Showing papers in "Journal of Cancer Research and Clinical Oncology in 2010"
TL;DR: The important role of the CD11b-/CD14−/CD15+/CD33+ MDSCs in mediating immunosuppression in NSCLC is suggested.
Abstract: Background
Immune aberrations have been demonstrated in tumorogenesis, and myeloid-derived suppressor cells (MDSC) have shown to play a pivotal role in mediating immune suppression in animal models of human tumors. In the present study, we explored the clinical relevance of CD11b+/CD14−/CD15+/CD33+ MDSCs and the association of MDSCs with CD8+ cytotoxic T lymphocytes in patients with non-small-cell lung cancer (NSCLC).
297 citations
TL;DR: Prevention is better than treatment, and the establishment of meticulous oral hygiene and surgical procedures prior to commencing BP treatment is important for preventing BIOJ.
Abstract: Purpose
Bisphosphonates (BPs) are bone-remodeling inhibitors that are used to manage bone metastases and osteoporosis. Osteonecrosis of the jaw, however, can occur during treatment. This complication is poorly understood and is called “bisphosphonate-induced osteonecrosis of the jaw” (BIOJ).
249 citations
TL;DR: It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.
Abstract: The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs and Tregs/CD8+ ratios in gastric cancer patients after R0 resection. From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan–Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff. It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (χ
2 test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458). Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.
180 citations
TL;DR: Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen, and improvements in PFS and OS benefits in medically fit older patients were consistent.
Abstract: Background
Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.
147 citations
TL;DR: Overexpression of let-7a can inhibit the growth of lung cancer transplanted subcutaneously in nude mice by suppression of k-Ras and c-Myc.
Abstract: Down-regulation of let-7 microRNA (miRNA) plays an important role in the pathogenesis of lung cancer. k-Ras and c-Myc, two key oncogenes in lung cancer, have been found to be targeted by let-7 in vitro. However, the in vivo relevance of these findings is unknown. The aim of the present study is to determine the effect of let-7a, a member of let-7 family, on the growth of lung cancer in vivo and to investigate whether let-7-induced suppression of k-Ras and c-Myc is involved in lung cancer. A549-let-7a cell line and A549-control cell line, two stable transfected cell lines over-expressing let-7a and the control miRNA, were established and preserved in our lab. A549, A549-control, and A549-let-7a cells were injected subcutaneously into nude mice, respectively. After 30 days, the mice were killed; the xenografts were excised and weighed. The expression of let-7a in tumor xenografts was assessed by real-time reverse transcription-PCR (RT-PCR). The expression of k-Ras and c-Myc in xenografts were determined by western blot and immunohistochemistry detection. Real-time RT-PCR showed the expression of let-7a was increased significantly in A549-let-7a cells-injected group, compared with A549-control cells-injected group and A549 cells-injected group (P < 0.01). In the xenografts of A549-let-7a cells-injected group, a significant depression in tumor weight (P < 0.05) and significant decrease of k-Ras and c-Myc protein were observed (P < 0.01), compared to A549 cells-injected group and A549-control cells-injected group. Overexpression of let-7a can inhibit the growth of lung cancer transplanted subcutaneously in nude mice by suppression of k-Ras and c-Myc.
130 citations
TL;DR: It is shown that expression of Bmi-1 was elevated in colon cancer and might serve as an independent prognostic marker.
Abstract: To investigate the clinicopathologic significance and predictive value of Bmi-1 expression in patients with colon cancer. Bmi-1 expression was assessed by immunohistochemistry, PCR, and western blotting in specimens from 203 patients and by immunohistochemistry in 66 specimens of lymph node metastasis (LNM). Positive staining of Bmi-1 occurred in 7.9% (16/203), 66.5% (135/203), and 86.4% (57/66) of specimens from normal tissue, colon cancer, and LNM, respectively. Staining was significantly correlated with clinical stage, depth of invasion, nodal involvement, distant metastasis, and Ki67 level. Bmi-1 was upregulated at the transcriptional and translational levels. Patients with Bmi-1-positive localized tumors had a much lower 5-year disease-free survival (relative risk 2.919, P < 0.0001) and overall survival (relative risk 5.056, P < 0.0001). Bmi-1 immunoreactivity emerged as an independent prognostic factor in the multivariate analysis. We have shown that expression of Bmi-1 was elevated in colon cancer and might serve as an independent prognostic marker.
115 citations
TL;DR: Investigation of expression profiles of miRNA (miRNA) in the clear cell subtype of kidney cancer supports that many miRNA expressions were altered in renal carcinoma, whose expression profiling may provide a useful clue for the pathophysiology research.
