Cell Surface Markers

• Chordomas frequently expressed alpha 2,6-ST and alpha 2,6-linked sialoglycoconjugates [1].
• Expression of the cell adhesion molecules (CAMs) E-cadherin, α-catenin, β-catenin, γ-catenin and neuralcell adhesion molecule was decreased in most of 15 chordoma specimens examined. Immunohistochemistryfor CAMs can be used as a diagnostic tool for differentiation between chordoma and chondrosarcoma. [2]
• Immunohistochemical analysis of 51 chordomas revealed extensive expression (>50% tissue stained) of E-cadherin, N-cadherin, b-Catenin, g-Catenin, a-Catenin was observed in 47, 36, 45, 37, and 15 percent of tumors, respectively. In the majority of chordomas, E-cadherin and N-cadherin expression was inversely correlated, whereas b-catenin and g-Catenin expression was directly correlated. [3]
• E-cadherin, N-cadherin, b-Catenin, g-Catenin, a-Catenin proteins were detected in 24, 82, 71, 60, and 53 percent of chordomas, respectively, by quantitative immunoblotting. [2]
• E-cadherin expression was reduced by twelve-fold and N-cadherin was increased by three-fold in a recurrent chordoma compared with the primary tumor. [2]
• No Ep-CAM expression was noted in chordomas, but E-cadherin was detected in most chordoma cells irrespective of histological subtypes. E-cadherin expression can be used to distinguish between chondroid chordomas and chordosarcomas. [4]
• In 15 chordomas, positive immunoreactivity for E-cadherin, alpha-catenin, beta-catenin, gamma-catenin, and NCAM was seen in 11, 7, 13, 10, and 14 specimens, respectively. Negative immunoreactivity was seen in the remaining chordomas. [2]
• Positivity for both epithelial membrane antigen and AE1/AE3 had a sensitivity of 90% and a specificity of 100% for detecting chordoma. [5]
• Expression of CAM5.2 was associated with proteinase expression; there was a correlation between CatB expression and CAM5.2 expression in primary lesions with tumor infiltration and 16 recurrent lesions with tumor infiltration of host bone. [6]
• TIMP-1 expression correlated with CAM5.2 expression in 16 recurrent lesions with tumor infiltration. [6]
• Among 16 chordoma samples, IHC for membranous immunoreactivity found 12 (75.0%) as positive for NCAM, 10 (62.5%) as positive for VCAM-1, 9 (56.3%) as positive for CD44, 8 (50%) as positive for N-cadherin, 4 (25%) as positive for ICAM-1, 6 (37.5%) as positive for beta-catenin, 1 (6.3%) as positive for P-cadherin, and 3 (18.8%) as positive for E-cadherin. [7]
• Among 16 chordoma samples, IHC for nuclear immunoreactivity found 11 (68.8%) as positive for E-cadherin. [7]
• Immunohistochemistry revealed expression of E-cadherin in 11 of 15 (73.3%) chordoma samples, compared with expression in 0 of 8 (0%) chondrosarcoma samples. 4 of the 11 (36.4%) chordoma samples demonstrated immunoreactivity in more than 50% of the investigated cells. [2]
• Immunohistochemistry revealed expression of NCAM in 14 of 15 (93.3%) chordoma samples, compared with expression in 2 of 8 (25.0%) chondrosarcoma samples. 5 of the 14 (35.7%) chordoma samples demonstrated immunoreactivity in more than 50% of the investigated cells. [2]
• Immunohistochemistry revealed positive staining for epithelial membrane antigen (EMA) in 14 of 16 (87.5%) classical chordoma samples and in 6 of 25 (24%) chondroid chordoma samples. [8]
• Immunohistochemistry revealed positive staining for carcinoembryonic antigen in 6 of 16 (37.5%) classical chordoma samples and in 6 of 25 (24%) chondroid chordoma samples. [8]
• Immunohistochemistry revealed positive staining for muscle actin, desmin, and carcinoembryonic antigen in 0 of 6 (0%) mediastinal chordoma samples. [9]
• Immunohistochemistry on 4 chordoma tumor samples found positive staining for carcinoembryonic antigen in 0 of 4 (0%) cases. [10]
• Immunohistochemistry on 5 osteosarcoma tumor samples found positive staining for carcinoembryonic antigen in 0 of 5 (0%) cases. [10]
• Immunohistochemistry on 17 colonic adenocarcinoma tumor samples found positive staining for carcinoembryonic antigen in 15 of 17 (88.2%) cases. [10]
• RT-PCR and immunohistochemical analyses revealed expression of c-KIT/CD117 in 3 of 15 (20%) tumor neoplastic samples of skull base chordoma. [11]

