Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-κB pathway

Local invasion and distant metastasis are difficult problems for surgical intervention and treatment in gastric cancer. Connective tissue growth factor (CTGF/CCN2) was considered to have an important role in this process. In this study, we demonstrated that expression of CTGF was significantly upregulated in clinical tissue samples of gastric carcinoma (GC) samples. Forced expression of CTGF in AGS GC cells promoted their migration in culture and significantly increased tumor metastasis in nude mice, whereas RNA interference-mediated knockdown of CTGF in GC cells significantly inhibited cell migration in vitro. We disclose that CTGF downregulated the expression of E-cadherin through activation of the nuclear factor-κappa B (NF-κB) pathway. The effects of CTGF in GC cells were abolished by dominant negative IκappaB. Collectively, these data reported here demonstrate CTGF could modulate the NF-κappaB pathway and perhaps be a promising therapeutic target for gastric cancer invasion and metastasis.     

Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall?

Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour. The published data have broadened the landscape towards a future molecular classification into several subtypes of gastric cancer, enabling a better selection of the optimal therapeutic strategy. The fibroblast growth factor receptor (FGFR) pathway plays a key role in gastric cancer pathogenesis, with 1.2%–9% of gastric cancer patients harbouring FGFR2 amplifications. Several selective FGFR inhibitors have been developed in the last years, with promising efficacy signals. However, there is still scarce evidence of the most reliant molecular determinants of response to these targeted agents. Homogeneous high-level clonal FGFR2-amplification, high FGFR2 mRNA or protein levels, specific FGFR2 C3 isoform expression, FGF ligand co-overexpression or detection of FGFR2 copy number in plasma circulating tumour DNA, are considered some of the potential predictive biomarkers to the FGFR inhibition. The successful development of highly specific FGFR inhibitors will rely on our capacity of establishing new personalized strategies, based on a deeper knowledge of the key alterations that drive oncogenesis in gastric cancer. Further efforts seem mandatory in order to implement accurate predictive biomarkers in the next stages of the FGFR inhibitors development.     

Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo

Radiation therapy is an important treatment approach for esophageal squamous cell carcinoma (ESCC). However, how to promote radiation sensitivity in ESCC remains a challenge. This study aimed to evaluate the effects of berberine, a common used Chinese medicine, on the radiosensitivity of ESCC. ECSS cell line ECA109 and TE13 were subjected to hypoxia and/or ionizing radiation (IR), in the presence or absence of berberine treatment. Cell growth and survival, and apoptosis were evaluated. In addition, ECA109 cells were xenografted into nude mice and subjected to IR and/or berberine treatment. The expression of HIF-1α and VEGF was detected by western blot and immunohistochemical analysis. Our results showed that berberine increased radiosensitivity of ESCC cells and xenografts, and this was associated with the inhibition of HIF-1α and VEGF expression. These data suggest that berberine may be a potential radiotherapy sensitization drugs due to its significant anti-hypoxia activity.     

miR-668 enhances the radioresistance of human breast cancer cell by targeting IκBα

Background

A large proportion of breast cancer patients are resistant to radiotherapy, which is a mainstay treatment for this malignancy, but the mechanisms of radioresistance remain unclear.

Methods and materials

To evaluate the role of miRNAs in radioresistance, we established two radioresistant breast cancer cell lines MCF-7R and T-47DR derived from parental MCF-7 and T-47D. Moreover, miRNA microarray, quantitative RT-PCR analysis, luciferase reporter assay and western blotting were used.

Results

We found that miR-668 was most abundantly expressed in radioresistant cells MCF-7R and T-47DR. miR-668 knockdown reversed radioresistance of MCF-7R and T-47DR, miR-668 overexpression enhanced radioresistance of MCF-7 and T-47D cells. Mechanically, bioinformatics analysis combined with experimental analysis demonstrated IκBα, a tumor-suppressor as well as an NF-κB inhibitor, was a direct target of miR-668. Further, miR-668 overexpression inhibited IκBα expression, activated NF-κB, thus, increased radioresistance of MCF-7 and T-47D cells. Conversely, miR-668 knockdown restored IκBα expression, suppressed NF-κB, increased radiosensitivity of MCF-7R and T-47DR cells.

