Aberrant Hedgehog Signaling and Clinical Outcome in Osteosarcoma

Lo, Winnie; Pinnaduwage, Dushanthi; Gökgöz, Nalan; Wunder, Jay S.; Andrulis, Irene L.

doi:10.1155/2014/261804

Cited by 37 publications

(41 citation statements)

References 30 publications

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“…Osteosarcoma (OS) is the most common bone cancer in children and young adults, affecting around 400 children in the US every year 1,2 . OS is a malignant neoplasm of the bone having a high propensity for pulmonary metastasis with approximately 20% of patients diagnosed with metastatic tumors and 80% developing metastasis despite standard of care treatment including surgery and chemotherapy 3,4 . Less than 15% of patients with metastatic OS experience 5-year survival rates with current non-targeted treatments, and, over the last three decade there was little improvement in survival rates [5][6][7][8] .…”

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confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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osteosarcoma (oS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. the proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMpoS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z HMPOS − z POS |), and "sensitivity" score (|z Hypoxia − z Normoxia ) to quantitatively evaluate the proteome shifts exhibited by oS cells in response to hypoxia. evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

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confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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“…In contrast to focused clinical genetic tests such as FISH, genomic profiling using next-generation DNA sequencing offers the ability to characterize genetic lesions genome-wide, with base-pair resolution necessary to confidently ascribe pathogenic functions. Indeed, clinical genomic profiling utilized in this case revealed deletions of genes characteristically inactivated in osteosarcomas, such as RB1, ATRX , and PTCH1 [13,14]. Thus, genomic profiling enhanced clinical diagnosis, leading to more precise therapy selection, given substantial differences in current treatment regimens for osteogenic and Ewing sarcomas [11].…”

Section: Discussionmentioning

confidence: 99%

Osteosarcoma With Apparent Ewing Sarcoma Gene Rearrangement

Mathias

Chou²,

Meyers

et al. 2016

Journal of Pediatric Hematology/Oncology

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Poorly differentiated round cell sarcomas present diagnostic challenges due to their variable morphology and lack of specific immunophenotypic markers. We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene. Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma. This illustrates the potential of clinical genomic profiling to improve diagnosis and enable specifically targeted therapies for cancers with complex pathologies.

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“…In a small cohort of 12 patients at diagnosis, expression of SMO, PTCH1 and Gli2 transcripts were variously increased [126]. Recently, an exploratory study of surgical biopsies of 43 high-grade OS also revealed high gene expression of IHH, PTCH1 and Gli1, and moderated expression of SMO, normalized to normal osteoblast samples [127]. The levels of IHH, SMO, PTCH1 and Gli1 were correlated with each other in small tumors, indicative of a ligand-independent activation whereas ligand-dependent activation of the HH pathway was suggested in large tumors, as high expression of IHH and PTCH1 were correlated.…”

Section: Shh Signaling In Os Et Esmentioning

confidence: 99%

SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression

Lezot¹,

Corre²,

Morice³

et al. 2020

Cells

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Primary bone tumors can be divided into two classes, benign and malignant. Among the latter group, osteosarcoma and Ewing sarcoma are the most prevalent malignant primary bone tumors in children and adolescents. Despite intensive efforts to improve treatments, almost 40% of patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma or Ewing sarcoma remains poor; less than 30% of patients who present metastases will survive 5 years after initial diagnosis. One common and specific point of these bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Over the past years, considerable interest in the Sonic Hedgehog (SHH) pathway has taken place within the cancer research community. The activation of this SHH cascade can be done through different ways and, schematically, two pathways can be described, the canonical and the non-canonical. This review discusses the current knowledge about the involvement of the SHH signaling pathway in skeletal development, pediatric bone sarcoma progression and the related therapeutic options that may be possible for these tumors.

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Aberrant Hedgehog Signaling and Clinical Outcome in Osteosarcoma

Cited by 37 publications

References 30 publications

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Osteosarcoma With Apparent Ewing Sarcoma Gene Rearrangement

SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression

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