Extracellular Matrix

• In 15 classic chordomas, the extracellular tumor matrix was mostly collagen-poor as shown by histochemical analysis. Type VI collagen could be demonstrated via IHC. Type I collagen and Type III collagen were found only focally. Type II collagen was absent in most tumor areas. Focal expression and deposition of type II collagen was seen in classic chordomas without histologically evident chondroid matrix formation. Histochemically, these areas had a relatively collagen-rich tumor matrix. [12]
• In 7 chondroid chordomas, high type II collagen mRNA and protein levels were found in the chondroid tumor compartments. Type VI collagen was mainly concentrated in the pericellular matrix compartment. Type I collagen and Type III collagen were focally present. [12]
• In 36 primary lesions with tumor infiltration, a significant correlation was found between the expression of TIMP-1 and TIMP-2, TIMP-1 and CatB, TIMP-1 and PAI1, MMP-2 and uPA , and TIMP-2 and PAI1. [6]
• In 9 primary lesions without tumor infiltration, correlations were observed between the expression of MMP-2 and uPA. [6]
• In 16 recurrent lesions with tumor infiltration of host bone and 9 recurrent lesions without tumor infiltration of host bone, correlations were observed between the expression of MMP-1 and MMP-2. [6]
• In 9 recurrent lesions without tumor infiltration of host bone, correlations were observed between the expression of MMP-1 and TIMP1, and between the expression of CatB and PAI1. [6]
• 25 of 36 (69.4%) chordomas were immunoreactive for MMP-9. The mean microvessel density in the MMP-9-positive group and the MMP-9-negative group was 15.504 ± 5.836 and 9.327 ± 4.450, respectively. VEGF expression correlated with that of MMP-9. [13]
• In tumor cells, the immunostaining pattern for each proteinase was found to be cytoplasmic, with diverse intensity in MMP-1 , MMP-2, TIMP-1, TIMP-2, CatB , uPA, and PAI1. On the other hand, osteocytes in host bone tissue showed no proteinase expression; fibroblast-like, spindle-shaped cells in intralesional fibrous septum were generally immunonegative for proteinases but sometimes weakly expressed MMP-1, MMP-2, TIMP-1, CatB, uPA, and PAI1. [6]
• Immunohistochemistry on 11 primary tumor samples from patients with skull base chordoma found 3 of 11 (27.3%) as negative for RECK (reversion-inducing cysteine-rich protein with Kazal motifs), 5 of 11 (45.5%) as negative for MMP-2, and 1 of 11 (9.1%) as negative for MMP-9. [14]
• Immunohistochemistry on 8 recurrent tumor samples from patients with skull base chordoma found 3 of 8 (37.5%) as negative for RECK (reversion-inducing cysteine-rich protein with Kazal motifs), 3 of 8 (37.5%) as negative for MMP-2, and 2 of 8 (25%) as negative for MMP-9. [14]
• Immunohistochemistry revealed a high level of heterogeneity with regards to cellular and tissue staining location for RECK (reversion-inducing cysteine-rich protein with Kazal motifs), MMP-2, and MMP-9 in 11 samples of human skull base chordoma. [14]
• Immunohistochemistry followed by statistical analysis revealed a statistically significant decrease in RECK (reversion-inducing cysteine-rich protein with Kazal motifs) expression in the recurrent compared to the primary tumor among 11 samples of human skull base chordoma. [14]
• Immunohistochemistry followed by statistical analysis revealed a statistically significant correlation between MMP-9 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) expression. [14]