Conclusion

Our findings suggest miR-668 is involved in the radioresistance of breast cancer cells and miR-668-IκBα-NF-κB axis may be a novel candidate for developing rational therapeutic strategies for human breast cancer treatment.

     

Sensitization of tumor cells to cancer therapy by molecularly targeted inhibition of the inhibitor of nuclear factor κB kinase

The inhibitor of nuclear factor κB kinase (IKK)-nuclear factor κB (NFκB) pathway is one of the most important cellular signal transduction pathways. It can be activated by diverse stimuli, resulting in liberation of cytoplasmic NFκB from inhibition by inhibitors of NFκB (IκB) after IκB are phosphorylated by IKKβ and IKKα via the canonical and non-canonical pathways, respectively. Activated NFκB then translocates into the nucleus to regulate various NFκB target genes. Through regulation of its target genes, NFκB can regulate various physiologic processes such as cell proliferation, migration and survival. More importantly, activation of the IKK-NFκB pathway has been implicated in carcinogenesis, tumor development, progression and metastasis, and cancer resistance to radiotherapy and chemotherapy. Therefore, molecularly targeted inhibition of the different components of this pathway has been widely explored for treatment of cancer either alone or in combination with other cancer therapies. A growing body of evidence suggests that IKKβ may be a better cancer treatment target in this pathway, because several novel NFκB-independent functions of IKKβ have been identified recently, including promotion of DNA double strand break repair to increase tumor cell resistance to ionizing radiation and chemotherapy in an apoptosis-independent manner. In this review, we highlight some of these new findings and discuss the therapeutic potential of IKKβ specific inhibitors as a novel tumor sensitizer.     

Is the hypoxia-inducible factor pathway important in gastric cancer?

Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1α (HIF-1α), which appears to be a master regulator of the cellular response to hypoxia. HIF-1α expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1α pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1α. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1α expression. Although a large study correlating HIF-1α expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1α target genes (Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1α has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1α pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.     

Mutant epidermal growth factor receptor contributes to head and neck cancer growth and resistance to EGFR targeting

Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous-cell carcinoma (HNSCC) and its expression levels correlate with decreased patient survival. Nonetheless, therapies aiming at blocking EGFR has shown limited efficacy in a proportion of patients with HNSCC in clinical trials. Sok et al. in a recent paper (Clin Cancer Res, 2006, 12:5064-5073 ) attempted to ascertain whether it is due to mutation of EGFR. As the most common form of mutation of EGFR seen in several other types of cancer is a truncation mutation, EGFR     

Angiotensin Ⅱ type 1 receptor antagonist inhibits growth of human bladder cancer xenograft

Angiotensin Ⅱ is known as a key biologically active peptide in rennin-angiotensin system, which regulates blood pressure, and angiotensin Ⅱ type 1 receptor （AT1R） antagonists are widely used as antihypertensive drugs. Since markedly inhibited growth of human bladder cancer （KU-19-19） xenograft in athymic nude mice （Clin Cancer Res 2006, 12：2888-2893）. Bladder cancer cell line KU-19-19 was shown to express AT1R by flow cytometric and immunocytochemical analysis, and to secrete VEGF and IL-8 to the culture medium by ELISA. In in vitro studies, angiotensin Ⅱ increased VEGF and IL-8 secretion of KU-19-19 while candesartan could block this effect. However, candesartan per se did not inhibit proliferation of KU-19-19 cells nor did it affect AT1R expression. In vivo, mice with KU-19-19 implant were given candesartan （2 or 10 mg/kg） by gavage daily, starting on the day of tumor inoculation, and sacrificed on day 28. As the results indicated, the growth of the engrafted tumors was significantly inhibited in mice treated with candesartan with a 35.4% and 33.5% reduction in tumor volume at 2 and 10 mg/kg, respectively, compared with the control mice （P 〈0. O301 ）. Significant differences in tumor volume were observed between the candesartan-treated and control mice as early as on day 13 of treatment. The reduction rates did not differ significantly between the two dosages of candesartan used. Microvessel density in the xenografts that in the control mice （2 mg ： 11.6 ± 0. 4, P 〈 0 was found significantly decreased in candesartan mice than 01; 10 mg： 9.79±0.6, P〈0.01 versus 17.6±1.0）.     