Abstract: MiRNAs are short single stranded RNAs that are associated with gene regulation at the transcriptional and translational level. Changes in their expression were found in a variety of human cancers. In the present study, we aimed to investigate expression profiles of miRNA (miRNA) in the clear cell subtype of kidney cancer and to develop further understanding of the molecular mechanisms involved in the pathogenesis of renal cell carcinoma. We analyzed the miRNA expression profiles in 30 pairs of renal cell carcinoma and adjacent nontumorous tissue (NT), using a mammalian miRNA microarray containing whole human mature and precursor miRNA sequences. Real-time quantitative PCR was performed to confirm the array results. The miRNA microarray chip analysis identified 86 miRNAs differentially expressed in renal cell carcinoma tissues and a total of 38 miRNAs exhibited higher expression in the renal cell carcinoma samples than that in the NT samples, while 48 miRNA demonstrated lower expression in the renal cell carcinoma samples than that in the NT samples. Quantitative real-time PCR analysis confirmed microarray data. The report supports that many miRNA expressions were altered in renal carcinoma, whose expression profiling may provide a useful clue for the pathophysiology research. However, further longer-term researches are required to investigate the relationship between miRNA and renal carcinoma as well as their role in carcinogenesis.
104 citations
TL;DR: Examining the expression levels of HIF-1α and MDR1/P-gp in human colon carcinoma tissues and cell lines suggests that hypoxia induce the expression of Hif-1 α and M DR1/ P- gp in Colon carcinoma and HIF -1α expression may be associated with the gene MDR 1 (P- gp) and interactively involved in the occurrence of tumor multidrug resistance.
Abstract: Purpose
Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) gene/transporter P-glycoprotein (P-gp) has not been clearly investigated. This study aims at examining the expression levels of HIF-1α and MDR1/P-gp in human colon carcinoma tissues and cell lines (HCT-116, HT-29, LoVo, and SW480) and ascertaining whether HIF-1α plays an important role in tumor multidrug resistance with MDR1/P-gp.
98 citations
TL;DR: In patients with LM an age >50, performance status ≤70%, interval between diagnosis of primary tumor and LM ≤12 months, primary tumor (lung cancer, malignant melanoma, and lack of cytologic response present negative prognostic factors.
Abstract: Leptomeningeal metastases (LM) are associated with very poor prognosis and data on outcome are limited. We evaluated prognostic factors and treatment options in patients (pts) with LM of different malignancies in a single center experience. Single center data on characteristics, treatment and outcome of 135 consecutive pts (73 solid tumors and 62 hematologic malignancies) with LM between 1989 and 2005 were retrospectively analyzed. Treatment consisted of systemic chemotherapy (SC) plus intrathecal chemotherapy (ITC) in 28%, ITC alone in 22%, radiotherapy (RT) plus ITC in 12% and other modalities (SC, RT, SC + RT) in 7%. Thirteen percent of pts received supportive care only (4% not evaluable on treatment). Median survival from diagnosis of LM was 2.5 months. Univariate analysis revealed age >50, interval between diagnosis of primary tumor and LM ≤12 months, lung cancer and malignant melanoma, and Karnofsky performance status ≤70 as significant negative predictors for overall survival. Positive predictive factors were response in cerebrospinal fluid and application of SC. In multivariate analysis, only SC was significantly associated with longer median survival (5.6 vs. 1.7 months). In patients with LM an age >50, performance status ≤70%, interval between diagnosis of primary tumor and LM ≤12 months, primary tumor (lung cancer, malignant melanoma) and lack of cytologic response present negative prognostic factors. Systemic chemotherapy is significantly associated with longer survival time than local treatment modalities.
97 citations
TL;DR: The use of a panel of plasma biomarkers for the identification of women with ovarian cancer delivers a significant increase in diagnostic performance when compared to the performance of CA-125 alone.
Abstract: Purpose
The primary hypothesis to be tested in this study was that the diagnostic performance (as assessed by the area under the receiver operator characteristic curve, AUC) of a multianalyte panel to correctly identify women with ovarian cancer was significantly greater than that for CA-125 alone.
93 citations
TL;DR: It is shown that good responders of cisplatin in NSCLC could be identified by the promoter methylation of TGM2 and that TGase 2 inhibition appears to be an effective cisPlatin-sensitizing modality inNSCLC.
Abstract: Recently, it was reported that expression of transglutaminase 2 plays an important role in doxorubicin/cisplatin resistance in breast and ovarian cancer. The aims of this study were to verify the role of transglutaminase 2 in cisplatin response in non-small cell lung cancer (NSCLC) and to study if transglutaminase 2 gene (TGM2) methylation can be a molecular marker for good response to cisplatin. TGM2 promoter methylation was analyzed by sodium bisulfite sequencing. Cisplatin sensitivity was analyzed by treatment of cisplatin in NSCLC cell lines with/without TGM2 or TGM2 siRNA transfection. In one-third of NSCLC cell lines, TGase 2 gene (TGM2) was silenced by promoter methylation. The TGM2 promoter-methylated cell lines (HCC-95 and HCC-1588) showed relatively higher sensitivity to cisplatin than the TGM2-expressing cell lines (NCI-H1299 and HCC-1195). Down-regulation and over-expression of TGM2 in those NSCLC cells also suggested a positive correlation of cisplatin sensitivity and TGM2 inhibition. With doxorubicin, the relationship was quite similar. We showed that good responders of cisplatin in NSCLC could be identified by the promoter methylation of TGM2 and that TGase 2 inhibition appears to be an effective cisplatin-sensitizing modality in NSCLC.