Receptor Tyrosine Kinase

• We conclude that c-MET expression as frequent as that observed in the notochordal tissue, chordomas, articular cartilage, and cartilaginous tumors is related to the development of both normal tissue and chondroid tumors. [15]
• Most chordomas displayed strong expression of EGFR and c Met, whereas a variable level of expression of HER2/neu was seen. [16]
• Most chordomas had strong expression of both the hepatocyte growth factor/scatter factor receptor and EGFR. [16]
• 47 of 50 (94%) chordomas showed immunoreactivity for at least one of the fibroblast growth factor receptors. FGFR1, FGFR2, FGFR3, and FGFR4 were detected in 56%, 80%, 78%, and 70% of cases,respectively. In the majority of cases, more than 50% of the tumour cells showed immunoreactivity. [17]
• The mean percentage of p75 expression was very similar in 10 chordoma samples and notochordal cells (P=0.394). [18]
• The mean percentages of TrkA and NGF expression were significantly higher in chordoma cells than in notochordal cells (P=0.002). [18]
• Among 23 chordomas hepatocyte growth factor (HGF) was expressed in less than 10% of tumor cells in 5 tumors, and not at all in the remaining 18 tumors. Among 34 chordomas five did not express c-MET, 9 expressed c-MET in 10-50% of cells and 20 expressed c-MET in greater than 50% of cells. [19]
• There was a significant correlation between the expression of c-MET and CAM5.2. [19]
• Lesions with higher c-MET expression had higher expression of of proteinases, including MMP-1, MMP-2, uPA and cathepsin B, than those with lower c-MET expression, and the differences were statistically significant for MMP-1 (P = 0.013) and MMP-2 (P = 0.022). [19]
• There were no correlations between HGF or c-MET expression and patient age, gender, nuclear pleomorphism, mitosis, apoptosis, necrosis or bleeding. [19]
• The HGF score was 1 (faint) in only a single primary skull base chordoma and was scored as 0 (negative) in the remaining 45 primary and 25 recurrent lesions. [20]
• c-MET immunoreactivy was detected in 77% of cases. [21]
• 32 of 46 primary chordomas and 22 of 25 recurrent lesions exhibited c-MET expression. [20]
• There were no correlations noted between c-MET expression and sex, subsequent disease recurrence(s), nuclear pleomorphism, mitosis, apoptosis, necrosis, bleeding, proliferative ability, MIB-1 labeling index, pancytokeratin, vimentin, or S-100 protein expression. [20]
• There was a significant correlation noted between the expression of c-MET and CAM5.2 in both primary and recurrent lesions. [20]
• Recurrent lesions with higher c-MET expression presented with higher average scores of MMP-1, MMP-2, TIMP-1, uPA, and CatB, and the differences were found to be statistically significant or nearly significant for MMP-1, MMP-2, TIMP-1, and uPA. In primary lesions, only uPA was found to be correlated with c-MET expression. [20]
• EGFR was detected by immunohistochemistry in 21 of 26 (81%) chordomas. [22]
• 10 of 21 chordoma cases showed strong expression of EGFR. 6 of these 10 presented with metastatic disease. 4 of 11 chordoma with low EGFR expression presented with metastatic disease. [22]
• EGFR immunoreactivity was detected in 32% (7/22) of cases. [21]
• 28 of 36 (77.8%) chordomas were immunoreactive for VEGF. The mean microvessel density of the VEGF-positive and VEGF-negative groups was 14.914 ± 6.073 and 9.075 ± 3.759,respectively. [13]
• VEGF expression correlated with that of MMP-9. [13]
• 66 of 66 chordomas were immunoreactive with antibodies against c-MET. [23]
• Among 7 chordomas analyzed with a phospho-RTK array all showed activated PDGFRB, FLT3, CSF1R , Axl and Dtk. EGFR, HER2/neu and HER4 were activated in 6, 3, and 5 of 7 chordomas, respectively. [24]
• PDGFRB protein was expressed and phosphorylated in 21 of 22 chordomas by western blot. [24]
• EGFR protein was expressed and phosphorylated in 17 of 22 chordomas by western blot. [24]
• Cytoplasmic PDGFRB was detected by IHC in more than 80% of the cells in 22 of 22 chordomas. [24]
• EGFR was detected by IHC in 7 of 20 cases (4 classified as strong, 2 as moderate, and 1 as low) showing a decoration mainly related to the cell membrane. [24]
• 22 of 22 chordomas were negative for HER2/neu via IHC. Among chordomas with activated EGFR, 6 of 6 showed co-immunoprecipitation of EGFR with PDGFRB and HER2/neu, suggesting heterodimer formation, and a possible mechanism of imatinib resistance. [24]
• HER2/neu was expressed by western blot in 6 of 14 chordomas and phosphorylated in 4 of these 6 cases. EGF, TGFa, and PDGFB were highly expressed in 22 chordomas by real time PCR. [24]
• PDGFRB was expressed by IHC in 22 of 22 chordomas. [24]
• The mean percentages of TrkA and NGF expression were significantly higher in chordoma cells than in notochordal cells (92.8% ± 4.0% vs. 11.5% ± 3.1%, P = 0.002; 96.0% ± 2.1% vs. 55.3% ± 8.2%, P = 0.002). [18]
• EGFR immunoreactivity was detected in 32% (7/22) of cases. [21]
• c-MET immunoreactivy was detected in 77% of cases. [21]
