angiogenin and Carcinoma--Squamous-Cell

Squamous cell carcinoma of the head and neck (HNSCC) is the eighth most common disease, affecting approximately 640,000 patients worldwide each year. Despite recent advances in surgery, radiotherapy, and chemotherapy, the overall cure for patients with HNSCC has remained at less than 50% for many decades. Patients with recurrent and metastatic disease have a median survival of only 6-10 months. Systemic chemotherapy is the only treatment option for those patients. New treatment options are thus desperately needed to supplement, complement, or replace currently available therapies. New agents that target molecular and cellular pathways of the disease pathogenesis of HNSCC are promising candidates. One class of these new agents is angiogenesis inhibitors that have been proven effective in the treatment of advanced colorectal, breast, and non-small cell lung cancers. Similar to other solid tumors, angiogenesis plays an important role in the pathogenesis of HNSCC. A number of angiogenic factors including vascular endothelial growth factor (VEGF) and angiogenin (ANG) have been shown to be significantly upregulated in HNSCC. Among them, ANG is unique in which it is a ribonuclease that regulates ribosomal RNA (rRNA) transcription. ANG-stimulated rRNA transcription has been shown to be a general requirement for angiogenesis induced by other angiogenic factors. ANG inhibitors have been demonstrated to inhibit angiogenesis and tumor growth induced not only by ANG but also by other angiogenic factors. As the role of ANG in HNSCC is being unveiled, the therapeutic potential of ANG inhibitors in HNSCC is expected.

Topics: Angiogenesis Inhibitors; Carcinoma, Squamous Cell; Female; Genetic Therapy; Head and Neck Neoplasms; Humans; Male; Neoplasm Proteins; Ribonuclease, Pancreatic; RNA, Ribosomal

Bladder carcinoma is an important worldwide health problem. Both cystoscopy and urine cytology used in detecting bladder cancer suffer from drawbacks where cystoscopy is an invasive method and urine cytology shows low sensitivity in low grade tumors. This study validates easier and less time-consuming techniques to evaluate the value of combined use of angiogenin and clusterin in comparison and combination with voided urine cytology in the detection of bladder cancer patients. This study includes malignant (bladder cancer patients, n = 50), benign (n = 20) and healthy (n = 20) groups. The studied groups were subjected to cystoscopic examination, detection of bilharzial antibodies, urine cytology, and estimation of urinary angiogenin and clusterin by ELISA. The overall sensitivity and specificity were 66 and 75 % for angiogenin, 70 and 82.5 % for clusterin and 46 and 80 % for voided urine cytology. Combined sensitivity of voided urine cytology with the two studied biomarkers was 88 % which is higher than the combined sensitivity of both markers alone (82 %) and that of the cytology with each marker (76 and 80 %) for angiogenin and clusterin respectively. In conclusion, combined use of the cytology with the studied biomarkers can improve the sensitivity for detecting bladder cancer, and may be very useful in monitoring the effectiveness of antiangiogenic and apoptotic therapies in bladder cancer.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Case-Control Studies; Clusterin; Cytodiagnosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prognosis; Ribonuclease, Pancreatic; ROC Curve; Urinary Bladder; Urinary Bladder Neoplasms; Urine

Squamous cell carcinoma is often associated with the deletion or mutation of zinc finger protein 750 (ZNF750), its deletion or mutation is associated with squamous epithelial malignant biological characteristics. The present study is to explore the mechanism of ZNF750 to suppress the tumor malignant process by regulation tumor microenvironment.. To evaluate the changes of tumor microenvironment in oral squamous cells carcinoma cell line CAL-27 cell, the expression of angiogenin, vascular endothelial growth factor (VEGF), prolyl hydroxylase 2 (PHD2), G protein signal regulated protein 5 (RGS5), integrin A5 (ITGA5), integrin B1 (ITGB1) and CD44 were detected by Western-blot. The changes of platelet derived growth factor (PDGFB) and tumor vascular marker CD105 (Endoglin) mRNA were estimated by qPCR. The effect of over-expressed ZNF750 on cell viability and lateral migration capacity was investigated by CCK-8 and cell scratch assay in three oral squamous cells carcinoma.. ZNF750 could effectively inhibit the protein or mRNA expression of angiogenin, VEGF, RGS5 and CD105, repressed the cell adhesion molecules ITGA5, ITGB1 and CD44, but up-regulate the protein or mRNA expression of PHD2 and PDGFB. The cell viability and lateral migration ability of three oral squamous cells carcinoma were reduced by over-expression of ZNF750.. ZNF750 could modulate the tumor vascular microenvironment to inhibit the oral squamous cells carcinoma malignant progression.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Genes, Tumor Suppressor; HEK293 Cells; Humans; Mouth Neoplasms; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Transcription Factors; Tumor Microenvironment; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor A

