Archives in Cancer Research

Keywords

Lung cancer; Traditional and advance treatment; Chemotherapy; Radiotherapy

Introduction

Lung cancer is an uncontrolled growth of lung cells that’s lead to form a tumour. More than 20% of total cancer death is due to the lung cancer. The mortality rate of lung cancer is very high and almost 1 in 5 cancer patients [1,2]. There are 2,24,210 new cases and 1,59,260 deaths are reported in the year 2014 [3]. Basically there are two major types of lung cancer viz. small cell lung cancer and non-small cell lung cancer [2]. Various treatments are being used on the basis of cancer progress. Major chances of lung cancer being diagnosed are between the age of 65 and 74 [2]. The major cause behind lung cancer is smoking. 90% of lung cancer cases are found to be associated with continuous exposure of carcinogen strongly found in the cigarette [3]. The survival of lung cancer is very poor but early detection and diagnosis can helps to complete resection in very early stage. overall outcome can be improved in cancer patients by using screening techniques [4-8].

Advance Treatment

Chest X-ray, sputum cytology

Till now for lung cancer screening there are many techniques are available, Chest X-ray, sputum cytology and computed tomography (CT), chest X-ray and sputum cytology is mainly being used to evaluate the smoker population [9]. The sensitivity and accuracy of chest X-ray technique ranges from 54% to 84% whereas for sputum cytology is from 27% to 66%. As per the study carried out earlier, it has been found that both the X-ray and sputum cytology cannot improve mortality, even though these techniques can detect lung cancer at an earlier stage [10-17].

Genomics, genetics and proteomics techniques

Proteomics, genetics and genomics research techniques are high dimensional and are being widely used in the treatment and research of cancer over the two decades. In these two decades different genetic, genomics and proteomics markers have been invented and discovered for the prediction as well as prognosis of the diseases [11-19]. This can allow us to understand the deep knowledge of molecular heterogeneity and target therapy. Now day’s medical imaging techniques has gained the considerable attention for early screening of cancer [20].

Blood-Based biomarker

The utilization of metabolomics to the revelation of bloodbased biomarker in disease has significant potential clinical pertinence. As of late, it has been recognized the polyamine deciding item N1, N12-diacetylspermine (DAS) as a novel preindicative serum biomarker for non-little cell lung growth [21].

PCR-based mutation testing kits and Sanger sequencing

PCR-based change testing units and Sanger sequencing have gotten to be as brilliant standard strategies for demonstrative purposes. Next generation sequencing (NGS) techniques are quick, sparing, delicate and multipliable, and they are gradually supplanting the conventional strategies [22-27]. However, before execution of NGS in indicative settings, it is critical to altogether test and contrast results with those with standard routine demonstrative techniques. Some past studies have demonstrated the Ion Torrent PGM framework to be precise in change investigation by utilizing Ion AmpliSeq Colon and Lung Disease Panel and/or the Ion AmpliSeq Colon and Lung Cancer Research Panel V2 contrasted and Sanger sequencing [28-31].

New and emerging drugs for squamous cell lung cancer

Agents focusing on the epidermal growth factor receptor (EGFR) have been utilized successfully as a part of both squamous and non-squamous NSCLC regardless of a low frequency of activating EGFR transformations in SQCLC [32]. This may be to some extent because of higher EGFR protein expression or expanded quality duplicate number/ intensification seen with squamous histology. Past trials with Erlotinib exhibited its unassuming advantage as second-line versus placebo treatment or as support treatment. In any case, different Phase III studies including TAILOR (Tarceva Italian Lung Optimization Trial) and DELTA (Docetaxel and Erlotinib Lung Cancer) showed the prevalence of second line docetaxel over erlotinib in both PFS and OS in the number of inhabitants in EGFR-WT patients (which incorporates most SQCLC patients), blocking far reaching appropriation of second line Erlotinib for SQCLC [33-35].

Recently, Necitumumab was approved by the FDA in November 2015 as first line treatment in combination with chemotherapy for SQCLC. The Phase III Study (SQUIRE) showed significantly improved OS (HR=0.84, p=0.012) and PFS (HR=0.85, p=0.020) with the addition of Necitumumab to Gemcitabine/Cisplatin [36-41].

