Skip to main content

Advertisement

Log in

From cancer genomics to thoracic oncology: discovery of new biomarkers and therapeutic targets for lung and esophageal carcinoma

  • Published:
General Thoracic and Cardiovascular Surgery Aims and scope Submit manuscript

Abstract

Over the last decade, many genetic and epigenetic alterations involved in the development and progression of lung and esophageal cancers have been reported, but their precise molecular mechanisms have remained unclear. Although novel drugs targeting some of these molecular targets have been developed, they provide limited survival benefits to only a small subset of cancer patients, and only a small number of practically useful biomarkers are presently available. To identify the molecules involved in lung and esophageal carcinogenesis and those applicable as novel tumor biomarkers and for the development of new molecular therapies, we performed gene expression profile analysis of 101 archived lung cancers and 19 esophageal squamous cell carcinomas whose tumor cells were purified by laser microdissection. Through a subsequent systematic approach using tissue microarray, RNA interference, and high throughput enzyme-linked immunosorbent assay techniques as well as bioinformatics, we have identified a set of molecules that fall into the category of oncoantigens. These molecules are potentially promising candidates for the development of novel diagnostic biomarkers, therapeutic drugs, and/or immunotherapy; there is also a small subset of biomarkers for predicting the presence of lymph node metastasis in surgically treated patients.

In this article, we introduce our sophisticated and integrated cancer genomics strategy for improving the treatment of cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Vital Statistics of Japan 2005, Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labor, and Welfare.

  2. Berwick M, Schantz S. Chemoprevention of aerodigestive cancer. Cancer Metastasis Rev 1997;16:329–347.

    Article  PubMed  CAS  Google Scholar 

  3. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.

    Article  PubMed  Google Scholar 

  4. Shimada H, Nabeya Y, Okazumi S, Matsubara H, Shiratori T, Gunji Y, et al. Prediction of survival with squamous cell carcinoma antigen in patients with reseable esophageal squamous cell carcinoma. Surgery 2003;133:486–494.

    Article  PubMed  Google Scholar 

  5. Tamoto E, Tada M, Murakawa K, Takada M, Shindo G, Teramoto K, et al. Gene-expression profile changes correlated with tumor progression and lymph node metastasis in esophageal cancer. Clin Cancer Res 2004;10:3629–3638.

    Article  PubMed  CAS  Google Scholar 

  6. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–543.

    Article  PubMed  CAS  Google Scholar 

  7. Naruke T, Tsuchiya R, Kondo H, Asamura H. Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience. Ann Thorac Surg 2001;71:1759–1764.

    Article  PubMed  CAS  Google Scholar 

  8. Rastel D, Ramaioli A, Cornillie F, Thirion B. CYFRA 21-1, a sensitive and specific new tumour marker for squamous cell lung cancer: report of the first European multicentre evaluation. CYFRA 21-1 Multicentre Study Group. Eur J Cancer 1994;30A:601–606.

    Article  PubMed  CAS  Google Scholar 

  9. Kawaguchi H, Ohno S, Miyazaki M, Hashimoto K, Egashira A, Saeki H, et al. CYFRA 21-1 determination in patients with esophageal squamous cell carcinoma: clinical utility for detection of recurrences. Cancer 2000;89:1413–1417.

    Article  PubMed  CAS  Google Scholar 

  10. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinumcontaining chemotherapy regimens: the TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–2362.

    PubMed  CAS  Google Scholar 

  11. Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al. Japan Clinical Oncology Group: surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol 2003;21:4592–4596.

    Article  PubMed  Google Scholar 

  12. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.

    Article  PubMed  CAS  Google Scholar 

  13. Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19:3210–3218.

    PubMed  CAS  Google Scholar 

  14. Perrone F, Di Maio M, Budillon A, Normanno N. Targeted therapies and non-small cell lung cancer: methodological and conceptual challenge for clinical trials. Curr Opin Oncol 2005;17:123–129.

    Article  PubMed  Google Scholar 

  15. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–1537.