Squamous cell carcinoma of the lung is one of the most aggressive cancers, and its aggressiveness is in part due to its intrinsic high rate of metastasis. Moreover, the process of epithelial-mesenchymal transition (EMT) appears to be involved in these neoplastic processes. Furthermore, EMT-type cells share many biological characteristics with the function of angiogenin (ANG) in squamous cell lung carcinoma. We conducted immunohistochemical analysis to detect the expression of ANG, E-cadherin, vimentin, N-cadherin, β-catenin and TGF-β1 in 60 cases of squamous cell lung carcinoma tissues. Western blot analysis was adopted to detect the protein expression levels of ANG and EMT markers. The effects of ANG on proliferation, migration and invasion of squamous cell lung carcinoma cells was analyzed by Cell Counting Kit-8, scratch assay and Transwell invasion chamber in order to reveal the role of ANG in the process of EMT in squamous cell lung carcinoma. The results revealed that ANG was aberrantly expressed in the squamous cell lung carcinoma specimens and was closely correlated with the differentiation of the cell lines. The expression of ANG was also significantly associated with metastasis and the stage of the squamous cell lung carcinoma cases. In addition, we validated that ANG influenced the expression of vimentin, E-cadherin, N-cadherin, β-catenin and TGF-β1 in SK-MES-1 cells. Most importantly, overexpression of ANG enhanced the migration and invasion of SK-MES-1 cells, while knockdown resulted in opposite effects. In the present study, we found that ANG plays an important role in EMT in squamous cell lung carcinoma and may be a valuable therapeutic target for squamous cell lung carcinoma.

Topics: beta Catenin; Cadherins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Neoplasm Invasiveness; Ribonuclease, Pancreatic; Transforming Growth Factor beta1; Vimentin

Combining primary surgery with postoperative radiotherapy (RT) significantly reduces locoregional recurrence rates in selected patients with laryngeal squamous cell carcinoma (SCC). A prognostic model was used to see if associating laryngeal SCC tissue markers (mammary serine protease inhibitor [MASPIN], CD105, angiogenin [ANG], and nm23-H1) with conventional criteria could better discriminate higher-risk patients warranting postoperative RT.. The study involved 76 consecutively operated patients with laryngeal SCC not recommended for postoperative RT, in accord with current guidelines.. On multivariate statistical modeling, non-nuclear MASPIN expression (p = .022), a CD105 expression ≥ 5.28% in vascular endothelial cells (p = .003), an nm23-H1 nuclear expression in carcinoma cells ≤ 12.0% (p = .028), and an ANG expression ≥ 5.0% (p = .07, statistical trend) showed a negative prognostic significance. The discriminatory power for disease recurrence of the 4 considered biomarkers generated an area under the curve (AUC; receiver operating characteristic [ROC]) of 0.872. The Hosmer-Lemeshow scale indicated an excellent discriminatory power.. This panel's ability to predict laryngeal SCC recurrence warrants further prospective, randomized studies to assess its use among the parameters routinely considered before recommending postoperative RT for patients with laryngeal SCC.

Topics: Aged; Analysis of Variance; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cohort Studies; Disease-Free Survival; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Laryngeal Neoplasms; Laryngectomy; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; NM23 Nucleoside Diphosphate Kinases; Pilot Projects; Predictive Value of Tests; Prognosis; Radiotherapy, Adjuvant; Ribonuclease, Pancreatic; ROC Curve; Sensitivity and Specificity; Serpins; Squamous Cell Carcinoma of Head and Neck; Survival Analysis

