Open Access

Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification

  • Authors:
    • Shuhai Li
    • Hui Tian
    • Weiming Yue
    • Lin Li
    • Cun Gao
    • Libo Si
    • Wensi Hu
    • Lei Qi
    • Ming Lu
    • Chuanle Cheng
    • Jingjing Cui
    • Guanqing Chen
  • View Affiliations

  • Published online on: October 29, 2015     https://doi.org/10.3892/ol.2015.3839
  • Pages: 224-230
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Based on previous findings regarding the angiogenic activities and prognostic roles of metastasis-associated protein 1 (MTA1) in early‑stage non‑small cell lung cancer, the clinicopathological and prognostic significance of MTA1 protein expression, and its correlation with angiogenesis in lung invasive adenocarcinoma, were further assessed in the present study, according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. High protein expression levels of MTA1 were commonly observed in patients with lung invasive adenocarcinoma, and were significantly correlated with tumor size (P=0.030), lymph node metastasis (P=0.021) and microvessel density (P=0.015). Survival analysis demonstrated that patients with high protein expression levels of MTA1 exhibited significantly shorter five‑year disease‑free and overall survival than those patients whose protein expression levels of MTA1 were low (24.5% vs. 48.7%, P=0.001, and 34.7% vs. 59.2%, P=0.005, respectively). In addition, Cox regression multivariate analysis demonstrated that high protein expression levels of MTA1 significantly correlated with unfavorable five‑year disease‑free survival (P=0.024). These findings indicate that MTA1 protein expression may possess clinical potential as an indicator of progressive phenotype. Therefore, MTA1 is a promising prognostic predictor to identify subgroups of patients with high risk of relapse, and a potentially novel therapeutic target for antiangiogenesis in patients with lung invasive adenocarcinoma.

Introduction

Lung cancer is the most common malignancy and the leading cause of cancer-associated mortality worldwide (13). The incidence of adenocarcinoma has gradually increased in the past decades, and has become the most prevalent histological subtype of primary lung cancer worldwide (46). Lung adenocarcinoma is characterized by its diverse clinical, radiological, pathological, histological and molecular heterogeneity. This histological heterogeneity has led to modifications in the classification of lung adenocarcinoma (7,8). According to the novel architectural classification of lung adenocarcinoma proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) in 2011, the previous morphological classification of the different histological subtypes of lung adenocarcinoma has been substituted by a comprehensive multidisciplinary classification (9). According to this novel classification, patients with adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are expected to present favorable five-year survival, whereas the prognoses of patients with lung invasive adenocarcinomas, including those with pathological stage IA, are relatively poor (1012). Clearly, a further understanding of the mechanisms underlying the pathogenesis and progression of lung invasive adenocarcinoma would promote the development of novel prognostic markers and therapeutic targets that may improve the treatments and clinical outcomes of patients with lung cancer (13,14).

Metastasis-associated protein 1 (MTA1) has been identified as a critical regulator of the carcinogenesis and aggressiveness of a wide variety of human malignancies (1519). Previous studies by Li et al (20) demonstrated that high protein expression levels of MTA1 are involved in tumor angiogenesis and unfavorable prognosis in patients with early-stage non-small cell lung cancer (NSCLC), and MTA1 acts as a proangiogenic factor by promoting the migration, invasion and angiogenesis of NSCLC cells in vitro (21), thus contributing to the aggressive biological behavior and metastatic propensity of this type of cancer. However, to the best of our knowledge, the clinicopathological and prognostic roles of MTA1 protein expression, and its correlation with angiogenesis in lung invasive adenocarcinoma, have not been investigated thus far.

To address these questions, the protein expression levels of MTA1 were analyzed in the present study, and its clinicopathological and prognostic significance, in addition to its angiogenic activity in lung invasive adenocarcinoma, were evaluated based on the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma (9).