VEGF targeted therapy

In 2014, Ramucirumab, a human IgG1 antiboy focusing on the extracellular area of the vascular endothelial development element receptor 2 (VEGFR-2) was endorsed for use in the second line in conjunction with docetaxel [42-48]. The Phase III REVEL Trial demonstrated a 1.4-months OS advantage (HR 0.86, p=0.023) and 1.5 month PFS advantage (HR 0.76, p<0.0001) with utilization of Ramucirumab/docetaxel versus Docetaxel alone as second line treatment in Stage IV NSCLC. The study incorporated all histologies of NSCLC, yet in light of impromptu subgroup examinations squamous and nonsquamous histologies demonstrated comparative advantage [49].

Immunotherapy

Nivolumab is a human IgG4 PD-1 antibody which was approved for the second line treatment of metastatic SQCLC in April 2015. The Phase II CheckMate 063 trial of 117 patients with advanced, refractory SQCLC showed objective response in 14.5% of patients with median duration of response not reached and stable disease in 26% of patients with median duration of 6 months [50,51]. Subsequently a Phase III study of nivolumab vs docetaxel as second line therapy for Stage IIIB or IV SQCLC who have failed platinum based chemotherapy also reported positive results [13]. The median OS was 9.2 months with nivolumab vs 6 months with docetaxel (HR for death 0.59, p<0.001). Response rate was 20% with nivolumab vs 9% with docetaxel (p=0.008) and reassuringly grade 3-4 adverse events were reported in only 7% of the nivolumab group versus 55% of the docetaxel patients. Interestingly, expression of PD-L1 was neither prognostic nor predictive of benefit [52]. Trials are ongoing to evaluate the use of nivolumab in the front line for metastatic NSCLC (NCT02041533), as neoadjuvant therapy in resectable NSCLC (NCT02259621) and as frontline for Stage IIIB/IV NSCLC in conjunction with nab-paclitaxel (NCT 02309177) [53-58].

Of all the late advances in treatment of SQCLC, the most encouraging have been in immunotherapy, especially in agents targeting immune check points. Programed death 1 (PD-1) is included in restricting the movement of T cells permitting tumor cells to sidestep the resistant reaction. SQCLC indicates expanded expression of ligands for PD-1 known as PD-L1. Blocking either the receptor or ligand could defeat invulnerable resistance prompting tumor relapse [59-63]. Nivolumab is a human IgG4 PD-1 antibody agent which was affirmed for second line treatment of metastatic SQCLC in April 2015. In October 2015, pembrolizumab turned into the second immunotherapy agent affirmed in NSCLC. Pembrolizumab is a humanised IgG4 antibody agent affirmed for use in patients with cutting edge NSCLC with archived PD-L1 expression after movement on chemotherapy and focused on agent. Extra accomplishment with immunotherapy has been observed with Ipilimumab and Tremelimumab, antibodies to cytotoxic Tlymphocyte-related protein 4 (CTLA-4) [64]. These therapeutics evolves the resistant reaction by hindering down regulation of the immunity systems brought about by CTLA-4 [65-68].

Notwithstanding these promising results, immune system is ruined by our failure to choose for patients who will appropriate and react. Further research is expected to recognize and approve prescient biomarkers for determination and checking of treatment.

Traditional Medicine

Herbal medicine

Compound derived from plants have been a vital source of several clinically useful activity against cancer. These incorporate vinblastine, vincristine, the camptothecin subsidiaries, topotecan and irinotecan, etoposide, got from epipodophyllotoxin, and paclitaxel (taxol®) [69-77]. Various promising new drugs are in clinical improvement in view of specific movement against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, while a few drugs which fizzled in before clinical studies are fortifying restored interest [78-82].

Acupuncture

This study is the first to show that needle therapy might be a viable methodology for minimising side effects specifically, agony and prosperity in a lung cancer disease populace [83-89]. Needle therapy is a safe and insignificantly obtrusive methodology, and it might have an especially helpful part in patients experiencing anticancer treatment, for example, the people who constituted the more significant degree of the patients in the present study [90,91].

A huge scale randomized controlled trial is expected to affirm the valuable impacts of acupuncture therapy in this populace and to accumulate more exact data about the recurrence and duration of acupuncture therapy medications required to accomplish ideal side effect control [92-96]. Patients and specialists need answers to critical questions about the symptoms that are very amiable to help through acupuncture therapy and the point in the patient's treatment direction when it is best to utilize acupuncture therapy [97,98].

