小细胞肺癌(small cell lung cancer, SCLC)是一种低分化且具有侵袭性的源于支气管粘膜或腺上皮内的神经内分泌肿瘤,其特点包括:生长迅速、侵袭性强、广泛转移、预后差且易复发。SCLC的临床治疗往往因疾病的侵袭性而复杂化,许多患者表现为胸内肿物和/或广泛转移的衰弱症状,且侵袭性强,预后较差,5年生存率 < 7%,所以很大一部分接受顺铂联合依托泊苷治疗的患者总是经历治疗失败和肿瘤复发。而靶向治疗及免疫治疗的问世使得一小部分患者从免疫治疗中获得了新的契机,所以寻找更加快速切且有效的诊断及预后生物标志物,提高肺癌患者生存率及生活质量、延长生存期。但目前尚缺乏对SCLC的诊断及预后有提示意义的简单易得、快速准确的实验室指标,本文将对SCLC患者外周血诊断及预后生物标志物的研究进展作一综述。
Small cell lung cancer (SCLC) is a poorly differentiated and invasive neuroendocrine tumor origi-nating from bronchial mucosa or glandular epithelium. It is characterized by rapid growth, strong invasivity, extensive metastasis, poor prognosis, and easy recurrence. The clinical treatment of SCLC is often complicated by the aggressiveness of the disease. Many patients present with debilitating symptoms of intrathoracic masses and/or extensive metastasis with strong aggressiveness, poor prognosis, and 5-year survival rate < 7%. Therefore, a large proportion of patients receiving cispla-tin combined with etoposide always experience treatment failure and tumor recurrence. However, the advent of targeted therapy and immunotherapy has provided a small number of patients with new opportunities from immunotherapy. Therefore, more rapid and effective diagnostic and prog-nostic biomarkers are sought to improve the survival rate and quality of life of lung cancer patients, and prolong the survival period. However, there is still a lack of simple, easy, rapid and accurate la-boratory indicators that have suggestive significance for the diagnosis and prognosis of SCLC. This paper will review the research progress of peripheral blood diagnosis and prognostic biomarkers of SCLC patients.
小细胞肺癌,预后,外周血炎性指标,分子生物学指标, Small Cell Lung Cancer Prognosis Peripheral Blood Inflammatory Index Molecular Biological
Index摘要
Small cell lung cancer (SCLC) is a poorly differentiated and invasive neuroendocrine tumor originating from bronchial mucosa or glandular epithelium. It is characterized by rapid growth, strong invasivity, extensive metastasis, poor prognosis, and easy recurrence. The clinical treatment of SCLC is often complicated by the aggressiveness of the disease. Many patients present with debilitating symptoms of intrathoracic masses and/or extensive metastasis with strong aggressiveness, poor prognosis, and 5-year survival rate < 7%. Therefore, a large proportion of patients receiving cisplatin combined with etoposide always experience treatment failure and tumor recurrence. However, the advent of targeted therapy and immunotherapy has provided a small number of patients with new opportunities from immunotherapy. Therefore, more rapid and effective diagnostic and prognostic biomarkers are sought to improve the survival rate and quality of life of lung cancer patients, and prolong the survival period. However, there is still a lack of simple, easy, rapid and accurate laboratory indicators that have suggestive significance for the diagnosis and prognosis of SCLC. This paper will review the research progress of peripheral blood diagnosis and prognostic biomarkers of SCLC patients.
张丽萍. 小细胞肺癌外周血生物标记物的研究进展Advances in Peripheral Blood Biomarkers of Small Cell Lung Cancer[J]. 临床医学进展, 2023, 13(01): 492-500. https://doi.org/10.12677/ACM.2023.131073
参考文献ReferencesJiménez Ruiz, C.A., Ramos Pinedo, A., Cicero Guerrero, A., et al. (2012) Characteristics of COPD Smokers and Effec-tiveness and Safety of Smoking Cessation Medications. Nicotine & Tobacco Research, 14, 1035-1039.