TL;DR: The increase in frequency of Treg cells might play a role in modulation of the immune response against HCC in different TNM stages and be acted as the route to evaluate the immunotherapy-based methods, promote therapy effect, and consequently to increase the survival rate in HCC.
Abstract: Few detailed studies about the correlations among the expanded prevalence, elevated function of Treg cells in tumor microenvironment of hepatocellular carcinoma (HCC), and different clinical tumor stage were reported. The purpose of the present study was to examine the presence and functions of CD4+CD25high regulatory T cell (Treg cell) in tumor microenvironment from early and late stages and reveal the potential underlying mechanisms that may be responsible. The prevalence of Treg in peripheral blood and fresh tissue samples from 31 patients with HCC after radical hepatectomy and 9 controls was detected. CD127 was selected as a Treg cell maker to test the cell populations and compared its expressions with ICOS. The expressions of FOXP3 mRNA were analyzed. The migration, proliferation, and suppression functions of Treg cell were observed. IFN-γ., IL-10, TGF-s, CCL-17, CCL-22, and SDF-1 in cell supernatant were detected. Among all of the tests, the relations among the different TNM tumor stages, populations, and functions of Treg cells were evaluated. The prevalence of Treg cell was significantly higher in the peripheral blood and in tumor tissue compared with those in normal donors. Increased numbers of Treg cell were showed in peripheral blood as well as in tumor tissue. High levels of IL-10 and TGF-s, but little IFN-γ, were detected in the tumor microenvironment. Treg cells potently suppressed the functions and proliferation of CD4+CD25− T cells. High levels of SDF-1 were detected in malignant biopsies compared with those in benign regions, significantly increased in stage III. Plasma from the same patient was able to chemoattract Treg cell but that was lesser extent than those in tumor supernatant. Also, supernatant in advanced stage tumors exhibited powerful chemoattractic activity. SDF-1 played an important role in the recruited functions of Treg cell into tumor microenvironment of early and advanced stages. The expressions of Foxp3 mRNA increased in different TNM stages. The increased prevalence and expanded function of Treg cells in the tumor microenvironment of HCC were correlated with the cancer stage. The increase in frequency of Treg cells might play a role in modulation of the immune response against HCC in different TNM stages. The substance secreted in tumor microenvironment recruited CD4+CD25+ Treg cells to tumor sites to contribute to the prosperity and growth of the tumors. The performance of Treg cells in different TNM stages of tumor microenvironment might be acted as the route to evaluate the immunotherapy-based methods, promote therapy effect, and consequently to increase the survival rate in HCC.
TL;DR: Tumor volume parameters, especially the combination of MTV and SUV in the “metabolic index”, are valuable for predicting long-term survival and may be useful for identifying patients requiring more aggressive treatment.
Abstract: The purpose of this study was to evaluate the prognostic value of metabolic tumor volume (MTV) and metabolic index (MI) from fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with nasopharyngeal carcinoma (NPC). From October 2002 to July 2004, 41 patients with NPC who underwent 18F-FDG PET-CT scan before and after radiotherapy were reviewed retrospectively. All patients received intensity-modulated radiotherapy using 6MV X-rays. We examined the association of MTV and the results of long-term follow-up of the patients. Patients having tumors with an MTV below 30 cm3 had significantly better 5-year overall survival (OS) (84.6:46.7%, P = 0.006) and disease-free survival (DFS) (73.1:40.0%, P = 0.014) than patients with an MTV of 30 cm3 or greater. And the patients with MI below 130 had significantly higher 5-year OS (88.0:43.8%, P = 0.002) and DFS (76.0:37.5%, P = 0.005) than other patients. In the Cox multivariate analysis, MI and metabolic response (MR) were predictive of DFS, and we did not find a significant relationship between standard uptake value (SUV) and OS or DFS. The present study shows that tumor volume parameters, especially the combination of MTV and SUV in the “metabolic index”, are valuable for predicting long-term survival. High MI may be useful for identifying patients requiring more aggressive treatment.
TL;DR: Although treatment strategies have changed, outcome has not improved significantly from 1995 to 2006, and many subsites of head and neck cancer have changing incidence.
