Shengling Fu

Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice

Estrogen receptor (ER) and insulin‐like growth factor‐1 receptor (IGF‐1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF‐1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor‐bearing mice were divided into seven groups: 17β‐estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF‐1, IGF‐1+AG1024 (IGF‐1 inhibitor), E2+IGF‐1, E2+IGF‐1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERβ, IGF‐1, IGF‐1R and Ki67 was examined using tissue‐microarray‐immunohistochemistry, and IGF‐1, p‐ERβ, p‐IGF‐1R, p‐MAPK and p‐AKT levels were determined based on Western blot analysis. Fluorescence‐quantitative polymerase chain reaction was used to detect the mRNA expression of ERβ, ERβ2 and IGF‐1R. Tumors were found in 93.88% (46/49) of urethane‐treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF‐1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF‐1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ERβ, p‐ERβ, ERβ2, IGF‐1, IGF‐1R, p‐IGF‐1R, p‐MAPK, p‐AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF‐1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2 and IGF‐1R play important roles.

Systemic immune-inflammation index, thymidine phosphorylase and survival of localized gastric cancer patients after curative resection

Systemic immune-inflammation index (SII), based on lymphocyte (L), neutrophil (N), and platelet (P) counts, was recently developed and reflects comprehensively the balance of host inflammatory and immune status. We explored its prognostic value in localized gastric cancer (GC) after R0 resection and the potential associations with Thymidine phosphorylase (TYMP), which was reported to increase the migration and invasion of gastric cancer cells. A total of 455 GC patients who received D2 gastrectomy were enrolled. Blood samples were obtained within 1 week before surgery to measure SII (SII = P × N/L). TYMP expression was measured on tumor sections by immunohistochemical analysis. Preoperative high SII indicated worse prognosis (HR: 1.799; 95% CI: 1.174-2.757; p = 0.007) in multivariate analysis and was associated with higher pathological TNM stage, deeper local invasion of tumor and lymph node metastasis (all p < 0.001). SII predicted poor overall survival in pathological TNM stage I subgroup also (p < 0.001). Furthermore we found that in high SII group, positive rate of TYMP expression increased (53.7% vs 42.7%, p = 0.046) and TYMP positive patients had higher SII score (median 405.9 vs. 351.9, p = 0.026). SII, as a noninvasive and low cost prognostic marker, may be helpful to identify higher-risk patients after R0 resection, even for stage I GC patients.

Advances in targeting insulin-like growth factor signaling pathway in cancer treatment.

Insulin-like growth factors (IGFs), along with their receptors and binding proteins, play key roles in human cell proliferation, differentiation and apoptosis. There is now substantial evidence suggesting that the IGF system is involved in the pathogenesis and progression of various malignancies. Recent studies have shown that targeting of the IGF-1 receptor (IGF-1R) signaling pathway might be a novel approach for the treatment of cancer. Presently numerous agents featuring different mechanisms of IGF targeting methods such as IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors and IGF ligand specific antibodies are being investigated in more than 170 clinical trials and appear to have potential therapeutic efficacy. However, advanced trials reiterate the importance of predictive biomarkers to guide the clinical efforts of these agents. As a result, current research strategies are emerging to identify the most suitable subpopulations of patients that might benefit from these treatments. Furthermore, newly presented toxicity and growth hormone response and implication of hybrid receptors in IGF signaling pathway pose unprecedented challenges in the design and application of anti-IGF agents. On the other hand, cross-talk in downstream signaling between IGF-1R and other tumor promoting pathways and the development of multi-target agents might encourage the IGF-1R-targeted therapies further into comprehensive treatments of cancer. With both challenges and prospects ahead, this paper reviewed the progress in this particular field.

Effects of Insulin-like Growth Factor 1 Receptor and Its Inhibitor AG1024 on the Progress of Lung Cancer

The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer (NSCLC). This study aimed to investigate the effects of IGF-1R and its inhibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues (n=198). Western blotting was used to determine the expressions of IGF-1 and phosphorylated IGF-1R (p-IGF-1R) in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+AG1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-1+AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF-1 and IGF inhibitor AG1024 promotes lung cancer progression.The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer (NSCLC). This study aimed to investigate the effects of IGF-1R and its inhibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues (n=198). Western blotting was used to determine the expressions of IGF-1 and phosphorylated IGF-1R (p-IGF-1R) in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+AG1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-1+AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF-1 and IGF inhibitor AG1024 promotes lung cancer progression.