Materials and methods

Patients

Medical records were reviewed to identify patients with primary lung invasive adenocarcinoma who had undergone complete lobectomy and systematic mediastinal lymph node dissection consecutively between January 2006 and December 2008 at the Department of Thoracic Surgery of Qilu Hospital, Shandong University (Jinan, China). Patients who received preoperative adjuvant chemotherapy and/or radiotherapy, succumbed to perioperative complications or were not subjected to follow-up examinations were excluded from the study. A total of 125 patients were selected for the study. The histology slides of each patient enrolled in the study were reviewed independently by two pathologists, and the histological subtypes were classified according to the criteria proposed by the 2011 IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma (9). The pathological staging was determined based on the 7th edition of the Union for International Cancer Control Tumor Node Metastasis classification of malignant tumors (22). Informed consent was obtained from all the individual participants included in the study. The present study was approved by the institutional review board of Qilu Hospital, Shandong University. The general clinicopathological characteristics of the patients are presented in Table I.

Table I.

Correlation between the protein expression levels of MTA1 and the clinicopathological factors of the patients.

Table I.

Correlation between the protein expression levels of MTA1 and the clinicopathological factors of the patients.

MTA1 protein expression levels

VariablesNo. of patientsLowHigh P-valuea
Gender 0.758
  Man543222
  Woman714427
Age (years) 0.204
  <60553025
  ≥60704624
Histological subtypes 0.351
  Lepidic1310  3
  Acinar1511  4
  Papillary512823
  Solid351916
  Micropapillary11  8  3
Differentiation 0.978
  Well372314
  Moderate553322
  Poor332013
Pleural invasion 0.819
  Absent523121
  Present734528
Tumor size (cm) 0.030
  ≤3614318
  >3643331
Lymph node metastasis 0.021
  Absent674720
  Present582929
Pathological stage 0.054
  I644519
  II402218
  III21  912

a χ2 test; MAT1, metastasis-associated protein 1.

Follow-up

All patients were regularly followed up subsequently to surgery. The patients were recommended to attend follow-up visits every three months for the first two years following surgery, and every six months thereafter. The follow-up protocol consisted of physical examination, blood tests, sonography, chest radiography, computed tomography (CT), magnetic resonance imaging, whole body bone scans and positron emission tomography-CT scans, if necessary. Recurrent disease was confirmed by fine-needle aspiration or cytopathological diagnosis when clinically feasible. All patients were followed up until mortality or last day of follow-up. The deadline of follow-up was December 2013, and the median clinical follow-up time was 58 months (range, 16–90 months).

Evaluation of MTA1 protein expression and microvessel density (MVD)

Immunohistochemical staining for MTA1 and cluster of differentiation (CD)105 was performed using an immunohistochemical detection kit (cat no. SP-9000; ZSGB-BIO, Beijing, China) according to the procedure previously described (20,23), using a goat anti-human polyclonal antibody against MTA1 (sc-9446; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) and a rabbit anti-human polyclonal antibody against CD105 (sc-20632; Santa Cruz Biotechnology, Inc.), respectively. The slides were incubated at 60°C for 30 min, and deparaffinized in xylene, followed by rehydration with graded alcohol. Antigen retrieval was performed in citrate buffer for 15 min using a microwave oven. Once cooled down to room temperature, the slides were immersed in 3% hydrogen peroxide for 10 min, and incubated in blocking serum for 30 min to reduce nonspecific binding. Upon discarding any excess of blocking solution, primary goat anti-MTA1 polyclonal antibody (1:100) and rabbit anti-CD105 polyclonal antibody (1:100) were applied to the slides, and incubated overnight at 4°C. Next, the slides were incubated at 37°C for 30 min with biotinylated antibodies and streptavidin-peroxidase complex, followed by the addition of 3,3-diaminobenzidine solution to visualize the staining corresponding to antibody-specific binding. Subsequently, the slides were counterstained with hematoxylin (ZLI-9609; ZSGB-BIO), and mounted with neutral balsam.

