Qiang Pu

The number and microlocalization of tumor-associated immune cells are associated with patient's survival time in non-small cell lung cancer

BackgroundTumor microenvironment is composed of tumor cells, fibroblasts, endothelial cells, and infiltrating immune cells. Tumor-associated immune cells may inhibit or promote tumor growth and progression. This study was conducted to determine whether the number and microlocalization of macrophages, mature dendritic cells and cytotoxic T cells in non-small cell lung cancer are associated with patients survival time.MethodsNinety-nine patients with non-small cell lung cancer (NSCLC) were included in this retrospective study. Paraffin-embedded NSCLC specimens and their clinicopathological data including up to 8-year follow-up information were used. Immunohistochemical staining for CD68 (marker for macrophages), CD83 (marker for mature dendritic cells), and CD8 (marker for cytotoxic T cells) was performed and evaluated in a blinded fashion. The numbers of immune cells in tumor islets and stroma, tumor islets, or tumor stroma were counted under a microscope. Correlation of the cell numbers and patients survival time was analyzed using the Statistical Package for the Social Sciences (version 13.0).ResultsThe numbers of macrophages, mature dendritic cells and cytotoxic T cells were significantly more in the tumor stroma than in the tumor islets. The number of macrophages in the tumor islets was positively associated with patients survival time, whereas the number of macrophages in the tumor stroma was negatively associated with patients survival time in both univariate and multivariate analyses. The number of mature dendritic cells in the tumor islets and stroma, tumor islets only, or tumor stroma only was positively associated with patients survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets and stroma was positively associated with patients survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets only or stroma only was not associated with patients survival time.ConclusionsThe number of macrophages in the tumor islets or stroma is an independent predictor of survival time in NSCLC patients. Counting macrophages in the tumor islets or stroma is more useful in predicting patients survival time than counting mature dendritic cells or cytotoxic T cells.

Interleukin-17 and Prostaglandin E2 Are Involved in Formation of an M2 Macrophage-Dominant Microenvironment in Lung Cancer

Introduction: Tumor-associated macrophages (TAMs) are divided into M1 and M2 macrophages. M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth and metastasis. The aim of this study was to examine the possible causes leading to the formation of an M2-macrophage–dominant tumor microenvironment in non–small-cell lung cancer. Methods: Forty-eight archived lung tumor samples were examined for the expression of interleukin-17 (IL-17) receptors, IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC), and the number of TAMs using immunohistochemical staining. Twenty fresh lung tumors and matched normal lung tissues were examined for expression of IL-17, cyclooxygenase-2, and prostaglandin E2 (PGE2), using enzyme-linked immunosorbent assay and Western blot analysis. Macrophage-migration assays were performed using fresh lung tumor tissues and IL-17 as chemoattractants. Induction of M2-macrophage differentiation was analyzed using real-time quantitative polymerase chain reaction. Results: TAMs expressed IL-17RA and IL-17RC. Lung tumors expressed higher levels of IL-17, cyclooxygenase-2, and PGE2, compared with normal lung tissues. Lung tumor tissues attracted migration of mouse RAW264.7 macrophages and primary peritoneal macrophages through IL-17, which was mediated by IL-17RA and IL-17RC. IL-17 did not induce either M1- or M2-macrophage differentiation. However, human lung cancer A549 cells strongly induced M2-macrophage differentiation of RAW264.7 macrophages when the two cell lines were cocultured. The inductive factor secreted by A549 cells was identified to be PGE2. Conclusions: IL-17 recruits macrophages, and PGE2 induces M2-macrophage differentiation, hence the increased levels of IL-17 and PGE2 in lung cancer contribute to the formation of an M2-macrophage–dominant tumor microenvironment.

A new concept of endoscopic lung cancer resection: Single-direction thoracoscopic lobectomy

Although video-assisted thoracoscopic surgery was introduced in the early 1990s, its use in the treatment of lung cancer has been limited. We examined the effectiveness of a simplified surgical method for thoracoscopic lobectomy in patients with lung cancer from May 2006 to October 2007. This novel single-direction thoracoscopic lobectomy was characterized by incisions convenient for the placement of instruments and the lobectomy proceeded progressively in a single direction from superficial to deep structures. The procedure was completed successfully in 26 of 28 patients, with no perioperative deaths. The average operation time was 135min (range, 100-200min), average blood loss was 125mL (range 10-500mL) and average number of lymph nodes dissected was 11.8 (range, 6-23). The average postoperative hospital stay was 7.4 days (range, 5-10 days). Single-direction thoracoscopic lobectomy is a simple, safe, and effective procedure for lobe resection with clear procedural steps. It overcomes the difficulty in manipulation of incomplete lung fissures and potentially extends the indications of thoracoscopic lobectomy.

Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis

Tumor-associated macrophages (TAMs) are important components of cancer microenvironment. In the present study, we searched PubMed, Embase, Cochrane library and Web of Science to perform a meta-analysis of 20 studies including a total of 2,572 non-small cell lung cancer (NSCLC) patients, in order to determine the association between TAMs and NSCLC prognosis. The combined hazard ratio (HR) of 9 studies showed that the density of total CD68+ TAMs in the tumor islet and stroma was not associated with overall survival (OS) of the patients. However, the pooled HR of 4 studies showed that high density of CD68+ TAMs in the tumor islet predicted better OS, while the pooled HR of 6 studies showed that high density of CD68+ TAMs in the tumor stroma was associated with poor OS. A high islet/stroma ratio of CD68+ TAMs was associated with better OS. A high density of M1 TAMs in the tumor islet was associated with better OS, while a high density of M2 TAMs in the tumor stroma predicted poor OS. These findings suggest that, although the density of total CD68+ TAMs is not associated with OS, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC.

