Jingyan Cao

Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.

The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. However, it remains unclear how IL-17 might contribute to tumor angiogenesis. In our study, IL-17 enhanced the formation of vessel-like tubes in HUVECs both directly (when HUVECs were incubated with IL-17) and indirectly (when HUVECs were incubated in conditioned cell media (CCM) from IL-17-treated cancer cells). Our results from experiments using siRNA-mediated knockdowns of STAT3 and GIV suggest that the effects of IL-17 were mediated by activating STAT3/GIV signaling in NSCLC cells and subsequently up-regulating its downstream target VEGF. Consistent with these findings, immunostaining experiments on human NSCLC tissues indicated that IL-17 and GIV expression were significantly and positively associated with increased tumor vascularity. The clinical significance of IL-17 was authenticated by our finding that the combination of intratumoral IL-17 + cells and GIV expression served as a better prognosticator for survival than either marker alone. Therefore, our finding highlights a novel aspect of STAT3/GIV pathway in the IL-17 promotes tumor angiogenesis of NSCLC.

miR-34c-3p functions as a tumour suppressor by inhibiting eIF4E expression in non-small cell lung cancer

MicroRNAs (miRNAs) are small non‐coding RNAs that post‐transcriptionally regulate gene expression and mediate diverse physiological processes. In this study, we investigated functions of miRNA miR‐34c‐3p in non‐small cell lung cancer (NSCLC).

Luffa echinata Roxb. induces human colon cancer cell (HT-29) death by triggering the mitochondrial apoptosis pathway.

The antiproliferative properties and cell death mechanism induced by the extract of the fruits of Luffa echinata Roxb. (LER) were investigated. The methanolic extract of LER inhibited the proliferation of human colon cancer cells (HT-29) in both dose-dependent and time-dependent manners and caused a significant increase in the population of apoptotic cells. In addition, obvious shrinkage and destruction of the monolayer were observed in LER-treated cells, but not in untreated cells. Analysis of the cell cycle after treatment of HT-29 cells with various concentrations indicated that LER extracts inhibited the cellular proliferation of HT-29 cells via G2/M phase arrest of the cell cycle. The Reactive oxygen species (ROS) level determination revealed that LER extracts induced apoptotic cell death via ROS generation. In addition, LER treatment led to a rapid drop in mitochondrial membrane potential (MMP) as a decrease in fluorescence. The transcripts of several apoptosis-related genes were investigated by RT-PCR analysis. The caspase-3 transcripts of HT-29 cells significantly accumulated and the level of Bcl-XL mRNA was decreased after treatment with LER extract. Furthermore, the ratio of mitochondria-dependent apoptosis genes (Bax and Bcl-2) was sharply increased from 1.6 to 54.1. These experiments suggest that LER has anticancer properties via inducing the apoptosis in colon cancer cells, which provided the impetus for further studies on the therapeutic potential of LER against human colon carcinoma.

Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis.

Objective Fibroblast activation protein (FAP) plays a vital role in tumor invasion and metastasis. Previous studies have reported its prognostic value in different tumors. However, the results of these reports remain controversial. In this study, a meta-analysis was performed to clarify this issue. Methods A search of the PubMed, Embase and CNKI databases was conducted to analyze relevant articles. The outcomes included the relations between FAP expression and histological differentiation, tumor invasion, lymph node metastasis, distant metastasis and overall survival (OS). Sensitivity analysis by FAP expression in different cells and tumor types were further subjected to sensitivity analyses as subgroups. Pooled odds ratios (ORs) and hazard ratios (HRs) were evaluated using the random-effects model. Results The global analysis included 15 studies concerning various solid tumors. For global analysis, FAP overexpression in tumor tissue displayed significant associations with poor OS and tumor progression (OS: HR = 2.18, P = 0.004; tumor invasion: OR = 4.48, P = 0.007; and lymph node metastasis: OR = 3.80, P = 0.004). The subgroup analyses yielded two notable results. First, the relation between FAP overexpression and poor OS and tumor lymph node metastasis was closer in the patients with FAP expression in tumor cells. Second, the pooled analyses of colorectal cancers or pancreatic cancers all indicated that FAP overexpression was associated with a detrimental OS (HR: 1.72, P = 0.009; HR: 3.18, P = 0.005, respectively). The magnitude of this effect was not statistically significant compared with that in patients with non-colorectal cancers or non-pancreatic cancers. These analyses did not display a statistically significant correlation between FAP expression and histological differentiation and distant metastasis in all of the groups. Conclusions FAP expression is associated with worse prognosis in solid tumors, and this association is particularly pronounced if FAP overexpression is found in the tumor cells rather than the stroma.