<br>https://doi.org/10.1093/ntr/nts001Semenova, E.A., Nagel, R. and Berns, A. (2015) Origins, Genetic Land-scape, and Emerging Therapies of Small Cell Lung Cancer. Genes & Development, 29, 1447-1462. <br>https://doi.org/10.1101/gad.263145.115Bray, F., et al. (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 68, 394-424. <br>https://doi.org/10.3322/caac.21492International Agency for Research on Cancer (2014) Cancer Incidence in Five Continents Volume X (IARC).Byers, L.A. and Rudin, C.M. (2015) Small Cell Lung Cancer: Where Do We Go from Here? Cancer, 121, 664-672.
<br>https://doi.org/10.1002/cncr.29098Pillai, R.N. and Owonikoko, T.K. (2014) Small Cell Lung Cancer: Thera-pies and Targets. Seminars in Oncology, 41, 133-142. <br>https://doi.org/10.1053/j.seminoncol.2013.12.015Coleman, M.P. and Allemani, C. (2015) Cancer: The Ele-phant in the Room. The Lancet, 385, 1047-1048.
<br>https://doi.org/10.1016/S0140-6736(15)60571-2Galluzzi, L., Vitale, I., Michels, J., et al. (2014) Systems Bi-ology of Cisplatin Resistance: Past, Present and Future. Cell Death & Disease, 5, e1257. <br>https://doi.org/10.1038/cddis.2013.428Paximadis, P., Beebe-Dimmer, J.L., George, J., et al. (2018) Compar-ing Treatment Strategies for Stage I Small-Cell Lung Cancer. Clinical Lung Cancer, 19, e559-e565. <br>https://doi.org/10.1016/j.cllc.2018.03.017De Wever, W.V., Erschakelen, J. and Coolen, J. (2014) Role of Imaging in Diagnosis, Staging and Follow-Up of Lung Cancer. Current Opinion in Pulmonary Medicine, 20, 385-392. <br>https://doi.org/10.1097/MCP.0000000000000066Lynette, M. and Sholl, M.D. (2016) The Molecular Pathol-ogy of Lung Cancer. Surgical Pathology Clinics, 9, 353-378.
<br>https://doi.org/10.1016/j.path.2016.04.003Inage, T., Nakajima, T., et al. (2018) Early Lung Cancer Detection. Clinics in Chest Medicine, 39, 45-55.
<br>https://doi.org/10.1016/j.ccm.2017.10.003张玉勤. 炎症与癌症[J]. 国外医学情报, 2002(1): 12-17.王冬燕, 朱昌, 陈玮, 等. 中性粒细胞与淋巴细胞比值和血小板与淋巴细胞比值在消化系统肿瘤中的应用进展[J]. 胃肠病学和肝病学杂志, 2019, 28(11): 1292-1295.Kay, J., Thadhani, E., Samson, L., et al. (2019) Inflam-mation-Induced DNA Damage, Mutations and Cancer. DNA Repair (Amst.), 83, Article ID: 102673. <br>https://doi.org/10.1016/j.dnarep.2019.102673Qian, B.Z. (2017) Inflammation Fires up Cancer Metastasis L. Seminars in Cancer Biology, 47, 170-176.
<br>https://doi.org/10.1016/j.semcancer.2017.08.006Yang, L. and Chen, H. (2019) Establishing the Prognostic Value of Platelet-Tolymphocyte Ratio in Cervical Cancer: A Systematic Review and Meta-Analysis. International Jour-nal of Gynecological Cancer, 29, 683-690.
<br>https://doi.org/10.1136/ijgc-2018-000090Ikeguchi, M., et al. (2014) Inflammation-Based Prognostic Scores and Nutritional Prognostic Index in Patients with Locally-Advanced Unresectable Colorectal Cancer. World Journal of Surgical Oncology, 12, 210.
<br>https://doi.org/10.1186/1477-7819-12-210Otowa, Y., et al. (2016) Changes in Modified Glasgow Prognostic Score after Neoadjuvant Chemotherapy Is a Prognostic Factor in Clinical Stage Ⅱ/Ⅲ Esophageal Cancer. Diseases of the Esophagus, 29, 146-151.
