloblastoma, and rhabomyosarcoma (4). Overexpression of SHH or IHH has been described in numerous tumor types (5)(6)(7)(8)(9), and concomitant upregulation of GLI1 and PTCH1 has been observed (9)(10)(11). Ectopic overexpression of SHH in preclinical models can induce tumor formation, including BCCs and pancreatic neoplasia (11,12), supporting the view that pathway activation promotes tumorigenesis in a liganddependent manner.…”

Section: Introductionmentioning

confidence: 84%

“…The mouse monoclonal antibody (mAb) 5E1 has been used extensively as a tool to probe hedgehog biology by specifically blocking ligand-dependent pathway activation (20). 5E1 neutralized the GLI1 reporter in cells, which correlated with inhibition of primary tumor cell proliferation in vitro (6,10), and it attenuated the growth of colorectal tumor xenografts and basal-like mouse mammary tumors in vivo (8,9).…”

Section: Introductionmentioning

confidence: 99%

Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling

Michaud

Wang

McEachern

et al. 2014

Molecular Cancer Therapeutics

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The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH. Mol Cancer Ther; 13(2); 386-98. Ó2013 AACR.

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Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Cited by 152 publications

References 34 publications

Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling

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