Conclusion

Late advances in lung cancer disease administration have to a great extent profited patients with the adenocarcinoma histologic subtype. In spite of SQCLC representing up to 25% of all lung cancer cases, treatment customarily comprises of established chemotherapy with long haul sickness control and survival staying subtle. Late leaps forward in genomic typing of SQCLC have uncovered different actionable mutations and pathways. As successful molecular targeted agents are distinguished, the battle will stay to discover prescient biomarkers for these treatments. Further trust exists as SQCLC has all the earmarks of being receptive to safe interceded treatments. Better comprehension of tumour science and revelation of prescient biomarkers will encourage enhancing clinical advantages and endeavours at customized treatments.

17237

References

1. Mathioudakis A, Hardavella G (2016) From lung cancer screening to targeted therapies: the endless race against lung cancer morbidity and mortality. J Lung Cancer Diagn Treat 1: e101.
2. Kim S, Erwin D, Wu D (2012) Efficacy of dual lung cancer screening by chest x-ray and sputum cytology using Johns Hopkins lung project data. J Biom Biostat 3: 139.
3. Chen YT, Erwin D, Wu D (2014) Over-diagnosis in lung cancer screening using the MSKC-LCSP Data. J Biomet Biostat 5: 201.
4. Butt SUR, Bhaumik S (2016) Acute demyelinating polyneuropathy caused by Nivolumab in a man with metastatic non-small cell lung cancer. J Gerontol Geriatr Res 5: 302.
5. Shimizu T, Nakagawa K (2016) Novel drug development of the next-generation T790M mutant specific epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer. Biochem Anal Biochem 5: 258
6. Mäki-Nevala S, Knuuttila A, Knuutila S, Sarhadi VK (2016) Concordant results of epidermal growth factor receptor mutation detection by real-time polymerase chain reaction and ion torrent technology in non-small cell lung cancer. J Clin Respir Dis Care 2: 107. 
7. Li L, Liu J, Hann SS, Chai X, Zhang L (2015) Effect of Chinese medicine XIAOJI decoction combined with platinum-based chemotherapy and transfusion of cytokine-induced killer cells in patients with stage III B/IV non-small cell lung cancer. J Drug Metab Toxicol 10: 001.
8. Zarogoulidis K (2015) Reasonable choices for cytotoxic or cytostatic treatment in elderly advanced non-small cell lung cancer Patients. Lung Dis Treat 1: e102.
9. Lee S, Cao J, May T, Li J, Corona L, et al. (2015) Performance characteristics of a PCR assay for the detection of KRAS mutations in formalin- fixed paraffin-embedded tissue samples of non-small cell lung cancer. J Mol Biomark Diagn 6: 246.
10. Giordano M, Macerola E, Boldrini L, Giannini R, Servadio A, et al. (2015) Tert promoter mutations and tert expression in early-stage (T1N0M0) non-small cell lung cancer (NSCLC). J Clin Exp Pathol 5: 248. 
11. Cummings AL, Mendenhall M, Goldman JW (2015) Low elderly participation in non-small cell lung cancer clinical trials. Gerontol Geriatr Res 4: 006. 
12. Genestreti G, Battista M, Cavallo G, Brandes A (2015) First-line platinum-based chemotherapy re-challenge in sensitive small cell lung cancer (SCLC): A standard treatment?. Chemo Open Access 4: 166.
13. Thierry L (2015) Maintenance therapy after first line chemotherapy shows benefit in advanced non-small cell lung cancer. Chemo Open Access 4: 153.
14. Zeng Y, Zhu J, Song X, Erfani SF, Qin H, et al. (2015) MicroRNA-205 promotes cell proliferation of non-small cell lung cancer by targeting Smad4. J Clin Cell Immunol 6: 328.
15. Said AF, Abd-Elnaeem EA, Mohamed BI, Ewis AA, Mohammed HY (2015) Prognostic value of CYFRA 21-1 and carcinoembryonic antigen in non-small cell lung cancer. J Clin Cell Immunol 6: 316.
16. Adamowicz K (2015) Combining systemic therapies with radiation in non-small cell lung cancer. J Cancer Sci Ther 7: 102-110.
17. Saida Y, Watanabe S, Baba J, Koshio J, Kondo R, et al. (2014) Recurrent interstitial lung disease induced by various therapies for non-small cell lung cancer. J Clin Case Rep 4: 471. 
18. Chen YM, Luo YH (2015) Interstitial lung disease induced by targeted therapy for non-small cell lung cancer: a review of diagnosis, workup, and management. J Palliat Care Med 5: 204. 