    Article  PubMed  CAS  Google Scholar 

  16. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, et al. National Cancer Institute of Canada Clinical Trials Group: erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.

    Article  PubMed  CAS  Google Scholar 

  17. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997;114:210–217.

    Article  PubMed  CAS  Google Scholar 

  18. Kakiuchi S, Daigo Y, Tsunoda T, Yano S, Sone S, Nakamura Y. Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice. Mol Cancer Res 2003;1:485–499.

    PubMed  CAS  Google Scholar 

  19. Kikuchi T, Daigo Y, Ishikawa N, Katagiri T, Tsunoda T, Yoshida S, et al. Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph node metastasis and sensitivity to anti-cancer drugs. Oncogene 2003;22:2192–2205.

    Article  PubMed  CAS  Google Scholar 

  20. Kakiuchi S, Daigo Y, Ishikawa N, Furukawa C, Tsunoda T, Yano S, et al. Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). Hum Mol Genet 2004;13:3029–3043.

    Article  PubMed  CAS  Google Scholar 

  21. Kikuchi T, Daigo Y, Ishikawa N, Katagiri T, Tsunoda T, Yoshida S, et al. Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. Int J Oncol 2006;28:799–805.

    PubMed  CAS  Google Scholar 

  22. Taniwaki M, Daigo Y, Ishikawa N, Takano A, Tsunoda T, Yasui W, et al. Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer. Int J Oncol 2006;29:565–567.

    Google Scholar 

  23. Yamabuki T, Daigo Y, Kato T, Hayama S, Tsunoda T, Miyamoto M, et al. Genome-wide gene expression profile analysis of esophageal squamous-cell carcinomas. Int J Oncol 2006;28:1375–1384.

    PubMed  CAS  Google Scholar 

  24. Saito-Hisaminato A, Katagiri T, Kakiuchi S, Nakamura T, Tsunoda T, Nakamura Y. Genome-wide profiling of gene expression in 29 normal human tissues with a cDNA microarray. DNA Res 2002;9:35–45.

    Article  PubMed  CAS  Google Scholar 

  25. Ochi K, Daigo Y, Katagiri T, Saito-Hisaminato A, Tsunoda T, Toyama Y, et al. Expression profiles of two types of human knee joint cartilage. J Hum Genet 2003;48:177–182.

    Article  PubMed  CAS  Google Scholar 

  26. Suzuki C, Daigo Y, Kikuchi T, Katagiri T, Nakamura Y. Identification of COX17 as a therapeutic target for non-small cell lung cancer. Cancer Res 2003;63:7038–7041.

    PubMed  CAS  Google Scholar 

  27. Ishikawa N, Daigo Y, Yasui W, Inai K, Nishimura H, Tsuchiya E, et al. ADAM8 as a novel serological and histochemical marker for lung cancer. Clin Cancer Res 2004;10:8363–8370.

    Article  PubMed  CAS  Google Scholar 

  28. Kato T, Daigo Y, Hayama S, Ishikawa N, Yamabuki T, Ito T, et al. A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis. Cancer Res 2005;65:5638–5646.

    Article  PubMed  CAS  Google Scholar 

  29. Furukawa C, Daigo Y, Ishikawa N, Kato T, Ito T, Tsuchiya E, et al. Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. Cancer Res 2005;65:7102–7110.

    Article  PubMed  CAS  Google Scholar 

  30. Ishikawa N, Daigo Y, Takano A, Taniwaki M, Kato T, Hayama S, et al. Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers. Cancer Res 2005;65:9176–9184.

    Article  PubMed  CAS  Google Scholar 

  31. Suzuki C, Daigo Y, Ishikawa N, Kato T, Hayama S, Ito T, et al. ANLN plays a critical role in human lung carcinogenesis through the activation of RHOA and by involvement in the phosphoinositide 3-kinase/AKT pathway. Cancer Res 2005;65:11314–11325.

    Article  PubMed  CAS  Google Scholar 

  32. Ishikawa N, Daigo Y, Takano A, Taniwaki M, Kato T, Tanaka S, et al. Characterization of SEZ6L2 cell-surface protein as a novel prognostic marker for lung cancer. Cancer Sci 2006;97:737–745.

