Novel therapeutic targets in chordoma

Bydon, Mohamad; Papadimitriou, Kyriakos; Witham, Timothy F.; Wolinsky, Jean Paul; Bydon, Ali; Sciubba, Daniel M.; Gokaslan, Ziya L.

doi:10.1517/14728222.2012.714772

Cited by 23 publications

(31 citation statements)

References 33 publications

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“…3,22 Of interest here is our observation that the novel primary chordoma cells, DVC-4, had molecular staining for brachyury for cells in vitro and partly for tumor xenografts in vivo, which was similar to the pattern for U-CH1 cells. A majority of xenografts from U-CH1 or DVC-4 were intensely positive for brachyury, and both xenografts were morphologically solid and intact tissues.…”

Section: Discussionmentioning

confidence: 55%

“…3 In this study, we documented and compared the potential to generate chordoma xenografts across 2 cell lines and a primary chordoma cell called “DVC-4.” We showed that all 3 sources of chordoma tumor cells were able to form tumors in the immunocom-promised NSG mouse, as has already been shown for the U-CH1 cells. 14 Importantly, this report is the first available on xenografts generated from U-CH2b cells, for which we discovered a relatively low tumorigenicity, with less than 50% of injected sites developing tumors at the latest time point.…”

Section: Discussionmentioning

confidence: 99%

“…A major contributor to the lack of efficacious therapy lies in the relative paucity of knowledge about in vivo chordoma biology and growth characteristics. 3 Chordomas are diagnosed by their molecular presentation of S100 protein, epithelial membrane antigen, select cytokeratins (cytokeratin 5/8, 18, or 19), and Brachyury (T), 14,22 a T-box transcription factor whose expression is limited to the notochord during development. Brachyury expression in adult tissue has been used as a specific and sensitive diagnostic aid for chordoma.…”

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confidence: 99%

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Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines

Karikari¹,

Gilchrist

Jing

et al. 2014

SPI

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Object Chordoma cells can generate solid-like tumors in xenograft models that express some molecular characteristics of the parent tumor, including positivity for brachyury and cytokeratins. However, there is a dearth of molecular markers that relate to chordoma tumor growth, as well as the cell lines needed to advance treatment. The objective in this study was to isolate a novel primary chordoma cell source and analyze the characteristics of tumor growth in a mouse xenograft model for comparison with the established U-CH1 and U-CH2b cell lines. Methods Primary cells from a sacral chordoma, called “DVC-4,” were cultured alongside U-CH1 and U-CH2b cells for more than 20 passages and characterized for expression of CD24 and brachyury. While brachyury is believed essential for driving tumor formation, CD24 is associated with healthy nucleus pulposus cells. Each cell type was subcutaneously implanted in NOD/SCID/IL2Rγnull mice. The percentage of solid tumors formed, time to maximum tumor size, and immunostaining scores for CD24 and brachyury (intensity scores of 0–3, heterogeneity scores of 0–1) were reported and evaluated to test differences across groups. Results The DVC-4 cells retained chordoma-like morphology in culture and exhibited CD24 and brachyury expression profiles in vitro that were similar to those for U-CH1 and U-CH2b. Both U-CH1 and DVC-4 cells grew tumors at rates that were faster than those for U-CH2b cells. Gross tumor developed at nearly every site (95%) injected with U-CH1 and at most sites (75%) injected with DVC-4. In contrast, U-CH2b cells produced grossly visible tumors in less than 50% of injected sites. Brachyury staining was similar among tumors derived from all 3 cell types and was intensely positive (scores of 2–3) in a majority of tissue sections. In contrast, differences in the pattern and intensity of staining for CD24 were noted among the 3 types of cell-derived tumors (p < 0.05, chi-square test), with evidence of intense and uniform staining in a majority of U-CH1 tumor sections (score of 3) and more than half of the DVC-4 tumor sections (scores of 2–3). In contrast, a majority of sections from U-CH2b cells stained modestly for CD24 (scores of 1–2) with a predominantly heterogeneous staining pattern. Conclusions This is the first report on xenografts generated from U-CH2b cells in which a low tumorigenicity was discovered despite evidence of chordoma-like characteristics in vitro. For tumors derived from a primary chordoma cell and U-CH1 cell line, similarly intense staining for CD24 was observed, which may correspond to their similar potential to grow tumors. In contrast, U-CH2b tumors stained less intensely for CD24. These results emphasize that many markers, including CD24, may be useful in distinguishing among chordoma cell types and their tumorigenicity in vivo.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines

Karikari¹,

Gilchrist

Jing

et al. 2014

SPI

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“…It has been reported that miR-1, miR-31 and potentially miR-663a act as a tumor suppressive miRNAs in chordoma [10]–[13]. We screened human chordoma cell lines and primary cells for miRNA expression by quantitative RT-PCR.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-608 and MicroRNA-34a Regulate Chordoma Malignancy by Targeting EGFR, Bcl-xL and MET

et al. 2014

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Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes’ copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.

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“…Chordoma can localize at Skull Base (SBC), sacral or spinal axis level, and accounts for approximately 0.1%–0.25% of intracranial tumors and 1%–4% of all malignant bone tumors [1, 2]. The treatment of choice for these tumors is en-bloc resection followed by postoperative radiation therapy [3].…”

Section: Introductionmentioning

confidence: 99%

FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

et al. 2014

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Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset.

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Novel therapeutic targets in chordoma

Cited by 23 publications

References 33 publications

Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines

Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines

MicroRNA-608 and MicroRNA-34a Regulate Chordoma Malignancy by Targeting EGFR, Bcl-xL and MET

FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

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