Cardiopulmonary exercise testing screening and pre-operative pulmonary rehabilitation reduce postoperative complications and improve fast-track recovery after lung cancer surgery: A study for 342 cases.

An evaluation of cardiopulmonary exercise testing (CPET) screening and pre‐operative pulmonary rehabilitation in reducing postoperative complications and improving fast‐track recovery in high‐risk patients who undergo resection for lung cancer.

Video-assisted thoracic surgery for pulmonary sequestration compared with posterolateral thoracotomy.

OBJECTIVES Pulmonary sequestration is a rare congenital malformation of the lungs. This study aims to evaluate the effectiveness of video-assisted thoracic surgery for the treatment of pulmonary sequestration in a larger series compared with posterolateral thoracotomy. METHODS The files of 42 patients with pulmonary sequestration treated via video-assisted thoracic surgery (18 cases) and posterolateral thoracotomy (24 cases) between September 2005 and May 2012 from a single institute were retrospectively reviewed. Data were collected regarding the patient demographics, medical history, preoperative investigations, intraoperative findings, and postoperative course. RESULTS All sequestration lung lesions were found in the lower lobes (31 on the left, 11 on the right), with feeding arteries arising from the thoracic aorta (34 cases) and the abdominal aorta (8 cases). Thirty-nine cases of sequestration were intralobar, and only 3 cases were extralobar. All patients achieved successful resection (including 37 lobectomies, 2 pneumonectomies, and 3 resections of the extralobar lesion). In the video-assisted thoracic surgery group, 1 case was converted to thoracotomy because of an injury to the aberrant artery; 1 case had injury to the left lower pulmonary vein and 1 case had injury to the aberrant artery, which were successfully treated without conversion. No significant differences were found between the 2 groups (video-assisted thoracic surgery vs posterolateral thoracotomy) in terms of the duration of operation, blood loss, amount of chest drainage, duration of chest drainage, length of postoperative hospital stay, and complications. CONCLUSIONS Video-assisted thoracic surgery resection for pulmonary sequestration is feasible, although it should be performed by an experienced surgeon with awareness of the potential risk of severe vascular injury.

Thoracoscopic bronchovascular double sleeve lobectomy for non-small-cell lung cancer

We present our preliminary experience of thoracoscopic bronchovascular double sleeve lobectomy (SL) for non-small-cell lung cancer in the upper lobe involving both the bronchus and the pulmonary artery. From May 2012 to July 2013, 4 patients were selected for this operation, including 3 cases of left upper lobectomy and 1 case of right upper lobectomy. Surgical procedures were performed with four ports for the first patient and three ports for the other patients. Systemic lymph node dissection was finished before removal of the diseased lobe. Thoracoscopic bronchovascular reconstruction was carried out using running Prolene stitches by directly watching a video monitor. The operations were uneventful. Two patients developed postoperative pneumonia with no mortalities. The reconstructed bronchus and artery worked well during postoperative follow-up visits. Though technically difficult, we believe that thoracoscopic bronchovascular SL is feasible if performed by skilled thoracoscopic surgeons in an experienced centre.

Interferon-γ and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment.

Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNγ and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNγ alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNγ alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNγ and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNγ and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNγ and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNγ and celecoxib have potential to be further optimized into a new anticancer therapy.

Tissue‐specific and plasma microRNA profiles could be promising biomarkers of histological classification and TNM stage in non‐small cell lung cancer

In a previous study, we determined that plasma miRNAs are potential biomarkers for cigarette smoking‐related lung fibrosis. Herein, we determine whether tissue‐specific and plasma miRNA profiles could be promising biomarkers for histological classification and TNM stage in non‐small cell lung cancer (NSCLC). Plasma miRNA profiling preoperatively and seven days postoperatively, and cancer and normal tissue miRNA profiling were performed in NSCLC patients and matched healthy controls. There was a > twofold change for all signature miRNAs between the NSCLC patients and controls, with P values of < 0.05. We found that tissue‐specific and plasma miR‐211‐3p, miR‐3679‐3p, and miR‐4787‐5p were promising biomarkers of different staging lung squamous cell carcinoma, and miR‐3613‐3p, miR‐3675‐3p, and miR‐5571‐5p were promising biomarkers of different staging lung adenocarcinoma. These results suggest that tissue‐specific and plasma miRNAs could be potential biomarkers of histological classification and TNM stage in NSCLC.

MiR-410 induces stemness by inhibiting Gsk3β but upregulating β-catenin in non-small cells lung cancer

Our previous research indicated miR-410 played a critical role in promoting the tumorigenesis and development of NSCLC (non-small cells lung cancer). MiR-410 has been recently reported to be crucial for development and differentiation of embryonic stem cells. But it remains elusive whether miR-410 stimulates the stemness of cancer until now. Herein, we identify miR-410 induces the stemness and is associated with the progression of NSCLC. We demonstrate miR-410 increases the levels of stem cells marker Sox2, Oct4, Nanog, CXCR4 as well as lung cancer stem cells surface marker CD44 and CD166. MiR-410 promotes stem cells-like properties such as proliferation, sphere formation, metastasis and chemoresistance. Moreover, Gsk3β is directly targeted and post-transcriptionally downregulated by miR-410. Also, the expression levels of miR-410 and Gsk3β may be correlated to clinicopathological differentiation in NSCLC tumor specimens. Additionally, we demonstrate miR-410 induces stemness through inhibiting Gsk3β but increasing Sox2, Oct4, Nanog and CXCR4, which binds to β-catenin signaling. In conclusion, our findings identify the miR-410/Gsk3β/β-catenin signaling axis is a novel molecular circuit in inducing stemness of NSCLC.