Abstract: To describe epidemiology and prognosis of head and neck cancer in Germany. We analyzed the Thuringian cancer registry database from 1996 to 2005. 3,821 cases with primary head and neck cancer were evaluated for patient’s characteristics, tumor stage, incidence, treatment, and trends in overall survival. During the period 1996–2005, the incidence of oropharynx, hypopharynx, larynx, and salivary gland cancer increased significantly for males, and of oral cavity and hypopharynx cancer for females. There was a significant trend using more multimodal therapy combining surgery, radiotherapy, and chemotherapy, and to use less radiotherapy as a single modality. The median follow-up time of patients alive was 42 months. The 5-year overall survival rate (OS) for all patients was 47.8%. The site-specific 5-year OS for lip, oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, salivary gland, and nose/paranasal sinus cancer was 75.7, 42.6, 43.5, 45.9, 27.2, 57.3, 61.0, and 34.9%, respectively. The multivariate analysis showed that male gender, age ≥60 years, therapy without surgery, higher T classification, N classification, and M classification were independent significant negative risk factors for OS (p < 0.0001). Cancer of the oral cavity and of the hypopharynx had a significant lower OS than lip cancer (p = 0.012 and p = 0.044, respectively). Comparing the periods 1996–2000 with the period 2001–2005, there was no significant improvement of OS for any subsite. Many subsites of head and neck cancer have changing incidence. Although treatment strategies have changed, outcome has not improved significantly from 1995 to 2006.
TL;DR: Investigating HMGB1 expression and its prognostic significance in CRC by performing immunohistochemical analysis suggests thatHMGB1 protein is a valuable marker for progression of CRC patients, and is associated with poor overall survival in patients with CRC.
Abstract: High-mobility group box 1 (HMGB1) has been implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, development, and extracellular signaling. The increased expression of HMGB1 has been described in colorectal cancer (CRC). However, there is no report about the correlation of HMGB1 with clinicopathologic features, including the survival of patients with CRC. In present study, we investigated HMGB1 expression and its prognostic significance in CRC by performing immunohistochemical analysis, using a total of 192 paraffin-embedded archival CRC samples. Moreover, disruption of endogenous HMGB1 protein through a siRNA knockdown technique was performed to investigate the possible role of HMGB1 in the process of tumor invasion and metastasis. Overexpression of HMGB1 was shown in 55.7% cases. Statistical analysis showed that HMGB1 expression was positively correlated with tumor invasion (P = 0.048), lymph node metastasis (P = 0.011), distant metastasis (P = 0.031), and Duke’s stage (P = 0.029) of CRC patients. Patients with higher HMGB1 expression had shorter overall survival time, whereas patients with lower level of HMGB1 had better survival. Multivariate analysis suggested that HMGB1 expression might be an independent prognostic indicator for the survival of patients with CRC. Disruption of endogenous HMGB1 protein through a siRNA knockdown technique was shown to suppress substantially the invasion ability of SW620 cells. Our results suggest that HMGB1 protein is a valuable marker for progression of CRC patients. High HMGB1 expression is associated with poor overall survival in patients with CRC.
TL;DR: The data suggest a different genotype association in glioma may be related to the diversity on the tissue origin, tumor type, tumorigenesis, and developing process, compared with the results from previous studies in lung cancer and breast cancer.
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in regulation of eukaryotic gene expression. Aberrant expression and structural alternation of miRNAs are considered to participate in tumorigenesis and cancer development. Recently, different genotypes of miR-196a polymorphisms (SNP, rs11614913) were found to be associated with the survival of patients with lung cancer and increased risk of breast cancer. To further investigate whether this polymorphism may influence glioma risk or not, we examined the SNP allele frequency in Chinese population. Our data shows the genotype CC of miR-196a (rs11614913) polymorphism is associated with decreased risk of glioma in the Chinese population (OR = 0.74, 95% CI:0.56–0.98). Furthermore, a significant association was observed between this genotype and glioma risk in the subgroups of adult glioma (OR = 0.73, 95% CI:0.55–0.98), male glioma (OR = 0.69, 95% CI:0.48–0.99) and patients with glioblastoma (OR = 0.58, 95% CI:0.37–0.91). This was the first study investigating the association between the miR-196a rs11614913 and glioma risk. Compared with the results from previous studies in lung cancer and breast cancer, our data suggest a different genotype association in glioma. This may be related to the diversity on the tissue origin, tumor type, tumorigenesis, and developing process.
TL;DR: The results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa and suggest clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa.
Abstract: Purpose
Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA.
TL;DR: DHA induces cell cycle arrest and apoptosis in pancreatic cancer cells, and this effect might be due to inhibition of NF-κB signaling, and it is suggested that DHA could be developed as a novel agent against pancreaticcancer.