Angiogenin (ANG) is a member of the ribonuclease superfamily and of medical interest largely because it supports the growth of primary and metastatic malignancies. This study is the first to investigate the potential role of ANG in tongue carcinoma neo-angiogenesis and cancer cell proliferation.. Angiogenin expression (in carcinoma cells and endothelial intratumor vessel cells), CD105-assessed micro-vessel density (MVD), and MIB-1 expression were correlated with prognostic parameters in 28 primarily consecutively operated pT1-T2 tongue carcinomas (squamous cell carcinoma [SCC]). Whenever feasible, a computer-based image analysis system was used for the immunohistochemical reaction analysis.. No significant correlations emerged between ANG expression in the tongue carcinoma cells or endothelial intratumor vessel cells and tongue SCC recurrence rate or disease-free survival (DFS). ANG expression was also unrelated to CD105-assessed MVD or MIB-1 expression. Conversely, CD105-assessed MVD correlated directly with recurrence rate (P = 0.02) and DFS was significantly shorter in cases with CD105-assessed MVD >167 micro-vessels/mm(2) than in those with CD105-assessed MVD ≤167 micro-vessels/mm(2) (P = 0.042).. Our results support the hypothesis that CD105-assessed MVD would be a valuable parameter for predicting which patients with tongue SCC are at greatest risk of disease recurrence. Despite our study results, the role of ANG in tongue carcinoma warrants further investigation in larger series.

Topics: Angiogenesis Inducing Agents; Antigens, CD; Carcinoma, Squamous Cell; Cell Proliferation; Disease-Free Survival; Endoglin; Endothelial Cells; Endothelium, Vascular; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Ki-67 Antigen; Microvessels; Neoplasm Recurrence, Local; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Receptors, Cell Surface; Ribonuclease, Pancreatic; Tongue Neoplasms; Treatment Outcome

Angiogenin (ANG) is a prominent angiogenic factor that has been shown to have a dual effect on tumor progression by inducing both angiogenesis and cancer cell proliferation through stimulating ribosomal RNA transcription in both endothelial cells and cancer cells. In the present study, we investigated the expression profiles of ANG and vascular endothelial growth factor (VEGF) in oral cancer and their correlation with hypoxia and evaluated the possible value of ANG as a therapeutic target for oral cancer.. Immunohistochemistry (IHC), ELISA, real-time RT-PCR and Western blotting were used to examine the expression of ANG, VEGF, and hypoxia-inducible factor 1α (HIF-1α) in oral squamous cell carcinoma (OSCC) specimens and human OSCC cell lines. In order to examine the role of ANG, we knocked down ANG expression in HSC-2 cells by means of plasmid-mediated RNA interference.. IHC showed that the expression of ANG was significantly correlated with that of HIF-1α in 50 OSCC specimens (P = 0.031). However, no significant correlation between VEGF and HIF-1α expression was found (P = 0.243). Consistently, ANG secretion increased under hypoxia in all of the 10 OSCC cell lines tested; and a significant increase was observed in 6 of them. In contrast, there was no noticeable increase in VEGF secretion under hypoxia in any of these cell lines. In HSC-2 and SAS OSCC cells, the increase in ANG mRNA expression correlated very well with that of HIF-1α protein expression after hypoxia onset. However, no noticeable increase in VEGF mRNA expression was observed even after 12 h of hypoxia. Down-regulation of ANG expression in HSC-2 cells highly expressing and secreting VEGF inhibited ribosome biogenesis, cell proliferation, tumor angiogenesis, and xenograft growth in athymic mice.. These results suggest that ANG is up-regulated in the hypoxic environment of oral cancers and that its inhibition can have a therapeutic implication.

Topics: Animals; Blotting, Western; Carcinoma, Squamous Cell; Cell Hypoxia; Enzyme-Linked Immunosorbent Assay; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, Nude; Mouth Neoplasms; Real-Time Polymerase Chain Reaction; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

