Abstract
Purpose
This study aimed to evaluate the clinicopathological significance of cancer stem-like cell (CSLC) markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC).
Methods
We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥10 represented positive expression.
Results
There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS.
Conclusions
The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988. doi:10.1073/pnas.0530291100
Asamura H et al (2006) Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol Off J Am Soc Clin Oncol 24:70–76. doi:10.1200/JCO.2005.04.1202
Chen S et al. (2012) SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells. PloS One 7:e36326. doi:10.1371/journal.pone.0036326
Chou YT et al (2013) The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. Stem Cells 31:2607–2619. doi:10.1002/stem.1518
de Boer M, van Dijck JA, Bult P, Borm GF, Tjan-Heijnen VC (2010) Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst 102:410–425. doi:10.1093/jnci/djq008
Fischer M et al (2011) Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Res 71:1520–1525. doi:10.1158/0008-5472.CAN-10-2817
Ginestier C et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567. doi:10.1016/j.stem.2007.08.014
Huang EH et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69:3382–3389. doi:10.1158/0008-5472.CAN-08-4418
Igawa S et al (2010) Comparison of chemotherapy for unresectable pulmonary high-grade non-small cell neuroendocrine carcinoma and small-cell lung cancer. Lung Cancer 68:438–445. doi:10.1016/j.lungcan.2009.07.003
Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T (2007) Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg 84:702–707. doi:10.1016/j.athoracsur.2007.03.093
Jia X et al. (2011) SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J mol cell biol 3:230–238. doi:10.1093/jmcb/mjr002
Jiang F et al (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7:330–338. doi:10.1158/1541-7786.MCR-08-0393
Kastan MB, Schlaffer E, Russo JE, Colvin OM, Civin CI, Hilton J (1990) Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood 75:1947–1950
Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14:275–291. doi:10.1016/j.stem.2014.02.006
Kuang RG, Kuang Y, Luo QF, Zhou CJ, Ji R, Wang JW (2013) Expression and significance of Musashi-1 in gastric cancer and precancerous lesions. World J Gastroenterol 19:6637–6644. doi:10.3748/wjg.v19.i39.6637
Leung EL et al (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One 5:e14062. doi:10.1371/journal.pone.0014062
Liao T et al (2013) Susceptibility to cytotoxic T cell lysis of cancer stem cells derived from cervical and head and neck tumor cell lines. J Cancer Res Clin Oncol 139:159–170. doi:10.1007/s00432-012-1311-2
Liu S et al (2013) Prognostic value of cancer stem cell marker aldehyde dehydrogenase in ovarian cancer: a meta-analysis. PloS One 8:e81050. doi:10.1371/journal.pone.0081050
Merlo LM, Maley CC (2010) The role of genetic diversity in cancer. J Clin Invest 120:401–403. doi:10.1172/JCI42088
Mezzanzanica D et al (2008) Subcellular localization of activated leukocyte cell adhesion molecule is a molecular predictor of survival in ovarian carcinoma patients. Clin Cancer Res Off J Am Assoc Cancer Res 14:1726–1733. doi:10.1158/1078-0432.CCR-07-0428
Nasgashio R et al (2011) The balance between the expressions of hASH1 and HES1 differs between large cell neuroendocrine carcinoma and small cell carcinoma of the lung. Lung Cancer 74:405–410. doi:10.1016/j.lungcan.2011.04.012
Noda K et al (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. New Engl J Med 346:85–91. doi:10.1056/NEJMoa003034
O’Flaherty JD, Barr M, Fennell D, Richard D, Reynolds J, O’Leary J, O’Byrne K (2012) The cancer stem-cell hypothesis: its emerging role in lung cancer biology and its relevance for future therapy. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 7:1880–1890. doi:10.1097/JTO.0b013e31826bfbc6
Ono S et al (2013) Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 143:963–970. doi:10.1378/chest.12-0913
Paci M, Cavazza A, Annessi V, Putrino I, Ferrari G, De Franco S, Sgarbi G (2004) Large cell neuroendocrine carcinoma of the lung: a 10-year clinicopathologic retrospective study. Ann Thorac Surg 77:1163–1167. doi:10.1016/j.athoracsur.2003.09.070
Palaniyandi K, Pockaj BA, Gendler SJ, Chang XB (2012) Human breast cancer stem cells have significantly higher rate of clathrin-independent and caveolin-independent endocytosis than the differentiated breast cancer cells. J Cancer Sci Ther 4:214–222
Park SY, Gonen M, Kim HJ, Michor F, Polyak K (2010) Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest 120:636–644. doi:10.1172/JCI40724
Pietanza MC, Ladanyi M (2012) Bringing the genomic landscape of small-cell lung cancer into focus. Nat Genet 44:1074–1075. doi:10.1038/ng.2415
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111. doi:10.1038/35102167
Rudin CM et al (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44:1111–1116. doi:10.1038/ng.2405
Sirop S et al (2011) Detection and prognostic impact of micrometastasis in colorectal cancer. J Surg Oncol 103:534–537. doi:10.1002/jso.21793
Sobin L, Wittekind C (2009) TNM classification of malignant tumours, 7th edn. Wiley, New York
Sterlacci W, Savic S, Fiegl M, Obermann E, Tzankov A (2014) Putative stem cell markers in non-small-cell lung cancer: a clinicopathologic characterization. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 9:41–49. doi:10.1097/JTO.0000000000000021
Sun JM et al (2012) Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer 77:365–370. doi:10.1016/j.lungcan.2012.04.009
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. doi:10.1016/j.cell.2006.07.024
Travis WD (2010) Advances in neuroendocrine lung tumors. Ann Oncol 21(Suppl 7):vii65–vii71. doi:10.1093/annonc/mdq380
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (2004) Pathology and genetics. Tumours of the lung, pleura, thymus and heart. IARC Press, Lyon
Vasiliou V, Pappa A, Estey T (2004) Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab Rev 36:279–299. doi:10.1081/DMR-120034001
Visus C et al (2011) Targeting ALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8(+) T cells Clinical cancer research : an official journal of the American Association for. Cancer Res 17:6174–6184. doi:10.1158/1078-0432.CCR-11-1111
Weichert W, Knosel T, Bellach J, Dietel M, Kristiansen G (2004) ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. J Clin Pathol 57:1160–1164. doi:10.1136/jcp.2004.016238
Wilbertz T et al (2011) SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol 24:944–953. doi:10.1038/modpathol.2011.49
Wu A, Luo W, Zhang Q, Yang Z, Zhang G, Li S, Yao K (2013) Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma. Cancer Lett 330:181–189. doi:10.1016/j.canlet.2012.11.046
Yamazaki S et al (2005) Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer 49:217–223. doi:10.1016/j.lungcan.2005.01.008
Zhang WC et al (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148:259–272. doi:10.1016/j.cell.2011.11.050
Zhou L, Jiang Y, Yan T, Di G, Shen Z, Shao Z, Lu J (2010) The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res Treat 122:795–801. doi:10.1007/s10549-010-0999-4
Acknowledgments
This work was supported by Grants-in-Aid for Young Scientists (B) Grant Number 24791481 from Japan Society for the Promotion of Science.
Conflict of interest
We declare that we have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Morise, M., Hishida, T., Takahashi, A. et al. Clinicopathological significance of cancer stem-like cell markers in high-grade neuroendocrine carcinoma of the lung. J Cancer Res Clin Oncol 141, 2121–2130 (2015). https://doi.org/10.1007/s00432-015-1985-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-015-1985-3