Association of preoperative serum IGF- I concentration with clinicopathological parameters in patients with non-small cell lung cancer

SummaryInsulin-like growth factor-I (IGF-I) is a mitogenic and anti-apoptotic factor. Serum IGF-I concentration is related to some cancer risk and tumor progression. The aim of this research was to study the association of preoperative serum IGF-I concentration with clinicopathological parameters and prognosis of non-small cell lung cancer (NSCLC). Preoperative serum IGF-I concentration was measured in 80 consecutive patients with NSCLC who underwent radical lung cancer resection, and 45 patients with benign pulmonary lesion (BPL) by using enzyme linked immunosorbent assay (ELISA). The results showed that the serum IGF-I concentration was elevated and correlated with clinicopathological parameters and overall survival (OS) in NSCLC patients. Serum IGF-I concentration was significantly higher in patients with NSCLC than in those with BPL. The IGF-I concentrations were significantly higher in NSCLC patients with ≥T2, N1-3, and in IIIA-IV but not in those with <T2, N0, or IA-IIB. The increased serum IGF-I concentration was significantly correlated with poor prognosis. Our data show the positive correlation between IGF-I serum concentration and the tumor size for the first time. It seems that IGF-I related to the progression of lung cancer may depend on autocrine/paracrine function. In addition, our study reveals that higher serum IGF-I concentration is correlated with larger tumor size, advanced stages, local lymph node metastasis and worse prognosis, indicating that endocrine IGF-I is also important for the progression for NSCLC.Insulin-like growth factor-I (IGF-I) is a mitogenic and anti-apoptotic factor. Serum IGF-I concentration is related to some cancer risk and tumor progression. The aim of this research was to study the association of preoperative serum IGF-I concentration with clinicopathological parameters and prognosis of non-small cell lung cancer (NSCLC). Preoperative serum IGF-I concentration was measured in 80 consecutive patients with NSCLC who underwent radical lung cancer resection, and 45 patients with benign pulmonary lesion (BPL) by using enzyme linked immunosorbent assay (ELISA). The results showed that the serum IGF-I concentration was elevated and correlated with clinicopathological parameters and overall survival (OS) in NSCLC patients. Serum IGF-I concentration was significantly higher in patients with NSCLC than in those with BPL. The IGF-I concentrations were significantly higher in NSCLC patients with ≥T2, N1-3, and in IIIA-IV but not in those with <T2, N0, or IA-IIB. The increased serum IGF-I concentration was significantly correlated with poor prognosis. Our data show the positive correlation between IGF-I serum concentration and the tumor size for the first time. It seems that IGF-I related to the progression of lung cancer may depend on autocrine/paracrine function. In addition, our study reveals that higher serum IGF-I concentration is correlated with larger tumor size, advanced stages, local lymph node metastasis and worse prognosis, indicating that endocrine IGF-I is also important for the progression for NSCLC.

IFN-γ-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling: IFN-γ in lung adenocarcinoma

IFN‐γ plays a crucial role in anti‐tumor responses and also induces expression of PD‐L1, a well‐established inhibitor of anti‐tumor immune function. Understanding how molecular signaling regulates the function of IFN‐γ might improve its anti‐tumor efficacy. Here, we show that the tumor expression of IFN‐γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN‐γ and PD‐L1 have the best prognosis compared to those with tumors expressing IFN‐γ or PD‐L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN‐γ display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD‐L1+ but not PD‐L1− tumors. The current concept is that PD‐L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)‐mediated anti‐tumor progression. However, our data indicate that PD‐L1 expression in the presence of IFN‐γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN‐γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN‐γ‐induced activation of JAK2‐STAT1 and PI3K‐AKT pathways. The activation of JAK2‐STAT1 is responsible for the anti‐proliferative effect of IFN‐γ. Inhibition of PI3K downregulated PD‐L1 expression and enhanced the anti‐proliferative effect of IFN‐γ, suggesting that blockade of PI3K might maximize the IFN‐γ‐mediated anti‐tumor effect. Our findings provide evidence for crosstalk between JAK2‐STAT1 and PI3K‐AKT pathways in response to IFN‐γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

Expression and clinical significance of insulin-like growth factor 1 in lung cancer tissues and perioperative circulation from patients with non-small-cell lung cancer