Basaloid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma (SCC). Angiogenin (ANG), a member of the ribonuclease super-family, is essential to tumor angiogenesis, but has also been implicated in tumor consolidation and proliferation.. ANG expression was first investigated in 12 head and neck basaloid squamous cell carcinomas (HNBSCCs) and compared with a control group of 24 site- and stage-matched conventional SCCs to establish whether the supposedly more aggressive biological behavior of HNBSCCs might be ANG-related.. No significant differences were found between HNBSCCs, and SCCs in terms of recurrence, disease-free survival (DFS), or overall survival rates. In HNBSCC, we identified a trend toward a significant inverse correlation between endothelial ANG expression and DFS (statistical trend, P = 0.08). Endothelial ANG expression did not differ significantly in HNBSCCs and SCCs. A high ANG expression in carcinoma cells was directly associated with pT in both the HNBSCC (P = 0.04) and the SCC (statistical trend, P = 0.07) groups. ANG expression in carcinoma cells was significantly lower in HNBSCCs than in SCCs (P = 0.005).. All the biological mechanisms investigated to date, including ANG-mediated angiogenesis or cell proliferation, have failed to confirm that HNBSCCs have a more aggressive behavior than matched SCC.

Topics: Aged; Carcinoma, Basosquamous; Carcinoma, Squamous Cell; Disease-Free Survival; Female; Head and Neck Neoplasms; Humans; Ki-67 Antigen; Male; Matched-Pair Analysis; Middle Aged; Neovascularization, Pathologic; Ribonuclease, Pancreatic

Patients with head and neck squamous cell carcinoma (SCC) respond very differently to radiotherapy (RT). Since clinical factors cannot accurately predict its effects, biological parameters have been investigated, including tumor hypoxia. CD105 is a hypoxia-inducible glycoprotein emerging as a potential prognostic indicator for several solid malignancies. Angiogenin is upregulated under hypoxic conditions and supports primary and metastatic tumor growth. Epidermal growth factor receptor (EGFR) activation stimulates tumor proliferation and angiogenesis. The aim of the present study was to ascertain the prognostic importance of hypoxia-inducible factors (CD105, angiogenin) and EGFR in a series of patients who underwent primary surgery followed by RT for laryngeal SCC. 25 consecutive patients with laryngeal SCC given postoperative RT have been investigated. CD105, angiogenin, and EGFR immunohistochemical expressions in primary laryngeal SCCs have been evaluated also with image analysis. The recurrence rate was significantly higher in SCC patients with a CD105 expression >10.0% (P = 0.012) and their disease-free survival (DFS) was shorter (P = 0.044). Neither angiogenin (in the carcinoma cells or endothelial cells) nor EGFR expression were associated with the prognosis in our patients after primary surgery followed by RT for laryngeal SCC. CD105 should be studied as a potentially predictive biomarker for identifying laryngeal SCCs at higher risk of early recurrence after postoperative RT. Targeted anti-CD105 therapy associated with RT should also be investigated in patients with laryngeal SCCs characterized by high CD105 expression.

Topics: Aged; Antigens, CD; Biomarkers, Tumor; Carcinoma, Squamous Cell; Disease-Free Survival; Endoglin; ErbB Receptors; Female; Follow-Up Studies; Humans; Immunohistochemistry; Italy; Laryngeal Neoplasms; Laryngectomy; Male; Neoplasm Staging; Postoperative Period; Prognosis; Receptors, Cell Surface; Retrospective Studies; Ribonuclease, Pancreatic; Survival Rate

  Angiogenin regulates angiogenesis supporting primary and metastatic tumour growth. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate for the first time angiogenin expression in laryngeal squamous cell carcinoma (LSCC) and to evaluate the relationship between angiogenin and CD105 expression, clinicopathological and prognostic parameters..   A total of 108 consecutive operable LSCCs were studied. Angiogenin expression was determined immunohistochemically in both carcinoma cells and intratumoral vessels. CD105 expression was evaluated in endothelial cells of LSCC and calculated by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed microvessels was determined. Angiogenin expression in carcinoma cells was higher in LSCC patients who experienced loco-regional recurrence of disease (P=0.032). Disease-free survival (DFS) was shorter in cases with carcinoma cells showing angiogenin expression >21.0% (P=0.035). Angiogenin expression in carcinoma cells was correlated strongly with the angiogenin score in endothelial cells of intratumoral vessels (P=0.0000). Higher loco-regional carcinoma recurrence rate and shorter DFS in patients with high CD105 expression were found (P=0.0004, P=0.0001)..   Angiogenin expression in laryngeal carcinoma cells and CD105 expression can be considered as potentially useful to detect LSCC patients with higher risk of disease recurrence who might benefit from more aggressive therapy.