Semiquantitative determination of MTA1 protein expression was performed based on the staining intensity, as follows: i) A value of 0 was assigned to negative staining; ii) a score of 1 was assigned to weak staining; iii) 2 indicated moderate staining; and 3, intense staining. The proportion of positively stained cancer cells was 0, 0~5%; 1, 6~25%; 2, 26~50%; 3, 51~75%; and 4, ≥76%. The sum of the scores corresponding to the staining intensity and the percentage of positively stained cells was used to classify the different cases, and those tumors that displayed a final staining score of ≥4 were defined as exhibiting high protein expression levels of MTA1.

CD105 was observed to be expressed in the cytoplasm and membrane of endothelial cells, and the MVD count was performed as previously described (23,24). Briefly, the number of CD105+ microvessels was counted in a ×200 microscopic field, and the mean value of the microvessels counted in five different vascular ‘hot spots’ was regarded as the final value for each case. All the immunostained slides were independently evaluated by two pathologists blinded to the clinicopathological and prognostic information of the patients. If disagreement emerged on the same slide, the reviewers would together use a multihead microscope, and discussed until a consensus score was achieved.

Statistical analysis

All data was statistically analyzed with SPSS statistical software version 18.0 (SPSS Inc., Chicago, IL, USA). The χ2 test was used to examine the association between the protein expression levels of MTA1 and the clinicopathological characteristics of the patients. The correlation between the protein expression levels of MTA1 and intratumoral MVD was analyzed by the nonparametric Mann-Whitney U test. Survival curves were plotted by the Kaplan-Meier method, and survival differences were compared by the log-rank test. Multivariate analysis was performed to identify significantly independent prognostic factors. P<0.05 was considered to indicate a statistically significant difference.

Results

Correlation between MTA1 protein expression and clinicopathological factors

Immunohistochemical analysis revealed positive immunostaining for MTA1 in the nuclei of the cancer cells, and different immunoreactivity for MTA1 protein was detected in regards to the percentage of positive cells stained and the intensity of the nuclear staining (Fig. 1A and B). Of the 125 primary lung invasive adenocarcinoma specimens analyzed, high protein expression levels of MTA1 were detected in 49 cases, and the association between the protein expression levels of MTA1 and the clinicopathological characteristics of the patients was analyzed by the χ2 test. As indicated in Table I, high protein expression levels of MTA1 were significantly correlated with the size of the tumor (P=0.030) and lymph node metastasis (P=0.021), whereas no significant differences were detected among the protein expression levels of MTA1 on the basis of the patients' gender (P=0.758), age (P=0.204), histological subtypes (P=0.351), differentiation (P=0.978), pleural invasion (P=0.819) and pathological stage (P=0.054, which may be considered borderline significance).

Correlation between MTA1 protein expression and tumor angiogenesis

Intratumoral MVD was quantified by counting the number of CD105+ endothelial cells present in the cancer tissues (Fig. 1C). The staining intensity of MVD varied from 6.6 to 49.6, with a median of 32.2/high power field (HPF). Double-staining of MTA1 and CD105 in the same serial sections of cancer tissues revealed that low protein expression levels of MTA1 were generally associated with few microvessels (6.6–49.4; median, 29.3/HPF), whereas high protein expression levels of MTA1 were generally associated with abundant microvessels (9.0–49.6; median, 37.0/HPF). Statistical analysis further demonstrated a significantly higher MVD in tumors with high protein expression levels of MTA1 than in those with low protein expression levels of MTA1 (P=0.015, Mann-Whitney U test; Fig. 2).

Follow-up results and analysis of prognostic factors

During the follow-up period, tumor relapse developed in 76 patients (60.8%), and 63 patients (50.4%) succumbed to the disease. The median survival time of the subgroup of patients exhibiting high protein expression levels of MTA1 was 48.0 months, while the median survival time of the subgroup of patients displaying low protein expression levels of MTA1 was 61.5 months. As indicated in Table II, the results of the log-rank test demonstrated that the protein expression levels of MTA1 were significantly associated with the five-year disease-free survival (P=0.001; Fig. 3A). Other parameters such as tumor size, lymph node metastasis and pathological stage were also observed to be significantly associated with five-year disease-free survival (P<0.001). Furthermore, the protein expression levels of MTA1 were significantly associated with the five-year overall survival (P=0.005; Fig. 3B), in addition to tumor size, lymph node metastasis and pathological stage (P<0.001). The significantly independent prognostic factors were further analyzed by a multivariate Cox regression model, and the results indicated that MTA1 protein expression, tumor size, lymph node metastasis and pathological stage were independent prognostic factors for five-year disease-free survival (P=0.024, 0.044, 0.029 and 0.001, respectively), whereas only the pathological stage (P=0.028) was identified as a significantly independent prognostic factor for five-year overall survival.