The efficacy and safety of low-molecular-weight heparin use for cancer treatment: A meta-analysis

BACKGROUND Low-molecular-weight heparin (LMWH) has an anti-tumour effect in-vitro and in animal models of malignancy; however, the evidence from clinical trials is controversial. Thus, we performed a meta-analysis from the results of randomised controlled trials (RCTs) to assess LMWH efficacy and safety in cancer patients who had no venous thromboembolism (VTE). METHODS We searched the MEDLINE, EMBASE and CENTRAL (The Cochrane Central Register of Controlled Trails) databases covering all papers published up until April 2012. Two reviewers (D. H. Che and J. Y. Cao) extracted the data independently. The inclusion criteria used were patients with cancer who had no VTE and were treated with LMWH. The outcomes of interest included the 1-year mortality rate, VTE, bleeding and major bleeding complications. The results were presented as a relative risk (RR), and the STATA 11.0 package was used for comprehensive quantitative analysis. RESULTS A total of 11 studies with 3835 cases and 3449 controls were included. The meta-analysis showed significant differences in the rates of bleeding with an RR: 1.32 [95% confidence interval (95% CI, 1.08-1.62)] and VTE with an RR: 0.53 (95% CI, 0.42-0.67) in cancer patients when LMWH was compared with placebo or no anticoagulant. There were no significant differences in the 1-year mortality rate with an RR: 0.97 (95% CI, 0.92-1.02) and major bleeding with an RR: 1.22 (95% CI, 0.87-1.71). CONCLUSION LMWH does not significantly reduce the 1-year mortality rate for cancer patients. Although LMWH can prevent VTE, we should consider the risk-effect ratio (in case of an increased bleeding event) when we use LMWH in the patients with cancer. Thus, further research is still needed to confirm these results.

Interleukin-17 levels correlate with poor prognosis and vascular endothelial growth factor concentration in the serum of patients with non-small cell lung cancer

Abstract Objective: The aim of this study was to explore the clinical role of serum interleukin-17 in patients with non-small-cell lung cancer (NSCLC). Materials and method: IL-17 expression and microvessel density (MVD) were measured via immunohistochemistry in 58 NSCLC tissues. Serum IL-17 and VEGF levels in NSCLC patients (n = 43) and healthy controls (n = 37) were analyzed via enzyme-linked immunosorbent assay. Results: Serum IL-17 was elevated and the levels positively correlated with VEGF concentration in NSCLC patients. Multivariate analyses revealed that serum IL-17 levels were an independent prognostic factor in NSCLC. Conclusion: IL-17 may play a role in NSCLC progression by promoting angiogenesis.