• 28 of 36 (77.8%) chordomas were immunoreactive for VEGF. The mean microvessel density of the VEGF-positive and VEGF-negative groups was 14.914 ± 6.073 and 9.075 ± 3.759, respectively. [13]
• 2/24 primary clival chordoma specimens demonstrated EGFR expression. There was, however, no statistically significant correlation between EGFR level and survival in these patients. [25]
• Tissue microarray analysis on 50 non-skull-based chordoma samples found 28/50 positive for FGFR1, 40/50 positive for FGFR2, 39/50 positive for FGFR3, and 35/50 positive for FGFR4. 47/50 of these samples were immunoreactive for at least one FGFR, 39/50 were immunoreactive for more than one FGFR, and 17/50 were immunoreactive for all four FGFRs. [26]
• Tissue microarray analysis on 49 skull-based chordoma samples found 24/49 positive for FGFR1, 31/49 positive for FGFR2, 40/49 positive for FGFR3, and 38/49 positive for FGFR4. 45/49 of these samples were were immunoreactive for at least one FGFR, 31/49 were immunoreactive for more than one FGFR, and 13/49 were immunoreactive for all four FGFRs. [26]
• 32/49 non-skull-based and 30/48 skull-based chordoma samples showed EGFR expression as determined by immunohistochemistry. [26]
• Amplification of EGFR was seen in 5/50 non-skull-based and 1/46 skull-based chordoma samples positive for EGFR by FISH. [26]
• Immunohistochemistry found moderate-to-strong staining of the miRNA-1 target Met in a chordoma tissue microarray. [27]
• RTK phosphorylation array on tumor samples from 7 patients with classic, sporadic chordoma found high activation of PDGFRB and moderate activation of FLT3 and CSF1R in all samples. Immunoprecipitation and Western blotting recapitulated these results in finding activation of PDGFRB in 21 of 22 (95%) tumor samples from patients with classic, sporadic chordoma. [24]
• RTK phosphorylation array on tumor samples from 7 patients with classic, sporadic chordoma found high activation of EGFR in 4 samples, moderate activation in 2 samples, and no activation in 1 sample. Immunoprecipitation and Western blotting recapitulated these results in finding activation of EGFR in 17 of 22 (77%) tumor samples from patients with classic, sporadic chordoma. [24]
• RTK phosphorylation array on tumor samples from 7 patients with classic, sporadic chordoma detected HER2/neu in 5 samples and HER4 in 3 samples. [24]
• RTK phosphorylation array on tumor samples from 7 patients with classic, sporadic chordoma detected activation of Axl and DTK in all samples. [24]
• PDGFRB was found to co-immunoprecipitate with EGFR in 6 of 6 (100%) tumor samples from patients with classic, sporadic chordoma. [24]
• Immunoprecipitation and Western blot analysis on tumor samples from 14 patients with classic, sporadic chordoma found expression of the phosphorylated form of HER2/neu in 4 samples and expression of the unphosphorylated form of HER2/neu in 2 samples, using an antibody against the C-terminal of HER2/neu in both cases. [24]
• HER2/neu was found to co-immunoprecipitate with EGFR in 9 of 22 (41%) tumor samples from patients with classic, sporadic chordoma. [24]
• Immunohistochemistry found cytoplasmic reactivity of PDGFRB in more than 80% of the cells in 22 of 22 (100%) tumor samples from patients with classic, sporadic chordoma. [24]
• Immunohistochemistry found expression of EGFR in 7 of 20 (35%) tumor samples from patients with classic, sporadic chordoma. [24]
• Immunohistochemistry found no expression of HER2/neu in 22 of 22 (100%) tumor samples from patients with classic, sporadic chordoma. [24]
• Immunohistochemistry on 15 primary tumor samples from patients with sacral classic chordoma and on 1 primary tumor sample from a patient with sacral chondroid chordoma found an average PCNA expression score of 2.4 ± 0.8 and an average bFGF expression score of 2.3 ± 0.7. [28]
• RT-PCR and immunohistochemical analyses revealed expression of PDGFRA/alpha in 15 of 15 (100%) tumor stromal and 13 of 15 (86.7%; 5 of 13 [38.5%] being focal expression) tumor neoplastic samples of skull base chordoma. [11]
• RT-PCR and immunohistochemical analyses revealed expression of PDGFRB/beta in 15 of 15 (100%) tumor stromal and 13 of 15 (86.7%; 7 of 13 [53.8%] being focal expression) tumor neoplastic samples of skull base chordoma. [11]
• Immunohistochemistry on 22 chordoma samples (19 from primary tumors, 3 from recurrent) found positive staining for EGFR in 7 of 22 (31.8%) cases. EGFR immunoreactivity was observed to correlate with female gender (P = 0.01), but not chromosome 7 status or c-MET gene expression. [21]
• Immunohistochemistry on 22 chordoma samples (19 from primary tumors, 3 from recurrent) found positive staining for c-MET in 17 of 22 (77.3%) cases. c-MET immunoreactivity was observed to correlate with gain in copy number of chromosome 7. [21]
• Immunohistochemistry found 52 of 68 (76.5%) non-skull-based and 27 of 46 (58.7%) skull-based chordoma samples to be positive for EGFR. On the other hand, 36 of 69 (52.2%) non-skull-based and 20 of 46 (43.5%) skull-based samples were immunoreactive for p-EGFR. [29]

