Hongxin Cao

Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis

Background The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer. Methodology/Principal Findings A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1 043 case subjects and 11 472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95% CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group. Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI: [0.802,1.367], P = 0.736) and 0.960 (95%CI: [0.591,1.559], P = 0.868) respectively; and SMDs were −0.079 (95%CI:[ −0.169, 0.011], P = 0.086) and −0.097 (95%CI:[ −0.264,0.071], P = 0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[ −0.035, 1.171], P = 0.065) and −0.780 (95%CI:[ −1.358, −0.201], P = 0.008) for IGF-1 and IGFBP-3 respectively. Conclusions/Significance Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies,and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.

The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy

Insulin‐like growth factor‐1 receptor (IGF‐1R) targeted therapies have become one of the intriguing areas in anticancer drug development during the last decade. As one of these therapies, anti‐IGF‐1R monoclonal antibodies (mAbs) are also advancing further in development. Our purpose was to conduct a systematic review of the adverse events (AEs) caused by anti‐IGF‐1R monoclonal antibodies in cancer therapy.

The Effect of Diabetes Mellitus on Lung Cancer Prognosis: A PRISMA-compliant Meta-analysis of Cohort Studies.

AbstractPrevious studies suggested that diabetes mellitus (DM) was associated with risk and mortality of cancer, but studies investigating the correlation between DM and lung cancer prognosis remain controversial. Herein, a meta-analysis was performed to derive a more precise estimate of the prognostic role of DM in lung cancer.Medline and Embase were searched for eligible articles from inception to October 25, 2015. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the correlation between DM and lung cancer prognosis. Subgroup meta-analysis was performed based on the histology and the treatment methods.A total of 20 cohort studies from 12 articles were included in the meta-analysis. Also, 16 studies investigated the overall survival (OS) and 4 studies investigated the progression-free survival (PFS). DM was significantly associated with the inferior OS of lung cancer with the pooled HR 1.28 (95% CI: 1.10–1.49, P = 0.001). The association was prominent in the nonsmall cell lung cancer (NSCLC) subgroup (HR 1.35, 95%CI: 1.14–1.60, P = 0.002), whereas the association was not significant in the small cell lung cancer (SCLC) subgroup (HR 1.33, 95% CI: 0.87–2.03, P = 0.18). When NSCLC patients were further stratified by treatment methods, DM had more influence on the surgically treated subgroup than the nonsurgically treated subgroup. There was no obvious evidence for publication bias by Beggs and Eggers test.The results of this meta-analysis exhibit an association of DM with inferior prognosis amongst lung cancer patients, especially the surgically treated NSCLC patients. Given the small number of studies included in this meta-analysis, the present conclusion should be consolidated with more high-quality prospective cohort studies or randomized controlled trials.

Metformin Enhances the Therapy Effects of Anti-IGF-1R mAb Figitumumab to NSCLC.

The insulin-like growth factor (IGF) signaling system plays a critical role in tumorigenesis, highlighting the potential of targeting IGF-1R as an anti-cancer therapy. Although multiple anti-IGF-1R monoclonal antibody (mAb) drugs have been developed, challenges remain in the validation of the therapeutic effects and understanding the molecular mechanism of these mAbs. Herein, we conducted a study to validate the effect of Figitumumab (CP), an anti-IGF-1R mAb, in a panel of non-small cell lung cancer (NSCLC) cell lines. We found all tested cell lines were sensitive to CP, and CP could block IGF-1R and the downstream PI3K/AKT pathway activation. Unexpectedly, we found CP could activate ERK signaling pathway in IGF-1R kinase independent manner, which we further verified was mainly mediated by β-arrestin2. We also investigated the anti-tumor effect of metformin alone as well as its combination with CP to target NSCLC. Metformin could target IGF-1R signaling pathway by attenuating PI3K/AKT and MEK/ERK signaling pathways and down-regulating IGF-1R. Finally, we found that combining metformin with CP could further induce IGF-1R down-regulation and was more effective to target NSCLC cells. Our data suggests the combining of metformin with CP has additive therapeutic value against NSCLC.

The Number of Resected Lymph Nodes (nLNs) Combined with Tumor Size as a Prognostic Factor in Patients with Pathologic N0 and Nx Non-Small Cell Lung Cancer