Combination of four gene markers to detect circulating tumor cells in the peripheral blood of patients with advanced lung adenocarcinoma using real-time PCR

The aim of this study was to establish a robust and reliable assay for the detection of circulating tumor cells (CTCs) in the peripheral blood (PB) of patients with advanced lung adenocarcinoma. We used real-time reverse transcription PCR (RT-PCR) to detect survivin, human telomerase reverse transcriptase (hTERT), cytokeratin-7 (CK-7) and thyroid transcription factor 1 (TTF-1) mRNA expression levels in 68 advanced lung adenocarcinoma patients and 30 healthy patients. Statistical analyses were additionally performed to examine the correlation between the mRNA expression levels of these markers with the clinicopathological features of advanced lung adenocarcinoma patients. The sensitivity of these four mRNA markers in the PB of advanced lung adenocarcinoma patients was 41.18, 61.76, 41.18 and 35.29%, respectively. The sensitivity of these four markers combined was 82.35%, which was significantly higher compared with single marker detection. Statistical analysis demonstrated that high expression levels of survivin, hTERT and TTF-1 mRNA are positively correlated with lymph node classification, and high expression levels of survivin, hTERT, CK7 and TTF-1 mRNA are positively correlated with distant metastasis (P<0.05). In addition, overexpression of these four mRNA markers is positively correlated with disease progression (P<0.05). Our data suggest that the combination of survivin, hTERT, CK-7 and TTF-1 mRNA markers may provide a valuable tool for CTC detection and is associated with disease progression in advanced lung adenocarcinoma patients.

Interleukin-22 promotes lung cancer cell proliferation and migration via the IL-22R1/STAT3 and IL-22R1/AKT signaling pathways

Lung cancer continues to be an enormous burden on current health care systems throughout the world, with more than a million deaths every year. Previous studies have shown that interleukin-22 (IL-22) promotes survival and resistance to chemotherapy in human lung cancer cells. However, the association of IL-22 expression with recurrence of lung cancer is still unclear. In this study, we found that expression of IL-22 was upregulated in tumor tissues and serum from patients with recurrent non-small cell lung cancer (NSCLC) as compared to primary NSCLC samples. Treatment with IL-22 promoted cell proliferation and enhanced migration and invasion in A549 and H125 cell lines. Furthermore, we revealed that phosphorylation of STAT3 and AKT was highly induced by treatment with IL-22 via IL-22R1. IL-22R1 was also consistently overexpressed in recurrent NSCLC tissues. Finally, we found that siRNA-mediated depletion of IL-22R1 completely abrogated the effects of IL-22 treatment on cell proliferation and migration activity in NSCLC cell lines. Our findings indicate that IL-22 and IL-22R1 may be novel therapeutic targets for treatment of advanced NSCLC.

Selected patients can benefit more from the management of etoposide and platinum-based chemotherapy and thoracic irradiation-a retrospective analysis of 707 small cell lung cancer patients

The management of small cell lung cancer (SCLC) has reached a plateau. Etoposide and platinum-based chemotherapy plus thoracic irradiation remain the standard treatment strategy for SCLC. Our study aims to assess the potential prognostic factors of patients treated with etoposide and platinum-based chemotherapy and explore which group of patients can benefit more from standard treatment strategies. On univariate analysis, age>65 years, male patients, KPS (Karnofsky Performance Status)≤80 points, positive smoking history, anemia, lymphocyte counts≤1.65×109/L, neutrophil to lymphocyte ratio (NLR)>3.18, lymphocyte to monocyte ratio (LMR)≤2.615, lactate dehydrogenase (LDH)>216.5 U/L, alkaline phosphatase (ALP)>119.5 U/L, absence of surgery, absence of thoracic irradiation, chemotherapy cycles<4, metastatic sites≥2 and extensive disease were correlated with a poor prognosis. Gender, KPS, chemotherapy cycles, thoracic irradiation, metastatic sites, LDH and tumor stage held statistical significance on multivariate analysis (p<0.05). High LDH was closely correlated with extensive disease, metastatic sites≥2, anemia, low LMR, high NLR and ALP levels. Subgroup analysis showed patients with male gender, KPS≤80 points, LDH≤216.5U/L, extensive disease and metastatic sites<2 could benefit more from ≥4 chemotherapy cycles. Patients with male gender, KPS>80 points, LDH≤216.5U/L, limited disease and metastatic sites<2 could benefit more from thoracic irradiation (p<0.05 on uni- and multivariate analysis). In conclusion, female patients, KPS>80 points, chemotherapy cycles≥4, thoracic irradiation, metastatic sites<2, LDH≤216.5U/L and limited disease were independent positive prognostic factors for SCLC patients treated with etoposide and platinum-based chemotherapy. Selected patients can benefit more from the management of ≥4 cycles of chemotherapy and thoracic irradiation.