<br>https://doi.org/10.1111/dote.12316徐茵, 王玉月, 徐婷, 等. 中性粒细胞CD64在恶性血液病伴感染诊断中应用的研究进展[J]. 白血病•淋巴瘤, 2020, 29(10): 630-633.Liew, P.X. and Kubes, P. (2019) The Neutro-phil’s Role during Health and Disease. Physiological Reviews, 99, 1223- 1248. <br>https://doi.org/10.1152/physrev.00012.2018Comen, E., Wojnarowicz, P., Seshan, V.E., et al. (2016) TNF Is a Key Cytokine Mediating Neutrophil Cytotoxic Activity in Breast Cancer Patients. NPJ Breast Cancer, 2, 16009. <br>https://doi.org/10.1038/npjbcancer.2016.9Ramakrishnan, G., Augustine, T.A., Jagan, S., et al. (2007) Effect of Silymarin on N-Nitrosodiethylamine Induced Hepatocarcinogenesis in Rats. Experimental Oncology, 29, 39-44.Manfroi, B., Moreaux, J., Righini, C., et al. (2018) Tumor-Associated Neutrophils Correlate with Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients. Blood Cancer Journal, 8, 66. <br>https://doi.org/10.1038/s41408-018-0099-yRahir, G. and Moser, M. (2012) Tumor Microenvironment and Lymphocyte Infiltration. Cancer Immunology, Immunotherapy, 61, 751-759. <br>https://doi.org/10.1007/s00262-012-1253-1Sakamuru, S., et al. (2016) Mitochondrial Membrane Potential Assay. Methods in Molecular Biology, 1473, 17-22.
<br>https://doi.org/10.1007/978-1-4939-6346-1_2Ruan, J.S., Liu, Y.P., Zhang, L., et al. (2012) Luteolin Reduces the Invasive Potential of Malignant Melanoma Cells by Targeting Beta-3-Integrin and the Epithelial-Mesenchymal Transi-tion. Acta Pharmacologica Sinica, 33, 1325-1331.
<br>https://doi.org/10.1038/aps.2012.93Guthrie, G.J., Charles, K.A., Roxburgh, C.S., et al. (2013) The Systemic Inflammation-Based Neutrophil-Lymphocyte Ratio: Experience in Patients with Cancer. Critical Reviews in Oncolo-gy/Hematology, 88, 218-230.
<br>https://doi.org/10.1016/j.critrevonc.2013.03.010Karantanos, T., Karanika, S., Seth, B. and Gignac, G. (2019) The Absolute Lymphocyte Count Can Predict the Overall Survival of Patients with Non-Small Cell Lung Cancer on Nivolumab: A Clinical Study. Clinical and Translational Oncology, 21, 206-212. <br>https://doi.org/10.1007/s12094-018-1908-2Lawrence, B., Gustafsson, B.I., Chan, A., et al. (2011) The Epi-demiology of Gastroenteropancreatic Neuroendocrine Tumors. Endocrinology & Metabolism Clinics of North America, 40, 1-18. <br>https://doi.org/10.1016/j.ecl.2010.12.005Schlesinger, M. (2018) Role of Platelets and Platelet Re-ceptors in Cancer Metastasis. Journal of Hematology & Oncology, 11, 125. <br>https://doi.org/10.1186/s13045-018-0669-2Varki, A. (2007) Trousseau’s Syndrome: Multiple Definitions and Multiple Mechanisms. Blood, 110, 1723-1729.
<br>https://doi.org/10.1182/blood-2006-10-053736Karpatkin, S., Ambrogio, C. and Pearlstein, E. (1988) The Role of Tumor-Induced Platelet Aggregation, Platelet Adhesion and Adhesive Proteins in Tumor Metastasis. Progress in Clinical and Biological Research, 283, 585-606.Wang, S., Li, Z. and Xu, R. (2018) Human Cancer and Platelet Interaction, a Potential Therapeutic Target. International Journal of Molecular Sciences, 19, 1246. <br>https://doi.org/10.3390/ijms19041246Waldmann, T.A. (2018) Cytokines in Cancer Immunotherapy. Cold Spring Harbor Perspectives in Biology, 10, a028472.