19. Crvenkova S (2014) Influence of prognostic factors on survival in locally advanced non-small cell lung cancer patients treated with combination of chemoradiotherapy. J Nucl Med Radiat Ther 5: 200.
20. Hanagiri T, Fukumoto M, Koyanagi Y, Furutani Y, Tanaka F (2014) Indoleamine 2,3-dioxygenase as a prognostic factor in patients with non-small cell lung cancer. J Clin Cell Immunol 5: 260.
21. Butt SUR, Bhaumik S (2016) Acute demyelinating polyneuropathy caused by nivolumab in a man with metastatic non-small cell lung cancer. J Gerontol Geriatr Res 5: 302.
22. Schieffer KM, Angstadt AY, Zhu J, Lazarus P, Gallagher CJ (2016) Associations between polymorphisms and haplotypes in the UDP-glucuronosyl transferase 1A gene family with lung cancer risk. Next Generat Sequenc& Applic 3: 124.
23. Dos Santos RS, Franceschini JP, Rasslan Z (2016) Lung cancer prevention in latin america in the era of CT screening. Lung Dis Treat 2: e014.
24. Urman A, Josyula S, Rosenberg A, Lounsbury D, Rohan T, et al. (2016) Burden of lung cancer and associated risk factors in Africa by region. J Pulm Respir Med 6: 340.
25. Bharti M, Yashila G (2016) Lung cancer and nicotine. J Chromatogr Sep Tech 7: 319.
26. Pan CM, Wang ML, Chiou SH, Chen HY, Wu CW (2016) Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signaling. oncotarget
27. Sun SJ, Wu CC, Sheu GT, Chang HY, Chen MY, et al. (2016) Integrin β3 and CD44 levels determine the effects of the OPN-a splicing variant on lung cancer cell growth. Oncotarget
28. Kong F, Gao F, Chen J, Sun Y, Zhang Y, et al. (2016) Over-expressed LAPTM4B-35 is a risk factor for cancer recurrence and poor prognosis in non-small-cell lung cancer. Oncotarget.
29. Cao H, Dong W, Qu X, Shen H, Xu J, et al. (2016) Metformin enhances the therapy effects of anti-IGF-1R mAb figitumumab to NSCLC. Sci Rep. 6: 31072.
30. Yong KJ, Basseres DS, Welner RS, Zhang WC, Yang H, et al. (2016) Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression. Sci Transl Med. 3;8 (350): 350ra104.
31. Karponis D, Azzawi M, Seifalian A (2016) An arsenal of magnetic nanoparticles; perspectives in the treatment of cancer. Nanomedicine (Lond)
32. Lim JS, Soo RA (2016) Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Ther Adv Respir Dis.
33. Bi N, Shedden K, Zheng X, Kong FM (2016) Comparison of the effectiveness of radiofrequency ablation with stereotactic body radiation therapy in inoperable stage I non-small cell lung cancer: a systemic review and pooled analysis. Int J Radiat Oncol Biol Phys 95: 1378-90.
34. Speicher PJ, Fitch ZW, Gulack BC, Yang CJ, Tong BC, et al. (2016) Induction chemotherapy is not superior to a surgery-first strategy for clinical N1 non-small cell lung cancer. Ann Thorac Surg.
35. McLaughlin KA, Nemeth Z, Bradley CA, Humphreys L, Stasik I, et al. (2016) FLIP: a targetable mediator of resistance to radiation in non-small cell lung cancer. Mol Cancer Ther.
36. Liu H, Li W, Yu X, Gao F, Duan Z, et al. (2016) EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis. Oncotarget.
37. Zhang M, Kim YK, Cui P, Zhang J, Qiao J, et al. (2016) Folate-conjugated polyspermine for lung cancer-targeted gene therapy. Acta Pharm Sin 6: 336-343.
38. Liang YH, Shao YY, Liao BC, Lee HS, Yang JC, et al. (2016) Cytotoxic chemotherapy as first-line therapy for advanced non-small-cell lung cancer in taiwan: daily practice. J Cancer 7: 1515-1523
39. Moore J, Megaly M, MacNeil AJ, Klentrou P, Tsiani E (2016) Rosemary extract reduces Akt/mTOR/p70S6K activation and inhibits proliferation and survival of A549 human lung cancer cells. Biomed Pharmacother. 83: 725-732.
40. Saida Y, Watanabe S, Baba J, Koshio J, Kondo R, et al. (2014) Recurrent interstitial lung disease induced by various therapies for non-small cell lung cancer. J Clin Case Rep 4: 471.
41. Verma A, Abisheganaden J, Teng PW, Mancer K, Edell ES (2015) EBUS-TBNA: Are two needle revolutions (back and forth movement of the needle inside the lymph node) adequate for diagnosis of lung cancer?. J Pulm Respir Med 5: 239.
42. Chung C (2015) Tyrosine kinase inhibitors for Egfr gene mutation-positive non-small cell lung cancers: An update for recent advances in therapeutics. J Pharmacovigilance 2: 155.
43. Fournel L, Mansuet-Lupo A, Revel MP, Régnard JF (2014) Thoracic myelolipoma: A rare case of mistake in lung cancer staging. J Clin Exp Pathol 5: 202.