Colonic invasion induced by malignant peritoneal mesothelioma.

Novelty: Malignant peritoneal mesothelioma (MPM) is a rare disease confined to peritoneal cavities in most cases, seldom seen in intraand extra-abdominal invasion. In addition, MPM is easy of misdiagnosis and has a poor prognosis. Here, we report a case of colonic invasion induced by MPM in order to help prevent from misdiagnosis and prolong survival time. A 53-year-old male who presented with constipation, weight loss, and occasional abdominal discomfort for 2 months was admitted to the Department of Surgical Oncology, Harbin Medical University Cancer Hospital, November 2013. He was a heavy smoker of 15 packs/month with a history of asbestos exposure in childhood and diabetes mellitus. On physical examination, he had a fixed mass in the right lower quadrant. Routine blood tests and evaluation for tumor markers CEA, CA724, CA19-9, and CA-125 were all in normal range except for a thrombocytosis of 397×10/L. A 3D-enhanced CT of the abdomen showed an irregular thickening wall of hepatic flexure of colon, and the thickener area can be reached 16.8 mm, closely adjacent to intestine. At the same time, an infiltrating mass of 67.7 mm in size, multiple small peritoneal nodules, and abdominal swelling lymph nodes can also be seen in abdominal CT. There were no remarkable findings on the endoscopic examination, and the colonoscopy suggested an infiltrating lesion located in the hepatic flexure of colon, ruptured in the surface, and easily bled when touched. Laparotomy was performed, peritoneal nodules were intraoperatively found throughout the peritoneum, and the infiltrating mass had penetrated the range of serosal and right side of the peritoneum, widely planting in the peritoneum, omentum, and surface of peritoneal cavities. Necrotic tissue sample was delivered for examination, and quick pathology revealed malignancy. In addition, 2.0 cm×1.5 cm×1.0 cm omental tissue was cut for detection during surgery. Histology revealed a well-differentiated epithelioid malignant mesothelioma. It was positive for HBME-1, CK5/6, CK7, and calretinin, supporting the diagnosis of MPM. After surgery, the patient was referred to the Department of Medical Oncology. Our patient recovered well after the operation, and he had successfully accepted 2 cycles of chemotherapy of pemetrexed combined with carboplatin; unfortunately, he did not tolerate the therapy, and the disease progressed with the appearance of ascites and rectum occupation revealed by abdominal and pelvic CT. However, there are no significant abnormalities found in colonoscopy. We deemed that rectum occupation was caused by the compression of swelling lymph nodes. Oxaliplatin and capecitabine were adjusted to the following treatment, and he felt symptoms released at present. MPM is an uncommon, fatal disease arising from the peritoneum with an increasing incidence of 7–40/million and a negative prognosis of within 12 months [1]. The main risk factor for MPM is asbestos exposure, and the onset of about 60 % of MPM patients was correlated with direct or indirect asbestos contact. In addition, exposure to radiation, talc, mica, erionite, Thorotrast, SV40, and Hodgkin’s disease has also been reported to be related to MPM [2]. The most common presentations of MPM are abdominal pain and distension which resulted from the accumulation of tumors and ascites, while constipation is exceptional. MPM is usually diagnosed at advanced stage due to its nonspecific clinical and S. B. Cao and S. Jin contributed equally to this work. S. B. Cao : S. Jin : J. Y. Cao : J. Shen : J. W. Zhang :Y. Yu (*) Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150 Hapin Road, 150081 Harbin, China e-mail: yuyan_hrb@126.com