Abstract: In a recent publication, we have shown that dihydroartemisinin (DHA), a derivative of antimalaria drug artemisinin, inhibits growth of pancreatic cancer cells in vitro and in vivo mediated by its anti-proliferative and pro-apoptotic effects. As it has been shown that the apoptosis might be induced due to cell cycle arrest, and that transcriptional factor nuclear factor-kappa B (NF-κB) plays vital roles in the apoptosis of pancreatic cancer cells, we extend our study to investigate the effects of DHA on cell cycle progression and NF-κB activity in pancreatic cancer cells to further reveal the anticancer effects of DHA on pancreatic cancer. Cell cycle progression was determined by propidium iodide staining and flow cytometry. Changes in the expression of cell cycle-associated proteins were detected using Western blot analysis. Measurement of NF-κB activity was performed with immunoblot analyzing the nuclear protein expression of NF-κB/p65 and ELISA detecting the NF-κB DNA-binding activity. The treatment with DHA resulted in a dose-dependent G0/G1 cell cycle arrest and regulated the expression of some cyclins, cdks and cdk inhibitors that involved in the G0/G1 cell cycle progression such as cyclin E, cdk2, cdk4 and p27Kip1 in pancreatic cancer BxPC-3 and AsPC-1 cells. The translocation and DNA-binding activity of NF-κB were inhibited in DHA-treated cells in a dose-dependent manner, indicated the inactivation effects of DHA in pancreatic cancer cells. Together with our previous observations, our data show that DHA induces cell cycle arrest and apoptosis in pancreatic cancer cells, and this effect might be due to inhibition of NF-κB signaling. We suggest that DHA could be developed as a novel agent against pancreatic cancer.
TL;DR: The EGFR mutations in the serum and the pleural effusion from advanced NSCLC patients can be detected with LightCycle PCR using Taqman-MGB probes and highly predict the efficacy of gefitinib in advanced NSclC.
Abstract: Recently, mutations in the epidermal growth factor receptor (EGFR) gene were reported to correlate with EGFR tyrosine kinase inhibitor response in advanced non-small cell lung cancer (NSCLC). In this study, we attempted to detect EGFR mutations in plasma and pleural effusion samples and to make clear its correlations with gefitinib response and survival in NSCLC patients. The free DNA was isolated from the plasma of 56 cases and pleural effusion of another 32 cases of advanced NSCLC. Five common types of EGFR mutations were analyzed by LightCycle PCR with Taqman-MGB probes. EGFR gene mutations were found in 22 of all the 88 (25%) NSCLC patients (23.2% of 56 plasma samples, 28.1% of another 32 pleural effusion samples). EGFR mutations were more frequently present in females, never-smokers and adenocarcinomas (P < 0.01). It also showed that patients with EGFR mutations had a significantly better response rate when compared with that of the wild-type patients (P < 0.001). The median progression-free survival (11.2 vs. 2.7 months P = 0.005) and overall survival (21.8 vs. 5.8 months P = 0.003) were significantly higher in patients with EGFR mutations than in patients with wild-type EGFR. The EGFR mutations in the serum and the pleural effusion from advanced NSCLC patients can be detected with LightCycle PCR using Taqman-MGB probes. The mutations highly predict the efficacy of gefitinib in advanced NSCLC.
TL;DR: In this article, the feasibility and treatment outcomes of recombinant adenovirus-p53 combined with fractionated stereotactic radiotherapy (fSRT) in treatment of primary hepatocellular carcinoma (HCC) were evaluated.
Abstract: The purpose of our study was to evaluate the feasibility and treatment outcomes of recombinant adenovirus-p53 (rAd-p53, trademarked as Gendicine) combined with fractionated stereotactic radiotherapy (fSRT) in treatment of primary hepatocellular carcinoma (HCC). We randomly enrolled 40 patients with HCC treated by fSRT alone (fSRT group) or rAd-p53 combined with fSRT (combined group). Tumor size was 2–5.2 cm (average 3.2 cm). We prescribed 50 Gy in 10 fractions at the 50%–80% isodose line of the planning target volume for 2 weeks in two groups. The combined group was treated with two intratumoral injections of rAd-p53 on day 1 and 8 while fSRT started on day 3. Tumor response was assessed after treatment using modified WHO criteria. The follow-up period was 11–44 months (median 35 months). The overall response rate of fSRT group was 70%, with 4 patients showing complete response (20%), 10 partial response (50%) and 6 stable disease (30%). Correspondingly the overall response rate of combined group was 85%, with 7 patients showing complete response (35%), 10 partial response (50%) and 3 stable disease (15%). The 1-year survival rates of fSRT group and combined group were 70.0% and 90.0%, respectively. The 1-year disease-free survival rates of fSRT group and combined group were 65% and 85%, respectively. These treatments were well tolerated, because grade 3 or 4 toxicity was not observed. These results suggest that rAd-p53 combined with fSRT is a relatively safe and effective method for treating primary hepatocellular carcinoma compared with only fSRT. Thus, rAd-p53 combined with fractionated SRT may be preferred as a choice of local treatment for primary HCC when the patients are inoperable or when the patients refuse operation.