44. Chen YM, Luo YH (2015) Interstitial lung disease induced by targeted therapy for non-small cell lung cancer: a review of diagnosis, workup, and management. J Palliat Care Med 5: 204.
45. Karthikeyan S, Hoti SL, Prasad NR (2014) Resveratrol modulates expression of abc transporters in non-small lung cancer cells: molecular docking and gene expression studies. J Cancer Sci Ther 6: 497-504.
46. Crvenkova S (2014) Influence of prognostic factors on survival in locally advanced non-small cell lung cancer patients treated with combination of chemoradiotherapy. J Nucl Med Radiat Ther 5: 200.
47. Kanaji N, Nanki N (2014) Delayed onset, long-term efficacy of s-1 monotherapy for an elderly patient with squamous cell lung cancer. Chemotherapy 3: 139.
48. Louis R, Louis E, Stinkens K, Mesotten L, De Jonge E, et al. (2016) Metabolic phenotyping of blood plasma by proton nuclear magnetic resonance to discriminate between colorectal cancer, breast cancer and lung cancer. Metabolomics (Los Angel) 6: 187
49. Monirul Islam KM, Wen J, Jiang X, Ryan J, Ann Fetrick RN, et al. (2014) Developing a web-based, patient-centered data collection and management approach for a multi-center lung cancer study. J Integr Oncol 3: 121.
50. Liu M, Liu B, Liu B, Dong X (2014) Cervical muscular metastasis from squamous lung cancer. Intern Med 4.
51. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, et al. (1991) Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83: 417-423.
52. Friess GG, Baikadi M, Harvey WH (1987) Concurrent cisplatin and etoposide with radiotherapy in locally advanced non-small cell lung cancer. Cancer Treat Rep 71: 681-684.
53. Stanley KE (1980) Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 65: 25-32.
54. Gandara DR, Chansky K, Albain KS, Leigh BR, Gaspar LE, et al. (2003) Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J ClinOncol 21: 2004-2010.
55. Chiyo M, Shimozato O, Yu L, Kawamura K, Iizasa T, et al. (2005) Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals. Int J Cancer 115: 437-442.
56. Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, et al. (2006) Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res 66: 6395-6404.
57. Jeremic B, Shibamoto Y (1995) Pre-treatment prognostic factors in patients with stage III non-small cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy. Lung Cancer 13: 21-30.
58. Wigren T (1997) Confirmation of a prognostic index for patients with inoperable non-small cell lung cancer. RadiotherOncol 44: 9-15.
59. Sealy R, Lagakos S, Barkley T, Ryall R, Tucker RD, et al. (1982) Radiotherapy of regional epidermoid carcinoma of the lung: a study in fractionation. Cancer 49: 1338-1345.
60. Coy P, Kennelly GM (1980) The role of curative radiotherapy in the treatment of lung cancer. Cancer 45: 698-702.
61. Chansky K, Sculier JP, Crowley JJ, Giroux D, Van Meerbeeck J, et al. (2009) The International Association for the Study of Lung Cancer Staging Project: Prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J ThoracOncol 4: 792-801.
62. Patz EF Jr, Rossi S, Harpole DH Jr, Herndon JE, Goodman PC (2000) Correlation of tumor size and survival in patients with stage IA non-small cell lung cancer. Chest 117: 1568-1571.
63. Zelen M (1973) Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3 4: 31-42.
64. Scott C, Sause WT, Byhardt R, Marcial V, Pajak TF, et al. (1997) Recursive partitioning analysis of 1592 patients on four radiation therapy oncology group studies in inoperable non-small cell lung cancer. Lung Cancer 17 Suppl 1: S59-74.
65. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR (1996) Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88: 1210-1215.
66. Janssen-Heijnen ML, Gatta G, Forman D, Capocaccia R, Coebergh JW (1998) Variation in survival of patients with lung cancer in Europe, 1985-1989. EUROCARE Working Group. Eur J Cancer 34: 2191-2196.
67. Merrill RM, Henson DE, Barnes M, Travis WD, Colby TV, et al. (1999) Survival among patients with carcinoma of the lung. Chest 166: 697-703.
68. Caro JJ, Salas M, Ward A, Goss G (2001) Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 91: 2214-2221.