Table II.

Results of univariate and multivariate survival analyses.

Table II.

Results of univariate and multivariate survival analyses.

Disease-free survivalOverall survival


Multivariate analysis Multivariate analysis


VariablesUnivariate analysis P-value95% CIP-valueUnivariate analysis P-value95% CIP-value
Gender   0.8930.549–1.4940.699   0.9560.528–1.5450.710
Age   0.6640.745–2.0600.409   0.3040.676–2.0230.575
Histological subtypes   0.1720.973–1.5170.086   0.2210.956–1.5250.114
Differentiation   0.0870.975–1.8190.072   0.0750.961–1.9000.083
Pleural invasion   0.3740.622–2.0470.690   0.2790.602–2.2270.660
Tumor size<0.0011.017–3.8090.044<0.0010.883–3.8930.103
Lymph node metastasis<0.0010.112–0.8880.029<0.0010.268–2.3500.676
Pathological stage<0.0011.682–6.6860.001<0.0011.088–4.3680.028
MTA1 protein levels   0.0011.076–2.8990.024   0.0050.773–2.2560.309

[i] CI, confidence interval; MTA1, metastasis-associated protein 1.

Discussion

Major advances in the treatment of lung adenocarcinoma are the result of the combined therapy that is currently administered to patients with lung cancer. This combined therapy consists of surgical resection, chemotherapy, radiotherapy and molecular targeting agents based on epidermal growth factor receptor (EGFR) (8). However, due to the high heterogeneity of lung adenocarcinoma, the overall five-year survival of patients affected by this disease is <30% (2528). This heterogeneity has led to modifications in the histological categories employed to classify the different types of lung adenocarcinoma, as described in the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma (9). According to this novel classification, patients with AIS and MIA present favorable five-year disease-free survival, whereas the prognoses of patients with lung invasive adenocarcinoma, including those with pathological stage IA, are relatively poor (11,12,29). The aim of the present study was to further investigate the underlying mechanisms involved in the invasive ability and metastatic properties of lung invasive adenocarcinoma, and to identify possible targets for novel treatments, including individualized therapy, which may improve the clinical outcomes of patients with this type of cancer.

MTA1 is a component of the nucleosome remodeling and histone deacetylation complex, which functions in histone deacetylation, alteration of chromatin structure and control of transcription (30,31). As a vital regulator, MTA1 has been observed to be aberrantly expressed in various human malignant tumors, and its expression levels are positively correlated with aggressive phenotypes characterized by their invasiveness and metastatic potential (15). Thus, MTA1 may be a target for overcoming tumor progression (15,17). The association between MTA1 expression, angiogenesis and unfavorable prognosis in patients with early-stage NSCLC has been previously reported (20). Thus, it is clinically required to further assess the protein expression levels of MTA1 and analyze its clinicopathological and prognostic significance in human lung invasive adenocarcinoma. A total of 125 patients with primary lung invasive adenocarcinoma were enrolled in the present study, which aimed to elucidate the angiogenic activities and the clinicopathological and prognostic significance of MTA1 protein expression. The results revealed that high protein expression levels of MTA1 were significantly associated with tumor size and lymph node metastasis, and markedly associated with pathological stage, all factors known to contribute to aggressive phenotypes.