    Article  PubMed  CAS  Google Scholar 

  33. Takahashi K, Furukawa C, Takano A, Ishikawa N, Kato T, Hayama S, et al. The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer. Cancer Res 2006;66:9408–9419.

    Article  PubMed  CAS  Google Scholar 

  34. Hayama S, Daigo Y, Kato T, Ishikawa N, Yamabuki T, Miyamoto M, et al. Activation of CDCA1-KNTC2, members of centromere protein complex, involved in pulmonary carcinogenesis. Cancer Res 2006;66:10339–10348.

    Article  PubMed  CAS  Google Scholar 

  35. Kato T, Hayama S, Yamabuki T, Ishikawa N, Miyamoto M, Ito T, et al. Increased expression of insulin-like growth factor-II messenger RNA-binding protein 1 is associated with tumor progression in patients with lung cancer. Clin Cancer Res 2007;13:434–442.

    Article  PubMed  CAS  Google Scholar 

  36. Suzuki C, Takahashi K, Hayama S, Ishikawa N, Kato T, Ito T, et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol Cancer Ther 2007;6:542–551.

    Article  PubMed  CAS  Google Scholar 

  37. Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, et al. Dickkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res 2007;67:2517–2525.

    Article  PubMed  CAS  Google Scholar 

  38. Hayama S, Daigo Y, Yamabuki T, Hirata D, Kato T, Miyamoto M, et al. Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis. Cancer Res 2007;67:4113–4122.

    Article  PubMed  CAS  Google Scholar 

  39. Kato T, Sato N, Hayama S, Yamabuki T, Ito T, Miyamoto M, et al. Activation of holliday junction-recognizing protein involved in the chromosomal stability and immortality of cancer cells. Cancer Res 2007;67:8544–8553.

    Article  PubMed  CAS  Google Scholar 

  40. Taniwaki M, Takano A, Ishikawa N, Yasui W, Inai K, Nishimura H, et al. Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. Clin Cancer Res 2007;13:6624–6631.

    Article  PubMed  CAS  Google Scholar 

  41. Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, et al. Cancer-testis antigen, LY6K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res 2007;67:11601–11611.

    Article  PubMed  CAS  Google Scholar 

  42. Mano Y, Takahashi, K, Ishikawa N, Takano A, Yasui W, Inai K, et al. Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer. Cancer Sci 2007;98:1902–1913.

    Article  PubMed  CAS  Google Scholar 

  43. Suda T, Tsunoda T, Daigo Y, Nakamura Y, Tahara H. Identification of HLA-A24-restricted epitope-peptides derived from gene products up-regulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci 2007;98:1803–1808.

    Article  CAS  Google Scholar 

  44. Hashimoto S, Hirose M, Hashimoto A, Morishige M, Yamada A, Hosaka H, et al. Targeting AMP1 and cortactin binding bearing an atypical src homology 3/ praline interface for prevention of breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 2006;103:7036–7041.

    Article  PubMed  CAS  Google Scholar 

  45. Harbour JW, Worley L, Ma D, Cohen M. Transducible peptide therapy for uveal melanoma and retinoblastoma. Arch Ophthalmol 2002;2:1341–1346.

    Google Scholar 

  46. Boon T, Old LJ. Cancer tumor antigens. Curr Opin Immunol 1997;9:681–683.

    Article  PubMed  CAS  Google Scholar 

  47. Scanlan MJ, Simpson AJ, Old LJ. The cancer/testis genes: review, standardization, and commentary. Cancer Immun 2004;4:1.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yusuke Nakamura.

Additional information

This review was submitted at the invitation of the editorial committee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daigo, Y., Nakamura, Y. From cancer genomics to thoracic oncology: discovery of new biomarkers and therapeutic targets for lung and esophageal carcinoma. Gen Thorac Cardiovasc Surg 56, 43–53 (2008). https://doi.org/10.1007/s11748-007-0211-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11748-007-0211-x

Key words

Navigation