TL;DR: A proteomic comparison of the two kinds of cells established and the results suggested that 2-DE would be an efficient way to screen the proteins responsible for specific biological function, imply that different proteins may be involved in the metastatic process in breast carcinomas.
Abstract: Distant metastasis represents the major lethal cause of breast cancer. To understand the molecular mechanisms of breast cancer metastasis and identify markers with metastatic potential, we established a highly metastatic variant of parental MDA-MB-231 cells (MDA-MB-231HM). Using two-dimensional electrophoresis (2-DE), we performed a proteomic comparison of the two kinds of cells. As much as 51 protein spots were differentially expressed between the selected variant and its parental counterpart in at least 3 experiments. Ten unique proteins were identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS), liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), and database searching software. Among them, nine proteins were up-regulated in MDA-MB-231HM cells, including Macrophage-capping protein (CapG), Galectin-1, Chloride intracellular channel protein 1, Endoplasmic reticulum protein ERp29 precursor, Stathmin-1 (STMN1), Isoform 1 of uridine-cytidine kinase 2(UCK2), Rho GDP-dissociation inhibitor 2 (ARHGDIB), isocitrate dehydrogenase [NADP] cytoplasmic (IDH1), and N-myc downstream regulated gene 1 (NDRG1) protein. Only transgelin-2 was down-regulated. Differential expression was confirmed for three proteins including CapG, STMN1, and transgelin-2 by Western blotting analysis. Transgelin-2 was chosen for further verification by immunohistochemistry. The results suggested that 2-DE would be an efficient way to screen the proteins responsible for specific biological function. Furthermore, the findings imply that different proteins may be involved in the metastatic process in breast carcinomas.
TL;DR: The data indicate that patients in the fifth decade and older fare worse than younger patients, and other variables such as tumor necrosis, tumor extension, and tumor location are likely responsible for the observed decline in overall survival and disease-free survival.
Abstract: It is unclear whether age at diagnosis is an important prognostic factor in patients with osteosarcoma. Understanding this relationship could yield valuable insight into therapeutic rationale, focus patient selection for clinical trials, advance molecular concepts and theories, and expand current principles guiding prognosis. Our aim was to understand if age at diagnosis is a prognostic indicator for eventual outcome, as measured by disease-free survival and overall survival in patients with osteosarcoma. Our cohort consisted of 438 patients of all ages who were diagnosed with osteosarcoma between 1 January 1980 and 31 December 2000 and who underwent the majority of their treatment at M.D. Anderson Cancer Center (MDACC). Patient and tumor specific variables were collected including patient demographics, patient history, primary tumor information (i.e., location, size, histology, extension, necrosis, etc.), treatment strategy (i.e., surgery, chemotherapy, and/or radiotherapy), metastatic disease information, long-term follow-up, and eventual outcome. Statistical analyses, including univariate and multivariate analyses were performed, with overall survival and disease-free survival as the primary outcome measures. The median age at diagnosis was 18.1 years (range 2 months to 78.8 years). Median follow-up was 4.2 years (range 5 days to 22.8 years) for all patients and 12.3 years (range 1 month to 22.8 years) for 209 surviving patients. Survival rates at 5, 10, and 15 years were 54.1, 47.2, and 45.2%, respectively. On univariate analyses, age ≥ 40 was found to be a poor prognostic factor. Other prognostic factors included tumor size, metastasis at diagnosis, soft-tissue tumor extension, surgery type, chemotherapy group, and tumor necrosis. Age was not identified a statistically significant prognostic variable on multivariate analysis. Age at diagnosis does not appear to be a significant independent prognostic variable for overall survival or disease-free survival in patients with osteosarcoma. Although our data indicate that patients in the fifth decade and older fare worse than younger patients, other variables such as tumor necrosis, tumor extension, and tumor location are likely responsible for the observed decline in overall survival and disease-free survival.
TL;DR: Results indicate that nucleolin acts as a receptor for Tipα and shuttles Tipα from cell surface to cytosol and nuclei and provide a new mechanistic insight into gastric cancer development with Tipα.
