The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy

2013 ◽  
Vol 44 (10) ◽  
pp. 2149-2158 ◽  
Author(s):  
Sophie Le Guellec ◽  
Elizabeth Cohen-Jonathan Moyal ◽  
Thomas Filleron ◽  
Marie-Bernadette Delisle ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Protein Expression ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Glycogen Synthase ◽  
High Grade ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Expression Profile ◽  
High Grade Osteosarcoma ◽  
Response To Neoadjuvant Chemotherapy

scholarly journals Glycogen synthase kinase 3β promotes osteosarcoma invasion and migration via regulating PTEN and phosphorylation of focal adhesion kinase

2021 ◽  
Author(s):  
Wei Mai ◽  
Lingyu Kong ◽  
Hongwei Yu ◽  
Junjie Bao ◽  
Chunyu Song ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Western Blotting ◽  
Focal Adhesion ◽  
Glycogen Synthase ◽  
Migration And Invasion ◽  
Glycogen Synthase Kinase 3Β ◽  
Sirna Transfection ◽  
Invasion And Migration ◽  
Human Osteosarcoma ◽  
And Migration

Aim: Typical features of human osteosarcoma are highly invasive and migratory capacities. Our study aimed to investigate the roles of glycogen synthase kinase 3β (GSK3β) in human osteosarcoma metastasis. Methods: GSK3β expressions in clinical osteosarcoma tissues with or without metastasis were examined by immunohistochemical staining. The expressions of GSK3β, p-GSK3βSer9, and p-GSK3βTyr216 in human osteoblast cells (hFOB1.19) and human osteosarcoma cells (MG63, SaOS-2 and U2-OS) were detected by western blotting. The GSK3β activity was measured by non-radio isotopic in vitro kinase assay. Migration and invasion abilities of MG-63 cells treated with small-molecular GSK3β inhibitors were respectively examined by monolayer-based wound-healing assay and transwell assay. The mRNA expressions of GSK3β, matrix metalloproteinase-2 (MMP-2), MMP-9, phosphatase with tensin homology (PTEN), and focal adhesion kinase (FAK) were detected after siRNA transfection for 72 h. Meanwhile, protein expressions of GSK3β, FAK, p-FAKY397, PTEN, MMP-2, and MMP-9 were measured by western blotting. Results: Clinical osteosarcoma tissues with metastasis showed higher GSK3β expressions. MG63 and U2-OS cells which were easy to occur metastasis showed significantly higher expressions and activities of GSK3β than SaOS-2 cells. Inhibition of GSK3β with small-molecular GSK3β inhibitors in MG63 cells significantly attenuated cell migration and invasion. These effects were associated with reduced expressions of MMP-2 and MMP-9. Moreover, increased PTEN and decreased p-FAKY397 expressions were observed following GSK3b knock-down by siRNA transfection. Conclusion: GSK3β might promote osteosarcoma invasion and migration via pathways associated with PTEN and phosphorylation of FAK.

Study of the expression of integrin pathway's proteins as predictive markers of response to neoadjuvant chemotherapy in pretreatment biopsies of patients with high-grade osteosarcoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10076-10076
Author(s):  
Elizabeth Laurence Cohen-Jonathan Moyal ◽  
Sophie Le Guellec ◽  
Thomas Filleron ◽  
Marie-Bernadette Delisle ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Surgical Resection ◽  
Preoperative Chemotherapy ◽  
Poor Response ◽  
Conservative Surgery ◽  
High Grade ◽  
Pre Treatment ◽  
Gsk 3Β ◽  
High Grade Osteosarcoma ◽  
Response To Neoadjuvant Chemotherapy

10076 Background: Up to now, chemosensitivity to neoadjuvant chemotherapy performed for patients with osteosarcoma is evaluated on the surgical resection by the evaluation of the percentage of necrotic cells. No predictive profile of chemotherapy has been described yet. Because we have previously shown that integrin pathway controls genotoxic-induced cell death and hypoxia via ILK, FAK and RhoB, we hypothesized that the expression of the proteins involved in this pathway in pre-treatment biopsies could be associated with sensitivity to chemotherapy in osteosarcoma. Methods: We studied by immunohistochemistry β1, β3, β5, integrins, ILK, FAK, GSK-3β, RhoB and Ang-2 expression in 36 osteosarcomas biopsies of patients obtained before treatment. All the patients were treated by the SFOP OS94 chemotherapy protocol and underwent wide conservative surgery. Response to preoperative chemotherapy was assessed on the surgical resection by the Rosen’s protocol. An immunoreactive score (IRS) was assessed, combining the percentage of positive tumour cells and staining intensity. We evaluated the correlation of the selected markers expression with response to preoperative chemotherapy and clinical outcome. Results: FAK expression was statistically linked with ILK expression (rho=0.43; p=0.020), β1integrin expression with FAK expression (rho=0.51); p=0.003), RhoB with ILK expression (rho=0.55; p=0.002), and β1 with β3integrin expression (rho=0.70; p<.001), suggesting that a regulation of the integrin pathway that we studied might exist in high grade osteosarcoma. Moreover, the combination of β5 integrin, FAK and GSK-3β discriminated good and poor responder to chemotherapy (89.9%; 95% CI= [77.4;1.00], yielding a sensitivity of 94.1%, a specificity of 85.7% and a diagnostic accuracy of 90.3%. Conclusions: We report for the first time a protein expression profile on pre-treatment biopsies associating β5 integrin FAK and GSK-3β related with a poor response to neoadjuvant chemotherapy. This profile could help to select patients for clinical trials using inhibitors of this pathway in association with chemotherapy.

Molecular response to neoadjuvant chemotherapy in high-grade serous ovarian carcinoma

2016 ◽  
Vol 141 ◽  
pp. 151-152
Author(s):  
R.C. Arend ◽  
Z.C. Dobbin ◽  
D.K. Crossman ◽  
B.K. Erickson ◽  
J.D. Boone ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Ovarian Carcinoma ◽  
Molecular Response ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Response To Neoadjuvant Chemotherapy

scholarly journals Clinical Features, Treatment, and Outcome in 102 Adult and Pediatric Patients with Localized High-Grade Synovial Sarcoma

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
H. Al-Hussaini ◽  
D. Hogg ◽  
M. E. Blackstein ◽  
B. O'Sullivan ◽  
C. N. Catton ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Synovial Sarcoma ◽  
Surgical Resection ◽  
Pediatric Patients ◽  
Response Rate ◽  
High Grade ◽  
En Bloc ◽  
Positive Surgical Margins ◽  
Response To Neoadjuvant Chemotherapy

Background. There remains controversy on the routine use of chemotherapy in localized SS.Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed.Results. Median age for AP and PP was 37.6 (range 15–76) and 14 (range 0.4–18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of10%and40%, respectively. 5-year EFS and OS was69.3±4.8%and80.3±4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without.Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive.

Effect on response to neoadjuvant chemotherapy in high-grade serous ovarian cancer by inhibiting the GAS6/AXL pathway and inducing homologous recombination deficiency.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Michael Driscoll Toboni ◽  
Hollie M Noia ◽  
Danny Wilke ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Neoadjuvant Chemotherapy ◽  
Mouse Models ◽  
Poor Response ◽  
Tumor Burden ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Response To Neoadjuvant Chemotherapy

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.

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