Antiangiogenesis is a pivotal strategy for treating malignancies (32), and MTA1 has been defined as a proangiogenic factor (15,21,33,34). A previous study demonstrated that high intratumoral protein expression levels of MTA1 were significantly associated with angiogenesis in NSCLC (20). In addition, RNA interference-mediated downregulation of MTA1 protein expression in the lung adenocarcinoma cell line 95D was able to substantially inhibit the formation of capillary tube-like structures in vitro (21). However, the correlation of MTA1 protein expression with tumor angiogenesis in lung invasive adenocarcinoma has not been investigated thus far. In the present study, the expression of CD105, a homodimeric cell membrane glycoprotein, was evaluated in order to quantify tumor angiogenesis, since this marker is able to discriminate immature neovascularization from mature and established blood vessels (35,36), thus indicating the presence of active angiogenesis in the tumor (3739). The results demonstrated that high protein expression levels of MTA1 were significantly associated with increased angiogenic activity, as measured by the number of CD105-associated intratumoral microvessels, suggesting that MTA1 may be involved in tumor progression by participating in the process of angiogenesis in lung invasive adenocarcinoma. Tumor angiogenesis is a complex process, and the mechanism by which MTA1 modulates angiogenesis remains unknown (22,3034). Therefore, further studies are required in order to elucidate the mechanisms by which MTA1 induces angiogenesis.

With regard to prognosis, the results of the univariate survival analysis conducted in the present study demonstrated that patients with high protein expression levels of MTA1 presented a significantly shorter five-year disease-free and overall survival than those patients with low protein expression levels of MTA1. Subsequent multivariate analysis demonstrated that high protein expression levels of MTA1 were an independent prognostic factor for unfavorable disease-free survival, but not for overall survival. Clinically, the long-term survival of patients with cancer may be influenced by multiple factors, including postoperative chemotherapy with different regimens and cycles, radiotherapy and EGFR-tyrosine kinase inhibitor therapy, which may cause statistical bias, thus resulting in the inability to objectively and adequately evaluate the prognostic significance of MTA1. Nevertheless, the subgroup of patients with high protein expression levels of MTA1 may require further oncologic evaluation and clinical attention following surgical resection than those patients with low protein expression levels of MTA1, due to their higher risk of relapse.

Taken together, the results of the present study demonstrated for the first time that aberrantly high protein expression levels of MTA1 are involved in the malignant phenotype and unfavorable prognoses of patients with lung invasive adenocarcinoma, possibly due to its potent angiogenic activity. However, the stepwise progression and facilitated neoangiogenesis is too complicated to be clearly elucidated by a simple clinical study like the present one. Therefore, future studies will contribute to a further understanding of the underlying mechanisms targeting MTA1, and provide a greater insight into the aggressive phenotype of lung invasive adenocarcinoma, which may aid the design of novel drugs targeting MTA1 and the development of more efficient antiangiogenic therapies aimed to improve the survival of certain subgroups of patients affected by lung cancer.

Acknowledgements

The present study was supported by the Independent Innovation Foundation of Shandong University (Jinan, China) (grant no. 2012DX005) and the National Natural Science Foundation of China (Beijing, China) (grant no. 81301832).

Glossary

Abbreviations

Abbreviations:

MTA1

metastasis-associated protein 1

IASLC/ATS/ERS

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society

AIS

adenocarcinoma in situ

MIA

minimally invasive adenocarcinoma

NSCLC

non-small cell lung cancer

MVD

microvessel density

References

1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Scarpa A, Sikora K, Fassan M, et al: Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel. PLoS One. 8:e804782013. View Article : Google Scholar : PubMed/NCBI