Abstract: Tumor necrosis factor-α inducing protein (Tipα) is a unique carcinogenic factor released from Helicobacter pylori (H. pylori). Tipα specifically binds to cells and is incorporated into cytosol and nucleus, where it strongly induces expression of TNF-α and chemokine genes mediated through NF-κB activation, resulting in tumor development. To elucidate mechanism of action of Tipα, we studied a binding protein of Tipα in gastric epithelial cells. Tipα binding protein was found in cell lysates of mouse gastric cancer cell line MGT-40 by FLAG-pull down assay and identified to be cell surface nucleolin by flow cytometry using anti-nucleolin antibody. Incorporation of Tipα into the cells was determined by Western blotting and expression of TNF-α gene was quantified by RT-PCR. Nucleolin was co-precipitated with Tipα-FLAG, but not with del-Tipα-FLAG (an inactive mutant). After treatment with Tipα-FLAG, incorporated Tipα was co-immunoprecipitated with endogenous nucleolin using anti-nucleolin antibody. The direct binding of Tipα to recombinant His-tagged nucleolin fragment (284–710) was also confirmed. Although nucleolin is an abundant non-ribosomal protein of the nucleolus, we found that nucleolin is present on the cell surface of MGT-40 cells. Pretreatment with anti-nucleolin antibody enhanced Tipα-incorporation into the cells through nucleolin internalization. In addition, pretreatment with tunicamycin, an inhibitor of N-glycosylation, decreased the amounts of cell surface nucleolin and inhibited both internalization of Tipα and expression of TNF-α gene. All the results indicate that nucleolin acts as a receptor for Tipα and shuttles Tipα from cell surface to cytosol and nuclei. These findings provide a new mechanistic insight into gastric cancer development with Tipα.
TL;DR: Cucurbitacin E has inhibited the growth of PANC-1 cells in a dose- and time-dependent manner, and has caused accumulation of cells at the G2/M phase as well as apoptosis.
Abstract: Purpose
Pancreatic cancer has been a serious disease worldwide for its high mortality. Cucurbitacin E is a member of triterpenoid family isolated from plants showing antiproliferative activity on various cancer cells. In this study, we have explored whether cucurbitacin E also has an anti-tumor effect on pancreatic cancer cells.
TL;DR: R763/AS703569 is a potent inhibitor of Aurora kinases and exhibited significant anti-proliferative activity against a wide range of tumor cells both in vitro and in vivo.
Abstract: Aurora kinases play a key role in mitotic progression. Over-expression of Aurora kinases is found in several human cancers and correlated with histological malignancy and clinical outcomes. Therefore, Aurora kinase inhibitors should be useful in the treatment of cancers. Cell-based screening methods have an advantage over biochemical approaches because hits can be optimized to inhibit targets in the proper intracellular context. We developed a novel Aurora kinase inhibitor R763/AS703569 using an image-based phenotypic screen. The anti-proliferative effect was examined in a panel of tumor cell lines and primary cells. The efficacy was determined in a broad panel of xenograft models. R763/AS703569 inhibits Aurora kinases, along with a limited number of other kinases including FMS-related tyrosine kinase 3 (FLT3), and has potent anti-proliferative activity against many cell types accompanying unique phenotypic changes such as enlarged cell size, endoreduplication and apoptosis. The endoreduplication cycle induced by R763/AS703569 was irreversible even after the compound was withdrawn from the culture. Oral administration of R763/AS703569 demonstrated marked inhibition of tumor growth in xenograft models of pancreatic, breast, colon, ovarian, and lung tumors and leukemia. An acute myeloid leukemia cell line MV4-11, which carries a FLT3 internal tandem duplication mutation, is particularly sensitive to R763/AS703569 in vivo. R763/AS703569 is a potent inhibitor of Aurora kinases and exhibited significant anti-proliferative activity against a wide range of tumor cells both in vitro and in vivo. Inhibition of Aurora kinases has the potential to be a new addition to the treatment of cancers.
TL;DR: LAPTM4B-35 expression showed a strong association with the potencies of recurrence and metastasis and progression of HCC, and that may be applied as a novel marker for the prediction of recurrent and metastatic potency of H CC, and helpful for improving the diagnosis, prognosis and treatment of Hcc.
Abstract: Lysosomal protein transmembrane 4 beta-35 (LAPTM4B-35) is a tetra-transmembrane glycoprotein that is abundantly localized on membrane-bound organelles including endosomes and lysosomes, and promotes cell proliferation and tumorigenesis through regulation of cell cycle and signaling pathways. The aim of the present study is to determine the potential clinical implications of LAPTM4B-35 expression in hepatocellular carcinoma (HCC). Immunohistochemistry assay was used to determine the expression of LAPTM4B-35 protein in normal and HCC tissues from 71 patients. The correlations of LAPTM4B-35 expression with clinicopathological parameters, including gender, age, background liver, viral status, tumor size, portal vein invasion, histopathological differentiation, serum AFP level, TNM staging and recurrence of HCC were assessed by Chi-squared test. Patient survival and their differences were determined by Kaplan–Meier method and log-rank test. Cox regression (Proportional hazard model) was adopted for multivariate analysis of prognostic factors. LAPTM4B-35 immunoreactivity was negative or low in normal liver tissues, but high in HCC tissues (51/71, 71.8%). The overexpression of LAPTM4B-35 was significantly associated with recurrence, TNM staging and portal vein invasion of HCC. Patients with high LAPTM4B-35 expression had significantly poorer overall survival (OS) and disease-free survival (DFS) (both P < 0.001) when compared with patients with the low expression of LAPTM4B-35. On multivariate analysis, LAPTM4B-35 expression was found to be an independent prognostic factor for OS and DFS (P = 0.018 and P = 0.001, respectively). LAPTM4B-35 expression showed a strong association with the potencies of recurrence and metastasis and progression of HCC, and that may be applied as a novel marker for the prediction of recurrence and metastasis potency of HCC, and helpful for improving the diagnosis, prognosis and treatment of HCC.