OBJECTIVE We explored the role of insulin-like growth factor 1 (igf-1) in the development of lung cancer. METHODS We used immunohistochemistry to measure the expression of igf-1 and igf-1 receptor (igf-1r) in specimens of tissue and perioperative circulation from 80 patients with primary non-small-cell lung cancer (nsclc) and from 45 patients with benign pulmonary lesions (bpls). Correlations of those measurements with clinicopathologic characteristics and clinical follow-up were analyzed. Circulating igf-1 was measured before and after surgery in all patients. RESULTS Compared with bpl specimens, nsclc specimens showed overexpression of igf-1and igf-1r (p < 0.001). The expression levels of igf-1 and igf-1r were significantly associated with advanced-stage disease (p = 0.034 and 0.029 respectively) and lymph node metastasis (p = 0.012 and 0.017 respectively), and expression of igf-1 correlated with tumour differentiation and tumour diameter (p = 0.011 and 0.021 respectively). Specimens positive for igf-1 or igf-1r were significantly correlated with shorter patient survival (p = 0.0012 and 0.0016 respectively). After surgery, circulating igf-1 was significantly elevated in patients with bpl (p = 0.0346) and significantly lower in patients with nsclc (p = 0.0030), especially in those with advanced-stage disease, a larger tumour size, regional lymphoid node metastasis, or lesser differentiation (p = 0.0092, 0.0051, 0.0131, and p < 0.001 respectively). CONCLUSIONS In nsclc, igf-1 and igf-1r are upregulated, and expression of those factors is correlated with tumour progression and prognosis in nsclc patients. Radical resection of nsclc can directly influence the serum concentration of igf-1. Autocrine/paracrine igf-1 might be playing an important role in the development of lung cancer.

Thymidine phosphorylase gene variant, platelet counts and survival in gastrointestinal cancer patients treated by fluoropyrimidines

The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF ≥ 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients.

Fulvestrant-mediated inhibition of estrogen receptor signaling slows lung cancer progression.

Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, development, and differentiation. They also play a major role in many pathological conditions, such as hormone-dependent cancer. The importance of inhibiting estrogen receptor signaling in diseases of estrogen target tissues, such as breast cancer, is well documented. However, the role of estrogen signaling in diseases of nontarget tissues, such as lung cancer, is not well characterized. The aim of the current study is to examine the expression of estrogen receptor β (ERβ) and the roles of estradiol (E2) and fulvestrant on the progression of lung cancer. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were used to detect the expression of aromatase, ERα, and ERβ in 198 patients. We performed analyses to determine if there was any correlation among these three proteins. A mouse model of urethane-induced lung adenocarcinoma was used in the study. Mice were divided into three treatment groups: blank control, E2 alone, and E2 + fulvestrant (ERβ antagonist). Western blot analysis and fluorescence quantitative PCR (FQ-PCR) were used to measure expression of ERβ protein and mRNA levels, respectively. ERβ, but not ERα, was overexpressed in NSCLC samples. Lung cancer progression in mice treated with E2 was significantly increased compared to either the control group or the E2 + fulvestrant group. Mice in the E2 treatment group had significantly increased expression of ERβ at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ERβ promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ERβ in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease.

Use of lung-preserving surgery in left inflammatory bronchial occlusion and distal atelectasis: preliminary results

OBJECTIVES Lung-preserving surgery was proved to be effective and safe to treat patients with benign bronchial strictures. However, this surgical treatment has been rarely reported in patients with complete occlusion in the left main bronchus. The aim of this study was to assess the value of this procedure and report our experience in the treatment of these patients with left atelectasis caused by inflammatory bronchial occlusion. METHODS We reviewed and analysed the medical records of 8 patients who had undergone left main bronchus sleeve resection for symptomatic left atelectasis caused by inflammatory bronchial occlusion from May 2007 to April 2011. RESULTS Eight patients (3 men and 5 women) with a medical history of active pulmonary tuberculosis were involved in this study. The median age was 23 years. Parenchyma-sparing left main bronchus resection was performed in 4 patients, 1 of whom received partial wedge resection in the lingual lobe. Left main bronchus sleeve resection plus superior lobectomy was performed in 2 patients and left main bronchus sleeve resection plus left inferior lobectomy in 2 patients, 1 of whom received additional partial wedge resection of the lingual lobe. The procedure was completed successfully in all 8 patients without postoperative deaths. The mean follow-up time was 49.3 months, ranging from 23 to 69 months. No major complications, including stenosis and atelectasis, were observed during the follow-up period. The symptoms of pulmonary atelectasis disappeared and pulmonary ventilation function improved significantly. CONCLUSIONS In symptomatic patients with left atelectasis caused by inflammatory bronchial occlusion, lung-preserving surgery is an effective and safe surgical treatment.