<br>https://doi.org/10.1101/cshperspect.a028472Wojtukiewicz, M.Z., Sierko, E., Hempel, D., Tucker, S.C. and Honn, K.V. (2017) Platelets and Cancer Angiogenesis Nexus. Cancer and Metastasis Reviews, 36, 249-262. <br>https://doi.org/10.1007/s10555-017-9673-1Palumbo, J.S., Talmage, K.E., Massari, J.V., et al. (2005) Platelets and Fibrin(ogen) Increase Metastatic Potential by Impeding Natural Killer Cell-Mediated Elimination of Tumor Cells. Blood, 105, 178-185.
<br>https://doi.org/10.1182/blood-2004-06-2272Schatzberg, D., Yang, J.J., Wagner, D.D., et al. (2011) Increased Efficacy of Breast Cancer Chemotherapy in Thrombocytopenic Mice. Cancer Research, 71, 1540-1549. <br>https://doi.org/10.1158/0008-5472.CAN-10-2038Abdulrahman, G.O., Das, N. and Lutchman Singh, K. (2019) The Predictive Role of Thrombocytosis in Benign, Borderline and Malignant Ovarian Tumors. Platelets, 31, 795-800. <br>https://doi.org/10.1080/09537104.2019.1686755O’Keefe, S.C., Marshall, F.F., Issa, M.M., Har-mon, M.P. and Petros, J.A. (2002) Thrombocytosis Is Associated with a Significant Increase in the Cancer Specific Death Rate after Radical Nephrectomy. Journal of Urology, 168, 1378- 1380. <br>https://doi.org/10.1016/S0022-5347(05)64453-9Templeton, A.J., Ace, O., McNamara, M.G., et al. (2014) Prognostic Role of Platelet to Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis. Cancer Ep-idemiology, Biomarkers & Prevention, 23, 1204-1212.
<br>https://doi.org/10.1158/1055-9965.EPI-14-0146El Asmar, A., Ghabi, E., Saber, T., et al. (2020) Plate-let-to-Lymphocyte Ratio Is Correlated with a Delay in Feeding Resumption Following a Transhiatal Esophagectomy with Cervical Anastomosis. World Journal of Surgical Oncology, 18, 267. <br>https://doi.org/10.1186/s12957-020-02035-yFang, T., Wang, Y., Yin, X., et al. (2020) Diagnostic Sensitivity of NLR and PLR in Early Diagnosis of Gastric Cancer. Journal of Immunology Research, 2020, Article ID: 9146042. <br>https://doi.org/10.1155/2020/9146042Elsberger, B., Lankston, L., McMillan, D.C., et al. (2011) Presence of Tumoural C-Reactive Protein Correlates with Progressive Prostate Cancer. Prostate Cancer and Prostatic Diseases, 14, 122-128.
<br>https://doi.org/10.1038/pcan.2011.5Tillett, W.S. and Francis, T. (1930) Serological Reactions in Pneumonia with a Non-Protein Somatic Fraction of Pneumococcus. Journal of Experimental Medicine, 52, 561-571. <br>https://doi.org/10.1084/jem.52.4.561Cevizci, R., Bezgin, S., Altin, G., et al. (2016) Treatment of Seborrheic Keratosis in Bilateral External Auditory Canal Using Fiber CO2 Laser. Kulak Burun Bogaz Ihtisas Dergisi, 26, 304-306.
<br>https://doi.org/10.5606/kbbihtisas.2016.04810陈冲, 葛鹏, 白银鹏, 等. CRP/Alb比值对肺癌患者预后的临床价值[J]. 检验医学, 2017, 32(3): 173-177.Akamine, T., Takada, K., Toyokawa, G., et al. (2018) Association of Preoperative Serum CRP with PD-L1 Expression in 508 Patients with Non-Small Cell Lung Cancer: A Comprehen-sive Analysis of Systemic Inflammatory Markers. Surgical Oncology, 27, 88-94.杨佳程, 蔡讯, 宋卫峰, 等. 晚期胰腺癌患者血清C反应蛋白水平动态变化与化疗疗效及预后的关系分析[J]. 临床肿瘤学杂志, 2014(12): 1097-1102.Nakayama, T., Saito, K., Kumagai, J., et al. (2018) Higher Serum C-reactive Protein Level Represents the Immunnosuppressive Tumor Microenvironment in Patients with Clear Cell Renal Cell Carcinoma. Clinical Genitou-rinary Cancer, 7, 1-8.Lee, R.C., Feinbaum, R.L. and Ambros, V. (1993) The C. elegans Heterochronic Gene lin-4 Encodes Small RNAs with Antisense Complementarity to lin-4. Cell, 75, 843-854. <br>https://doi.org/10.1016/0092-8674(93)90529-YWightman, B., Ha, I. and Ruvkun, G. (1993) Posttranscriptional Regulation of the Heterochronic Gene lin-14 by lin-14 Mediates Temporal Pattern Formation in C. elegans. Cell, 75, 855-862. <br>https://doi.org/10.1016/0092-8674(93)90530-4Lagos-Quintana, M., Rauhut, R., Lendeckel, W. and Tuschl, T. (2001) Identification of Novel Genes Coding for Small Expressed RNAs. Science, 294, 853-858. <br>https://doi.org/10.1126/science.1064921Lee, R.C. and Ambros, V. (2001) An Extensive Class of Small RNAs in Caenorhabditis elegans. Science, 294, 862-864.