TL;DR: MRI seemed to be a more useful supplement to current surveillance techniques to assess patients with suspected recurrent and/or metastatic breast cancer.
Abstract: Background and purpose
Breast carcinoma is the most common cancer in female patients with a propensity for recurrence and metastases. The accuracy of ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), scintimammography (SMM) and positron emission tomography (PET) in diagnosing the recurrent and/or breast cancer has never been systematically assessed, and present systematic review was aimed at this issue.
TL;DR: A set of biomarkers that could discriminate breast cancer from non-cancer controls is identified and an efficient strategy, including SELDI-TOF-MS analysis, HPLC purification, MALDI-to-MS trace and LC-MS/MS identification, has been proved very successful.
Abstract: Noninvasive and convenient biomarkers for early diagnosis of breast cancer remain an urgent need. The aim of this study was to discover and identify potential protein biomarkers specific for breast cancer. Two hundred and eighty-two (282) serum samples with 124 breast cancer and 158 controls were randomly divided into a training set and a blind-testing set. Serum proteomic profiles were analyzed using SELDI-TOF-MS. Candidate biomarkers were purified by HPLC, identified by LC-MS/MS and validated using ProteinChip immunoassays and western blot technique. A total of 3 peaks (m/z with 6,630, 8,139 and 8,942 Da) were screened out by support vector machine to construct the classification model with high discriminatory power in the training set. The sensitivity and specificity of the model were 96.45 and 94.87%, respectively, in the blind-testing set. The candidate biomarker with m/z of 6,630 Da was found to be down-regulated in breast cancer patients, and was identified as apolipoprotein C-I. Another two candidate biomarkers (8,139, 8,942 Da) were found up-regulated in breast cancer and identified as C-terminal-truncated form of C3a and complement component C3a, respectively. In addition, the level of apolipoprotein C-I progressively decreased with the clinical stages I, II, III and IV, and the expression of C-terminal-truncated form of C3a and complement component C3a gradually increased in higher stages. We have identified a set of biomarkers that could discriminate breast cancer from non-cancer controls. An efficient strategy, including SELDI-TOF-MS analysis, HPLC purification, MALDI-TOF-MS trace and LC-MS/MS identification, has been proved very successful.
TL;DR: Rh-endostatin could normalize the tumor vasculature and microenvironment in Lewis lung carcinoma probably via modulation of the balance between vascular endothelial growth factor-A and thrombospondin-1.
Abstract: Purpose
Normalization of the tumor vasculature and microenvironment by several angiogenesis inhibitors has been reported. Given that recombinant human endostatin (rh-endostatin) is also an endogenous angiogenesis inhibitor, a comprehensive evaluation of the effects of rh-endostatin on tumor vasculature and microenvironment and chemotherapy sensitivity would be favorable.
TL;DR: The data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of malignant glioma, and may constitute a therapeutic target for anti-angiogenesis therapy in patients with the disease.
Abstract: Tumor angiogenesis is an important factor for the continuous growth of human malignancies and can be used to predict the prognosis for patients. In the current study, we examined the expression of EGF-like domain 7 (EGFL7), an endothelial cell-derived secreted factor, in malignant gliomas and explored its clinical significance. We determined the steady-state mRNA levels of EGFL7 from 36 fresh glioma samples by semi-quantitative RT–PCR and the protein levels from 45 paraffin-embedded glioma samples by immunohistochemistry, respectively. Normal brain tissues from 10 patients with brain trauma were used as control. We also analyzed the correlations between the expression levels of EGFL7 and various clinical parameters, including patient gender, age, tumor grade, tumor proliferation marker Ki-67, and microvessel density (MVD). We found that EGFL7 was not detectable in normal brain tissues, but was up-regulated in both tumor cells and vascular endothelial cells within malignant glioma. The expression level of EGFL7 in malignant glioma significantly correlated with the tumor grade, Ki-67 expression and MVD (P < 0.01). Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of malignant glioma, and may constitute a therapeutic target for anti-angiogenesis therapy in patients with the disease.