Prognostic relevance of transforming growth factor alpha (TGF-α) and tumor necrosis factor alpha (TNF-α) detected in breast cancer tissues by immunohistochemistry

Summary The function of different growth factors in the development and progression of malignant tumors and the role of cytotoxic cytokines in the host response generated against neoplasms have been recently studied. Anti-TGF- and anti-TNF- monoclonal antibody families have been developed and characterized previously by our laboratory. Libraries of anti-TGF- and anti-TNF- monoclonal antibodies were selected for equal immunoreactivity both in native (frozen) and in formaldehyde fixed, paraffin embedded histological sections. No differences were found between native and fixed samples demonstrated in 10 cases in the present prospective study. Retrospective investigation was performed in 35 histopathological specimens of breast cancer patients detailed clinically and observed during 5 years after the surgical treatment. Correlation between TGF- and/or TNF- expression and clinical staging - TNM score, lymph node metastasis, tumor recurrence and survival time - was analyzed. According to our present study, the TGF- positive patients had worse clinical prognosis than the TNF- positive and double positive cases during long term observation.     

Does remnant gastric cancer really differ from primary gastric cancer? A systematic review of the literature by the Task Force of Japanese Gastric Cancer Association

Remnant gastric cancer, most frequently defined as cancer detected in the remnant stomach after distal gastrectomy for benign disease and those cases after surgery of gastric cancer at least 5 years after the primary surgery, is often reported as a tumor with poor prognosis. The Task Force of Japanese Gastric Cancer Association for Research Promotion evaluated the clinical impact of remnant gastric cancer by systematically reviewing publications focusing on molecular carcinogenesis, lymph node status, patient survival, and surgical complications. A systematic literature search was performed using PubMed/MEDLINE with the keywords “remnant,” “stomach,” and “cancer,” revealing 1154 relevant reports published up to the end of December 2014. The mean interval between the initial surgery and the diagnosis of remnant gastric cancer ranged from 10 to 30 years. The incidence of lymph node metastases at the splenic hilum for remnant gastric cancer is not significantly higher than that for primary proximal gastric cancer. Lymph node involvement in the jejunal mesentery is a phenomenon peculiar to remnant gastric cancer after Billroth II reconstruction. Prognosis and postoperative morbidity and mortality rates seem to be comparable to those for primary proximal gastric cancer. The crude 5-year mortality for remnant gastric cancer was 1.08 times higher than that for primary proximal gastric cancer, but this difference was not statistically significant. In conclusion, although no prospective cohort study has yet evaluated the clinical significance of remnant gastric cancer, our literature review suggests that remnant gastric cancer does not adversely affect patient prognosis and postoperative course.     

Inhibition of the growth of cultured human meningioma cells by recombinant interferon-α

In this paper the results of investigations on the effect of interferon-α (IFN-α) on the growth of meningioma cells in culture is reported. A consecutive series of six meningiomas and one meningioma/neurofibroma derived from a patient with neurofibromatosis type 2 was investigated and it was found that the growth of all seven tumours in response to mitotic stimuli (fetal bovine serum or epidermal growth factor) is strongly inhibited by IFN-α. Maximal response varied between 100% and 70% inhibition of the incorporation of tritiated thymidine. In some cases an inhibitory response was obtained already at very low doses (≤10 U of IFN-α per ml). These results indicate that further clinical investigation of the application of IFN-α to the treatment of meningioma is warranted.