4 

Fan Z and Schraeder R: The changing pathology of lung cancer. Surg Oncol Clin N Am. 20:637–653. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Bremer RE, Scoggin TS, Somers EB, OShannessy DJ and Tacha DE: Interobserver agreement and assay reproducibility of folate receptor α expression in lung adenocarcinoma: A prognostic marker and potential therapeutic target. Arch Pathol Lab Med. 137:1747–1752. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Sunaga N, Kaira K, Tomizawa Y, et al: Clinicopathological and prognostic significance of interleukin-8 expression and its relationship to KRAS mutation in lung adenocarcinoma. Br J Cancer. 110:2047–2053. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Shim HS, Lee da H, Park EJ and Kim SH: Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification. Arch Pathol Lab Med. 135:1329–1334. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Shimada Y, Saji H, Nomura M, Matsubayashi J, Yoshida K, Kakihana M, Kajiwara N, Ohira T and Ikeda N: Cancer stem cell-related marker expression in lung adenocarcinoma and relevance of histologic subtypes based on IASLC/ATS/ERS classification. Onco Targets Ther. 6:1597–1604. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6:244–285. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Maeda R, Yoshida J, Ishii G, Hishida T, Nishimura M and Nagai K: Prognostic impact of histology on early-stage non-small cell lung cancer. Chest. 140:135–145. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Zhang J, Wu J, Tan Q, Zhu L and Gao W: Why do pathological stage IA lung adenocarcinomas vary from prognosis? A clinicopathologic study of 176 patients with pathological stage IA lung adenocarcinoma based on the IASLC/ATS/ERS classification. J Thorac Oncol. 8:1196–1202. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Ha SY and Roh MS: The new 2011 international association for the study of lung cancer/american thoracic society/european respiratory society classification of lung adenocarcinoma in resected specimens: Clinicopathologic relevance and emerging issues. Korean J Pathol. 47:316–325. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Cagle PT and Chirieac LR: Advances in treatment of lung cancer with targeted therapy. Arch Pathol Lab Med. 136:504–509. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Huang JY, Cui SY, Chen YT, Song HZ, Huang GC, Feng B, Sun M, De W, Wang R and Chen LB: MicroRNA-650 was a prognostic factor in human lung adenocarcinoma and confers the docetaxel chemoresistance of lung adenocarcinoma cells via regulating Bcl-2/Bax expression. PLoS One. 8:e726152013. View Article : Google Scholar : PubMed/NCBI

15 

Toh Y and Nicolson GL: The role of the MTA family and their encoded proteins in human cancers: Molecular functions and clinical implications. Clin Exp Metastasis. 26:215–227. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Li Y, Chao Y, Fang Y, et al: MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b. J Exp Clin Cancer Res. 32:332013. View Article : Google Scholar : PubMed/NCBI

17 

Wang H, Fan L, Wei J, et al: Akt mediates metastasis-associated gene 1 (MTA1) regulating the expression of E-cadherin and promoting the invasiveness of prostate cancer cells. PLoS One. 7:e468882012. View Article : Google Scholar : PubMed/NCBI

18 

Zhou H, Xu X, Xun Q, et al: microRNA-30c negatively regulates endometrial cancer cells by targeting metastasis-associated gene-1. Oncol Rep. 27:807–812. 2012.PubMed/NCBI

19 

Song Q, Li Y, Zheng X, Fang Y, Chao Y, Yao K and Zhu X: MTA1 contributes to actin cytoskeleton reorganization and metastasis of nasopharyngeal carcinoma by modulating Rho GTPases and Hedgehog signaling. Int J Biochem Cell Biol. 45:1439–1446. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Li SH, Tian H, Yue WM, Li L, Li WJ, Chen ZT, Hu WS, Zhu YC and Qi L: Overexpression of metastasis-associated protein 1 is significantly correlated with tumor angiogenesis and poor survival in patients with early-stage non-small cell lung cancer. Ann Surg Oncol. 18:2048–2056. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Li S, Tian H, Yue W, Li L, Gao C, Si L, Li W, Hu W, Qi L and Lu M: Down-regulation of MTA1 protein leads to the inhibition of migration, invasion and angiogenesis of non-small-cell lung cancer cell line. Acta Biochim Biophys Sin (Shanghai). 45:115–122. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Rami-Porta R, Crowley JJ and Goldstraw P: The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg. 15:4–9. 2009.PubMed/NCBI

23 

Deng X, Du L, Wang C, Yang Y, Li J, Liu H, Zhang J, Wang L, Zhang X, Li W, et al: Close association of metastasis-associated protein 1 overexpression with increased angiogenesis and poor survival in patients with histologically node-negative gastric cancer. World J Surg. 37:792–798. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Vermeulen PB, Gasparini G, Fox SB, Colpaert C, Marson LP, Gion M, Beliën JA, de Waal RM, Van Marck E, Magnani E, et al: Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 38:1564–1579. 2002. View Article : Google Scholar : PubMed/NCBI