Topics: Aged; Antigens, CD; Biomarkers, Tumor; Carcinoma, Squamous Cell; Disease-Free Survival; Endoglin; Female; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Kaplan-Meier Estimate; Laryngeal Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Neovascularization, Pathologic; Receptors, Cell Surface; Ribonuclease, Pancreatic

We evaluated the diagnostic efficacy of urinary angiogenin (ANG) and cytokeratin 20 (CK-20) mRNA in comparison with voided urine cytology in the detection of bladder cancer patients.. A total of 97 Egyptian patients provided a single voided urine sample for ANG, CK-20 and cytology before cystoscopy. Of the 97 cases, 63 were histologically diagnosed as bladder cancer; 33 with transitional cell carcinoma (TCC) and 30 with squamous cell carcinoma (SCC), whereas the remaining 34 had benign urological disorders. A group of 46 healthy volunteers were also included in this study. Voided urine was centrifuged and the supernatant was used for estimation of ANG by EIA and confirmed by Western blotting (WB). The urine sediment was used for cytology and RNA extraction. CK-20 RNA was detected by RT-PCR.. The best cutoff value for ANG was calculated by a ROC curve as 322.7 ng/mg protein. The median urinary ANG level in bladder carcinoma, benign urological disorders and healthy volunteer groups was: 802.7, 425 and 33 pg/mg protein, respectively. The positivity rate for urinary CK-20 mRNA of the control, benign and malignant groups was 0%, 2.9% and 82.3%, respectively (P = 0.000); while the rates for ANG were 11.6%, 54.8% and 75.4%, respectively (P = 0.000). There was no significant difference in positivity rates of CK-20 and ANG with respect to sex, smoking, schistosomiasis, urine cytology, tumor grade, tumor stage, hematuria or pus cells. The overall sensitivity and specificity were 71.4% and 90% for voided urine cytology, 75.4% and 70.3% for ANG, and 82.3% and 98.8% for CK-20. Combined sensitivity of voided urine cytology with ANG and CK-20 together (98.2%) was higher than either the combined sensitivity of voided urine cytology with ANG (96.5%) or with CK-20 (91.6%) or than that of the biomarker alone. We demonstrated significant positive correlation between CK-20 positivity with age (P = 0.043) and nodal involvement (P = 0.037); however, there was no significant correlation between CK-20 and ANG with the other clinicopathological parameters.. Our data indicate that CK-20 and ANG in voided urine had higher sensitivities compared to voided urine cytology. However, when specificity was considered, CK-20 alone had superior sensitivity and specificity compared to ANG and voided urine cytology.

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Chi-Square Distribution; Female; Humans; Intermediate Filament Proteins; Keratin-20; Male; Middle Aged; Prospective Studies; Ribonuclease, Pancreatic; RNA; Statistics, Nonparametric; Urinary Bladder Neoplasms

This pilot study investigated the potential use of three circulating angiogenesis-related cytokines, basic fibroblast growth factor (bFGF), angiogenin (ANG) and endostatin, as tumour markers and prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). A total of 30 patients with HNSCC treated with curative intent and 15 healthy controls were studied. Serum (bFGF and ANG) and plasma (endostatin) was assayed by enzyme-linked immunoabsorbance assay (ELISA). None of the cytokines was raised in HNSCC patients when compared with controls. Serum bFGF was not associated with any clinico-pathological or outcome parameters, although there was a trend towards higher levels in more advanced and aggressive tumours. Lower serum angiogenin (sANG) levels were associated with loco-regional disease recurrence (P = 0.036). Using a cut-off level of 400 pg/mL, a low level of sANG predicted tumour recurrence with a relative risk of 4.0 (95% CI: 0.7-24.0). Plasma endostatin was associated with higher histological grade (P = 0.01) and with both disease recurrence (P = 0.045) and death from disease (P = 0.021). Plasma endostatin above a cut-off point of 70 ng/mL could predict tumour recurrence with a relative risk of 4.7 (95% CI: 1.1-19.7). These data suggest that plasma endostatin and sANG have potential roles as prognostic factors and require further investigation.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Squamous Cell; Collagen; Endostatins; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Head and Neck Neoplasms; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Peptide Fragments; Pilot Projects; Prognosis; Prospective Studies; Ribonuclease, Pancreatic