69. Socinski MA, Zhang C, Herndon JE 2nd, Dillman RO, Clamon G, et al. (2004) Combined modality trials of the Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis of factors influencing survival and toxicity. Ann Oncol 15: 1033-1041.
70. Kirane A, Toombs JE, Larsen JE, Ostapoff KT, Meshaw KR, et al. (2012) Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. Carcinogenesis 33: 1639-1646.
71. Ho MY, Leu SJ, Sun GH, Tao MH, Tang SJ, et al. (2009) IL-27 directly restrains lung tumorigenicity by suppressing cyclooxygenase-2-mediated activities. J Immunol 183: 6217-6226.
72. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9: 671-675.
73. Sherry DM, Parks EE, Bullen EC, Updike DL, Howard EW (2013) A simple method for using silicone elastomer masks for quantitative analysis of cell migration without cellular damage or substrate disruption. Cell AdhMigr 7: 469-475.
74. Huang S, Bucana CD, Van Arsdall M, Fidler IJ (2002) Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene 21: 2504-2512.
75. Stephanou A, Latchman DS (2003) STAT-1: A novel regulator of apoptosis. Int J ExpPathol 84: 239-244.
76. Hosui A, Klover P, Tatsumi T, Uemura A, Nagano H, et al. (2012) Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression. Int J Cancer 131: 2774-2784.
77. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE Jr (1996) Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. ProcNatlAcadSci U S A 93: 7673-7678.
78. Battle TE, Lynch RA, Frank DA (2006) Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis. Cancer Res 66: 3649-3657.
79. Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, et al. (2004) STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J BiolChem 279: 5811-5820.
80. Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19: 2468-2473.
81. 83. Fidler IJ (2003) The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3: 453-458.
82. Liotta LA, Stetler-Stevenson WG (1991) Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 51: 5054s-5059s.
83. Sun S, Schiller JH, Spinola M, Minna JD (2007) New molecularly targeted therapies for lung cancer. J Clin Invest 117: 2740-2750.
84. Brown JR, DuBois RN (2004) Cyclooxygenase as a target in lung cancer. Clin Cancer Res 10: 4266s-4269s.
85. Deng JY, Sun D, Liu XY, Pan Y, Liang H (2010) STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol 16: 5380-5387.
86. Niu G, Wright KL, Huang M, Song L, Haura E, et al. (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21: 2000-2008.
87. Horiguchi A, Oya M, Shimada T, Uchida A, Marumo K, et al. (2002) Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome. J Urol 168: 762-765.
88. Chang KC, Wu MH, Jones D, Chen FF, Tseng YL (2006) Activation of STAT3 in thymic epithelial tumours correlates with tumour type and clinical behaviour. J Pathol 210: 224-233.
89. Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, et al. (2006) COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol 26: 73-85.
90. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442-454.
91. Ho MY, Liang SM, Hung SW, Liang CM (2013) MIG-7 controls COX-2/PGE2-mediated lung cancer metastasis. Cancer Res 73: 439-449.
92. Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G (2001) COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 15: 2742-2744.
93.  Hwang DH, Fung V, Dannenberg AJ (2002) National Cancer Institute workshop on chemopreventive properties of nonsteroidal anti-inflammatory drugs: role of COX-dependent and -independent mechanisms. Neoplasia 4: 91-97.
94. Grösch S, Maier TJ, Schiffmann S, Geisslinger G (2006) Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98: 736-747.
95. Zhang X, Morham SG, Langenbach R, Young DA (1999) Malignant transformation and antineoplastic actions of non-steroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts. J Exp Med 190: 451-459.
96. Denkert C, Fürstenberg A, Daniel PT, Koch I, Köbel M, et al. (2003) Induction of G0/G1 cell cycle arrest in ovarian carcinoma cells by the anti-inflammatory drug NS-398, but not by COX-2-specific RNA interference. Oncogene 22: 8653-8661.
97. Ramer R, Walther U, Borchert P, Laufer S, Linnebacher M, et al. (2013) Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib. J Lipid Res 54: 3116-3129.
98. Mitchell JA, Belvisi MG, Akarasereenont P, Robbins RA, Kwon OJ, et al. (1994) Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone. Br J Pharmacol 113: 1008-1014.