25 

Xu C, Gui Q, Chen W, Wu L, Sun W, Zhang N, Xu Q, Wang J and Fu X: Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo. J Exp Clin Cancer Res. 30:632011. View Article : Google Scholar : PubMed/NCBI

26 

Ma Q, Li P, Xu M, Yin J, Su Z, Li W and Zhang J: Ku80 is highly expressed in lung adenocarcinoma and promotes cisplatin resistance. J Exp Clin Cancer Res. 31:992012. View Article : Google Scholar : PubMed/NCBI

27 

Kauffmann M, Krüger T and Aebert H: Surgery on extracorporeal circulation in early and advanced non-small cell lung cancer. Thorac Cardiovasc Surg. 61:103–108. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Huang J, Song H, Liu B, Yu B, Wang R and Chen L: Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma. J Exp Clin Cancer Res. 32:842013. View Article : Google Scholar : PubMed/NCBI

29 

Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW and Travis WD: Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: Prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 24:653–664. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A and Reinberg D: Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13:1924–1935. 1999. View Article : Google Scholar : PubMed/NCBI

31 

Manavathi B, Peng S, Rayala SK, Talukder AH, Wang MH, Wang RA, Balasenthil S, Agarwal N, Frishman LJ and Kumar R: Repression of Six3 by a corepressor regulates rhodopsin expression. Proc Natl Acad Sci USA. 104:13128–13133. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

33 

Jang KS, Paik SS, Chung H, Oh YH and Kong G: MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Sci. 97:374–379. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Kai L, Wang J, Ivanovic M, Chung YT, Laskin WB, Schulze-Hoepfner F, Mirochnik Y, Satcher RL Jr and Levenson AS: Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). Prostate. 71:268–280. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Minhajat R, Mori D, Yamasaki F, Sugita Y, Satoh T and Tokunaga O: Organ-specific endoglin (CD105) expression in the angiogenesis of human cancers. Pathol Int. 56:717–723. 2006. View Article : Google Scholar : PubMed/NCBI

36 

Paschoal JP, Bernardo V, Canedo NH, Ribeiro OD, Caroli-Bottino A and Pannain VL: Microvascular density of regenerative nodule to small hepatocellular carcinoma by automated analysis using CD105 and CD34 immunoexpression. BMC Cancer. 14:722014. View Article : Google Scholar : PubMed/NCBI

37 

Tanaka F, Otake Y, Yanagihara K, Kawano Y, Miyahara R, Li M, Yamada T, Hanaoka N, Inui K and Wada H: Evaluation of angiogenesis in non-small cell lung cancer: Comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res. 7:3410–3415. 2001.PubMed/NCBI

38 

Wikström P, Lissbrant IF, Stattin P, Egevad L and Bergh A: Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate. 51:268–275. 2002. View Article : Google Scholar : PubMed/NCBI

39 

Yang W, Zhang Y, Fu Z, Sun X, Mu D and Yu J: Imaging proliferation of 18F-FLT PET/CT correlated with the expression of microvessel density of tumour tissue in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging. 39:1289–1296. 2012. View Article : Google Scholar : PubMed/NCBI

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Li, S., Tian, H., Yue, W., Li, L., Gao, C., Si, L. ... Chen, G. (2016). Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification. Oncology Letters, 11, 224-230. https://doi.org/10.3892/ol.2015.3839
MLA
Li, S., Tian, H., Yue, W., Li, L., Gao, C., Si, L., Hu, W., Qi, L., Lu, M., Cheng, C., Cui, J., Chen, G."Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification". Oncology Letters 11.1 (2016): 224-230.
Chicago
Li, S., Tian, H., Yue, W., Li, L., Gao, C., Si, L., Hu, W., Qi, L., Lu, M., Cheng, C., Cui, J., Chen, G."Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification". Oncology Letters 11, no. 1 (2016): 224-230. https://doi.org/10.3892/ol.2015.3839