PI3K

• 4EBP1 protein was expressed by western blot in 21 of 22 chordomas and phosphorylated in 13 of these 21 cases. [24]
• 4EBP1 protein was hyper-phosphorylated at Thr70 in 13 cases, not expressed in 1, and expressed but not phosphorylated in 8, which means that eIF4E was released in 14 of 22 cases, thus favoring protein synthesis, cell proliferation, and tumor progression. [24]
• Chordomas were immunoreactive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). [30]
• PTEN was not detected by IHC in 16% of chordomas. [30]
• Six of six chordomas analysed by western blot were positive for the rapamycin-sensitive S6K isoform 1, 70 kDa. [30]
• Of the 13 (27%) immunoreactive chordomas for p-mTOR, 12 were immunoreactive for total mTOR protein and showed two copies of mTOR by FISH, and all showed phosphorylation of 4E-BP1 and expressed eIF-4E. Eleven of these 13 p-mTOR-positive cases showed activation of p-p70S6K, and 7 showed activation of p-RPS6. The two cases negative for p-p70S6K activation were also negative for p-RPS6. [30]
• 13 of 48 (27%) chordomas exhibit ed phosphorylated mTOR and a further 18 of 48 cases express ed p-p70S6K without p-mTOR, indicating that 65% of the chordomas studied may be responsive to mTOR inhibitors. [30]
• P85 protein was detected by western blotting 21 of 22 chordomas. mTOR protein was expressed and phosphorylated (Ser2448) in 21 of 22 chordomas. AKT was expressed and phosphorylated (Ser473) in 21 of 22 chordomas. PTEN was expressed in 21 of 22 chordomas. [24]
• The p85 subunit of PI3K was found to co-immunoprecipitate with activated PDGFRB in 22 of 22 (100%) tumor samples from patients with classic, sporadic chordoma. [24]
• Western blot analysis found activation of AKT in 21 of 22 (95%) tumor samples from patients with classic, sporadic chordoma. [24]
• Western blot was positive for p-mTOR in 20 of 22 (91%) tumor samples from patients with classic, sporadic chordoma. [24]
• Western blot analysis on tumor samples from patients with classic, sporadic chordoma found hyper-phosphorylation of 4E-BP1 in 13 of 22 (59%) samples, no expression of 4E-BP1 in 1 of 22 (5%) samples, and expression of the unphosphorylated form of 4E-BP1 in 8 of 22 (36%) samples. [24]
• Immunohistochemistry on 147 chordoma samples found 19 (12.9%) to have no PTEN staining. Among these, 16 (84.2%) were also negative for EGFR by FISH. [29]

Sonic Hedgehog

• Immunohistochemistry found Shh expression in 22/23 (96%) chordoma samples and 5/5 (100%) chondroid chordoma samples. [31]
• Immunohistochemistry found co-expression of PTCH1 in 18/22 (82%) chordoma samples positive for Shh, and 4/5 (80%) chondroid chordoma samples positive for Shh. [31]
• Immunohistochemistry found expression of Shh in 2/4 (50%) benign notochordal cell tumor samples, with co-expression of PTCH1 in 1 of these 2 (50%) samples. [31]
• Immunohistochemistry found expression of Shh in 3/6 (50%) and expression of PTCH1 in 2/6 (33%) 12 and 28 weeks gestational age human notochord samples. [31]
• Immunohistochemistry found expression of Shh in 3/8 (38%) and 0/5 (0%) intervertebral disc samples. [31]
• Immunohistochemistry found Shh expression in 13/16 (81%) chondrosarcoma samples, with co-expression of PTCH1 in 8/13 (62%) of these samples. [31]

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References