Background The prognostic role of the number of resected lymph nodes (nLNs) in pathologic N0 (lymph node negative) and Nx (no lymph node examined) non-small cell lung cancer (NSCLC) patients remains uncertain. Guidelines for optimal nLNs have not been established. In the current study, we evaluated whether a higher number of resected lymph nodes (LNs) results in better survival in different tumor size categories among NSCLC patients without metastatic LNs. Method A retrospective study was conducted. Based on nLNs (LN = 0, 1–7, >7) and tumor size (Ta: ≤3.5cm, Tb: >3.5cm) during surgery, patients were categorized into 6 groups (LN0Ta, LN0Tb, LN1–7Ta, LN1–7Tb, LN7-Ta and LN7-Tb). Survival and multivariate analyses were carried out to determine whether nLNs combined with tumor size was significant for overall survival (OS) or disease free survival (DFS) after adjusting for potential confounders. Results A total of 428 patients were enrolled in the study. Multivariate analysis demonstrated that nLNs, tumor size and pathological stage were the independent prognosticators for OS and DFS. Data from our study suggested that lung cancer lymphadenectomy with more than 7 LNs removed should be considered a benchmark for surgery or pathology at an early stage. Survival was significantly better in the LN7-Ta group, compared with other 5 groups (p<0.001). Conclusions The combined predictor (nLNs combined with tumor size) is an independent prognostic factor and a reasonable stratification criterion in patients with pathologic N0 and Nx NSCLC. The validation of our finding is warranted in further investigation.

Haemoptysis as a prognostic factor in lung adenocarcinoma after curative resection.

Background:Haemoptysis is a common symptom of lung cancer. Its prognostic role and mechanisms are still poorly understood.Methods:We retrospectively reviewed 666 consecutive patients with primary lung adenocarcinoma who underwent complete resection. The prognostic value of haemoptysis with respect to overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) was analysed. To further explore the possible mechanisms of haemoptysis, we evaluated vascular endothelial growth factor (VEGF) expression, tumour necrosis, vascular invasion and extratumoural microvessel density (MVD) in 112 randomly selected patients.Results:Haemoptysis predicted poor OS, DSS and DFS in operable lung adenocarcinoma (all P<0.001). In addition, haemoptysis was associated with high white blood cell (WBC) count (P=0.032), high fibrinogen (Fib; P<0.001), high tumour greatest dimension (P<0.001), severe vascular invasion (P=0.002) and central tumour location (P<0.001). We obtained no statistically significant differences of VEGF expression, tumour necrosis and extratumoural MVD in haemoptysis and non-haemoptysis groups.Conclusion:Our study demonstrates that haemoptysis predicts poor OS, DSS and DFS in lung adenocarcinoma after curative resection. Vascular invasion rather than angiogenesis or tumour necrosis could be the most important mechanism of haemoptysis in lung adenocarcinoma.

ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response.

ARRB1 (also known as β-arrestin-1) serves as a multifunctional adaptor contributing to the regulation of signaling pathways. ARRB1 may be involved in DNA damage accumulation; however the underlying mechanism involved is unclear. In the present study, non-small cell lung cancer (NSCLC) cell lines (H520 and SK-MES-1) were transfected with ARRB1 plasmids or small interfering ribonucleic acid (siRNA) and received treatment with DNA-damaging agents (cisplatin and etoposide). A mouse xenograft model was used to assess the impact of ARRB1 on the efficacy of cisplatin in vivo. A total of 30 surgically resected NSCLC patients were recruited for the present study and qRT-PCR was performed to determine the mRNA levels in cancer tissues compared with para-carcinoma tissues. Our data showed that DNA damage was abrogated in the ARRB1-knockdown cells and enhanced in the ARRB1-overexpressing cells. ATR and Chk1 were more activated in the ARRB1-overexpressing cells compared to the ARRB1-knockdown cells, followed by increased H2AX phosphorylation. DNA damage and apoptosis were increased in the ARRB1-overexpressing cells treated with cisplatin. These data provided strong evidence that ARRB1 contributes to the response of NSCLC to DNA-damaging agents and is essential for DNA damage response (DDR). ARRB1 may enhance the efficacy of DNA-damaging agents in NSCLC.

Combinational Therapy Enhances the Effects of Anti-IGF-1R mAb Figitumumab to Target Small Cell Lung Cancer.

Background Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality. Methods We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy. Results Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation. Conclusion Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies.

The Synergistic Effect of Humanized Monoclonal Antibodies Targeting Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Chemotherapy

IGF-1R, an important member of the IGF signaling system, is a plasma-membrane-bound receptor composed of two α-subunits and two β-subunits. IGF-1R has been revealed to play a pivotal role in cancer cell proliferation, differentiation, apoptosis and phenotype transformation, resulting uncontrolled tumor-cell growth. During the last decades, IGF-1R monoclonal antibody combined with chemotherapeutic agents as a novel cancer treatment approach has shown synergistic effect in cancer treatment in some preclinical and clinical trials. Prolonged progression-free survival rate, objective response rate and stable disease were shown in some sorts of cancer patients compared to those implemented traditional standard chemotherapy. However, not all related clinical trials demonstrated expected promising outcomes. Most treatment-related adverse events in those studies are mild and manageable. The most frequently happened side effect is hyperglycemia in majorities of combined cancer therapy studies. Herein, we summarized the recent online and published literatures concerning the safety, tolerability, anti-tumor activity and adverse events of this novel strategy. Besides, this work attempts to provide convincible evidence to warrant further investigation to identify prognostic biomarkers on neoplasm.