<br>https://doi.org/10.1126/science.1065329Lau, N.C., Lim, L.P., Weinstein, E.G. and Bartel, D.P. (2001) An Abundant Class of Tiny RNAs with Probable Regu- latory Roles in Caenorhabditis elegans. Science, 294, 858-862. <br>https://doi.org/10.1126/science.1065062Mertens-Talcott, S.U., Chintharlapalli, S., Li, X., et al. (2007) The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Check-point in MDA-MB-231 Breast Cancer Cells. Cancer Research, 67, 11001-11011. <br>https://doi.org/10.1158/0008-5472.CAN-07-2416Lal, A., Pan, Y., Navarro, F., et al. (2009) miR-24-Mediated Down Regulation of H2AX Suppresses DNA Repair in Terminally Differentiated Blood Cells. Nature Structural & Molecular Biology, 16, 492-498.
<br>https://doi.org/10.1038/nsmb.1589Esquela-Kerscher, A. and Slack, F.J. (2006) Oncomirs—microRNAs with a Role in Cancer. Nature Reviews Cancer, 6, 259-269. <br>https://doi.org/10.1038/nrc1840Mazan-Mamczarz, K. and Gartenhaus, R.B. (2013) Role of microRNA Deregulation in the Pathogenesis of Diffuse Large B-Cell Lymphoma (DLBCL). Leukemia Research, 37, 1420-1428. <br>https://doi.org/10.1016/j.leukres.2013.08.020Ouyang, M., Li, Y., Ye, S., et al. (2014) MicroRNA Profiling Implies New Markers of Chemoresistance of Triple- Negative Breast Can-cer. PLOS ONE, 9, e96228. <br>https://doi.org/10.1371/journal.pone.0096228Dong, Y., Wu, W.K.K., Wu, C.W., et al. (2011) MicroRNA Dysregulation in Colorectal Cancer: A Clinical Perspective. British Journal of Cancer, 104, 893-898. <br>https://doi.org/10.1038/bjc.2011.57Maugeri-Sacca, M., Coppola, V., Bonci, D. and De Maria, R. (2012) MicroRNA and Prostate Cancer: From Preclinical Research to Translational Oncology. Cancer Journal, 18, 253-261. <br>https://doi.org/10.1097/PPO.0b013e318258b5b6Du, L., Schageman, J.J., et al. (2010) MicroRNA Expression Distinguishes SCLC from NSCLC Lung Tumor Cells and Suggests a Possible Pathological Relationship between SCLCs and NSCLCs. Journal of Experimental & Clinical Cancer Research, 29, 75. <br>https://doi.org/10.1186/1756-9966-29-75杨梦珠. 弥漫大B细胞淋巴瘤患者外周血NLR、PLR以及LDH的水平及其临床意义[D]: [硕士学位论文]. 新乡: 新乡医学, 2021. <br>https://doi.org/10.27434/d.cnki.gxxyc.2021.000083Smit, M.J., Duursma, A.M., Bouma, J.M. and Gruber, M. (1987) Receptor-Mediated Endocytosis of Lactate Dehydrogenase M4 by Liver Macrophages: A Mechanism for Elimina-tion of Enzymes from Plasma, Evidence for Competition by Creatine Kinase MM, Adenylate Kinase, Malate, and Alcohol Dehydrogenase. Journal of Biological Chemistry, 262, 13020-13026. <br>https://doi.org/10.1016/S0021-9258(18)45160-5Pelicano, H., Martin, D.S., Xu, R.H. and Huang, P. (2006) Glycolysis Inhibition for Anticancer Treatment. Oncogene, 25, 4633-4646. <br>https://doi.org/10.1038/sj.onc.1209597Ding, J., Karp, J.E. and Emadi, A. (2017) Elevated Lactate Dehydro-genase (LDH) Can Be a Marker of Immune Suppression in Cancer: Interplay between Hematologic and Solid Neoplastic Clones and Their Microenvironments. Cancer Biomark, 19, 353-363. <br>https://doi.org/10.3233/CBM-160336Dawson, D.M., et al. (1964) Lactic Dehydrogenases: Functions of the Two Types Rates of Synthesis of the Two Major Forms Can Be Correlated with Metabolic Differentiation. Science, 143, 929-933.
