PDGFRα, PDGFRβ and KIT expression/activation in conventional chondrosarcoma

Ms, Lagonigro; Tamborini, Elena; Negri, Tiziana; Staurengo, Samantha; Dagrada, Gian Paolo; Miselli, Francesca; Gabanti, Elisa; Greco, Angela; Casali, Paolo G.; Carbone, Antonino; Pierotti, Marco A.; Pilotti, Silvana

doi:10.1002/path.1945

Cited by 48 publications

(67 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and PDGFR", with the latter showing greater protein expression and phosphorylation levels. Conversely, no activating mutations were found [21]. These findings are in keeping with the existence of an autocrine/paracrine loop which could play an important role in the development of conventional central CS.…”

Section: Discussionsupporting

confidence: 71%

See 1 more Smart Citation

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

et al. 2012

View full text Add to dashboard Cite

Peripheral dedifferentiated chondrosarcoma (DCS) is an exceedingly rare aggressive surface bone neoplasm in which a high-grade sarcoma arises within an osteochondroma. Four such examples were identified in our files, representing 11.1% of all DCS treated at our hospital in the years 1995-2010, and were the object of the present study. The patients were two men and two women ranging in age between 30 and 64 years, with tumors located in the pelvis (n 0 2), in the scapula (n 0 1), and the tibia (n 0 1). Radiologically, there was evidence of a preexisting osteochondroma associated with aggressive osteolytic areas at the base and periphery of the exostosis, extending to the bone segment of origin and to the soft tissues. Immunohistochemical analysis of cell cycle regulators showed consistent loss in the expression of p16 and overexpression of cyclin D1, and to a lesser extent of RB and p53, in the anaplastic compartments of peripheral DCS in comparison with the well-differentiated cartilaginous components, while no significant expression of MDM2 was observed in any of the cases studied. Moreover, PDGFR! was absent in both tumor components, and PDGF-R" was strongly and diffusely positive in all the cases. Finally, no mutations were identified in exons 4-9 of the TP53 gene in both cases, showing positivity for p53 in the anaplastic component. In conclusion, our study shows that alterations of genes implicated in the regulation of the G1 to the S phase cell cycle checkpoint contribute to the process of dedifferentiation in peripheral secondary chondrosarcoma (CS), although the molecular mechanisms seem at least in part to differ from those involved in the process of dedifferentiation of central CS. PDGFR" could represent a potential target for treatments with receptor tyrosine kinase inhibitors in peripheral DCS.

show abstract

Section: Discussionsupporting

confidence: 71%

“…Recent studies [20,21] have investigated the status of platelet-derived growth factor (PDGF) receptors and their ligands in conventional CS as they could represent possible Fig. 6 (continued) candidates for molecular therapies with receptor tyrosine kinase (RTK) inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Adequate bone marrow and organ function were also requested. In all cases, PDGFRB was assessed by immunohistochemistry and PDGFB mRNA was confirmed by RT-PCR on fixed material (19).…”

Section: Clinical Methods and Treatmentmentioning

confidence: 99%

“…Presence or absence of mRNA of EGF and transforming growth factor α (TGFα; EGFR ligands), and IGFI and IGF2 (IGFIR ligands) were analyzed by means of real-time PCR using specific EGF (Hs00153181_M1), TGFα Hs00608187_M1), IGFI (Hs01547656_M1), and IGF2 (Hs01005963_M1) probes (Applied Biosystems). The presence of PDGFB (PDGFRB ligand) mRNA was analyzed by RT-PCR as previously described (19).…”

Section: Translational Methodsmentioning

confidence: 99%

Sunitinib Malate and Figitumumab in Solitary Fibrous Tumor: Patterns and Molecular Bases of Tumor Response

Stacchiotti

Negri

Palassini

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Antiangiogenic treatment activity has been reported in solitary fibrous tumor (SFT), a rare and little chemosensitive sarcoma. We explored the activity of sunitinib malate (SM) in SFT and studied receptor tyrosine kinase (RTK) activation profile. Eleven patients with progressive metastatic SFT resistant to chemotherapy were treated with continuous-dosing 37.5 mg/d SM on a named-use basis. One of them also received the insulin-like growth factor I receptor (IGFIR) inhibitor figitumumab after developing secondary resistance to SM. Besides, biochemical, molecular, and fluorescence in situ hybridization analyses were done in eight naïve SFTs whose cryopreserved material was available to clarify RTK upstream and downstream signaling. In two cases treated with SM and belonging to the naïve series, both pretreatment and posttreatment samples were available. Ten patients were evaluable for response to SM. The best response according to the Choi criteria was six partial response (all with Response Evaluation Criteria in Solid Tumors stable disease), one stable disease, and three progressive disease. Responses lasted >6 months in five patients. The eight naïve samples showed high expression/phosphorylation of PDGFRB, epidermal growth factor receptor, and IGFIR/IR, in the presence of their cognate ligands. Downstream pathways revealed expression/activation of Akt, extracellular signal-regulated kinase 1-2 and, closely related to SFT subtypes, of S6 and 4E-BP1. In two patients, whose pretreatment and posttreatment clinical and molecular status were available, biochemical data confirmed the activity of SM, although they also suggested a possible time-dependent shift of dominant RTK from PDGFRB to IGFIR/insulin receptor. A Response Evaluation Criteria in Solid Tumors partial response to figitumumab corroborated these findings. SM has antitumor activity in SFT, possibly through a PDGFRB-mediated mechanism, but treatments with IGFIR/ insulin receptor and possibly epidermal growth factor receptor inhibitors are worth testing. Mol Cancer Ther; 9(5); 1286-97. ©2010 AACR.

show abstract

“…BAC clone RP11-586A2 (KIT gene, 4q12) was labeled with spectrum green (SG; Vysis, Downers Groove, IL) and CEP4 was labeled with spectrum orange (SO; Vysis) to evaluate chromosome 4 integrity and copy number as previously described. 16 The samples were stained with DAPI II antifade (Vysis) to visualize nuclei and the probe mixtures evaluated under microscopy. The slides were visualized using a camera-equipped Zeiss Axioscope with DAPI, SG and SO filters (Vysis).…”

Section: Fluorescent In Situ Hybridizationmentioning

confidence: 99%

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

Kleinbaum

Lazar

Tamborini

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

Germ-line mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45-71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wild-type KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germ-line deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual. ' 2007 Wiley-Liss, Inc.

show abstract

PDGFRα, PDGFRβ and KIT expression/activation in conventional chondrosarcoma

Cited by 48 publications

References 28 publications

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

Sunitinib Malate and Figitumumab in Solitary Fibrous Tumor: Patterns and Molecular Bases of Tumor Response

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

Contact Info

Product

Resources

About