<br>https://doi.org/10.1126/science.143.3609.929肖蓉, 姜涛, 万纯黔等. 弥漫大B细胞淋巴瘤治疗后血清β2-MG VEGF与LDH水平变化及其临床意义[J]. 中国肿瘤临床, 2018, 45(19): 994-999.黄天骄, 周虹, 刘松涛, 王雪梅, 张睿, 蒋博文, 王晓, 杨雪. 弥漫大B细胞淋巴瘤患者血清中乳酸脱氢酶、β2微球蛋白及尿酸临床意义[J]. 临床血液学杂志, 2021, 34(6): 412-414.
<br>https://doi.org/10.13201/j.issn.1004-2806.2021.06.008Tischer, E., Gospodarowicz, D., Mitchell, R., et al. (1989) Vascular Endothelial Growth Factor: A New Member of the Platelet-Derived Growth Factor Gene Family. Bio-chemical and Biophysical Research Communications, 165, 1198-1206.
<br>https://doi.org/10.1016/0006-291X(89)92729-0Tammela, T., Enholm, B., Alitalo, K. and Paavonen, K. (2005) The Biology of Vascular Endothelial Growth Factors. Cardiovascular Research, 65, 550-563. <br>https://doi.org/10.1016/j.cardiores.2004.12.002Takahashi, H. and Shibuya, M. (2005) The Vascular Endothe-lial Growth Factor (VEGF)/VEGF Receptor System and Its Role under Physiological and Pathological Conditions. Clin-ical Science (London), 109, 227-241.
<br>https://doi.org/10.1042/CS20040370Delghanian, F., Hojati, Z. and Kay, M. (2014) New Insights into VEGF-A Alternative Splicing: Key Regulatory Switching in Pathological Process. Avicenna Journal of Medical Biotech-nology, 6, 192-199.Giacca, M. (2010) Non-Redundant Functions of the Protein Isoforms Arising from Alternative Splicing of the VEGF-A Pre-mRNA. Transcription, 1, 149-153. <br>https://doi.org/10.4161/trns.1.3.13229刘军, 朱晓华. 血管内皮生长因子对小细胞肺癌诊治的应用价值研究[J]. 中国肺癌杂志, 2007(5): 406-410.Salven, P., Ruotsalainen, T., Mattson, K., et al. (1998) High Pre-Treatment Serum Level of Vascular Endothelial Growth Factor VEGF Is Associated with Poor Outcome in Small Cell Lung Cancer. International Journal of Cancer, 79, 144-146.
<br>https://doi.org/10.1002/(SICI)1097-0215(19980417)79:2<144::AID-IJC8>3.0.CO;2-T陆永绥, 张伟民. 临床检验管理与技术规程[M]. 杭州: 浙江大学出版社, 2004: 760-761.Schneider, J., Philipp, M., Velcovsky, H.G., et al. (2003) Pro-Gastrin-Releasing Peptide (ProGRP), Neuron Specific Enolase (NSE), Carcinoembryonic Anti-gen (CEA) and Cytokeratin 19-Fragments (CYFRA 21-1) in Patients with Lung Cancer in Comparison to Other Lung Diseases. Anticancer Research, 23, 885-893.