大细胞肺癌移植瘤组织中HIF-1α、VEGF、Ki67、血清蛋白的表达及其与功能性血管数目的关系

doi:10.3969/j.issn.1004-616x.2022.06.006

癌变·畸变·突变 ›› 2022, Vol. 34 ›› Issue (6): 439-444.doi: 10.3969/j.issn.1004-616x.2022.06.006

• 论著 • 上一篇

大细胞肺癌移植瘤组织中HIF-1α、VEGF、Ki67、血清蛋白的表达及其与功能性血管数目的关系

吴宝¹, 白玉勤², 李丹丹², 杨占民², 孔凡龙³

1. 赤峰学院基础医学院组织胚胎学教研室, 内蒙古赤峰 024000;
2. 赤峰市肿瘤医院/赤峰学院第二附属医院病理科, 内蒙古赤峰 024000;
3. 锦州医科大学, 辽宁锦州 121000

收稿日期:2022-02-27 修回日期:2022-06-30 发布日期:2022-12-03
通讯作者: 白玉勤
作者简介:吴宝，E-mail：wbxw666@163.com。
基金资助:
内蒙古自治区高等学校科学研究项目(NJZZ18202,NJZY22178)

Expression of HIF-1α, VEGF, Ki67 and serum proteins in large-cell lung cancer cell line xenografts and their relationship with numbers of functional blood vessels

WU Bao¹, BAI Yuqin², LI Dandan², YANG Zhanmin², KONG Fanlong³

1. Department of Histology and Embryology, Medical College of Chifeng University, Chifeng 024000;
2. Department of Pathology, Chifeng Tumor Hospital/Second Affiliated Hospital of Chifeng University, Chifeng 024000, Inner Mongolia;
3. Jinzhou Medical University, Jinzhou 121000, Liaoning, China

Received:2022-02-27 Revised:2022-06-30 Published:2022-12-03

摘要/Abstract

摘要： 目的：研究大细胞肺癌(LCLC)Lu65和Lu99细胞株裸鼠移植瘤组织中缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)、Ki67以及血清蛋白Albumin、IgG1、IgM的表达，及其与功能性血管数目的关系。方法：将大细胞肺癌Lu65和Lu99细胞注射至裸鼠背部皮下建立异种移植模型，利用活体冷冻技术(IVCT)制备标本，免疫组织化学法分析移植瘤侵袭组织中HIF-1α、VEGF、Ki67和血清蛋白(Albumin、IgG1、IgM)的表达，根据血管周围细胞外基质内IgM蛋白的表达情况区分功能性血管和非功能性血管并分别计数，采用t检验、[χ²]检验及Spearman秩相关分析进行统计学分析。结果：Lu65移植瘤中可见少数肿瘤细胞核中有HIF-1α蛋白表达，Lu99移植瘤细胞核中未见HIF-1α蛋白表达，二者差异有统计学意义(P<0.05)；两种移植瘤组织中VEGF和Ki67蛋白均呈高表达。HIF-1α蛋白表达水平与VEGF和Ki67蛋白无明显相关(P>0.05)。Lu65和Lu99移植瘤组织内功能性血管数目高于非功能性血管(P<0.05)。结论：Lu65和Lu99移植瘤组织中HIF-1α蛋白表达水平与VEGF、Ki67蛋白无明显相关，与细胞异质性有关。IVCT技术制备的组织标本可区分功能性血管与非功能性血管，Lu65和Lu99移植瘤组织中功能性血管数目高于非功能性血管，血清蛋白能否透过血管壁可能与其相对分子质量和血管结构有关。

关键词: 大细胞肺癌, 移植瘤组织, 活体冷冻技术, 缺氧诱导因子-1α, 功能性血管

Abstract: OBJECTIVE:To investigate expression of hypoxia-inducible factor-1α (HIF-1α),vascular endothelial growth factor (VEGF),Ki67,serum protein albumin,IgG1 and IgM,and their relationship with numbers of functional blood vessels in large-cell lung cancer (LCLC) Lu65 and Lu99 cell line xenografts in nude mice. METHODS:The LCLC cells were injected subcutaneously into the back of nude mice to establish a xenograft model,and the in vivo specimens were prepared by cryotechnique (IVCT). Protein (albumin,IgG1,IgM) protein expressions were determined. According to the expression of IgM protein in the extracellular matrix around blood vessels,the number of functional blood vessels and non-functional blood vessels were distinguished and counted. t test,[χ²] test and Spearman rank correlation analyses were used for statistical evaluations. RESULTS:Expression of HIF-1α protein was found in a few tumor cell nuclei in the Lu65 but not in the Lu99 xenograft tumors and the difference was statistically significant (P<0.05). Both VEGF and Ki67 proteins were highly expressed in the tumors. The expression levels of HIF-1α protein were not significantly correlated with the VEGF and Ki67 proteins. The numbers of functional blood vessels in Lu65 and Lu99 tumors were higher than that of non-functional blood vessels (P<0.05). CONCLUSION:The expression levels of HIF-1α protein in the Lu65 and Lu99 tumors had no significant correlation with the VEGF and Ki67 proteins but were related to cellular heterogeneity. On the other hand,the IVCT technology was useful in distinguishing functional from non-functional blood vessels. The numbers of functional blood vessels in both Lu65 and Lu99 tumors were higher than that of non-functional blood vessels. Whether serum proteins were capable of penetrating blood vessel walls may be related to their molecular weights and structures of blood vessels.

Key words: large cell lung cancer, xenograft modeltissues, in vivo cryotechnique, hypoxia-inducible factor-1α protein, functional blood vessels

中图分类号:

R730.231

吴宝, 白玉勤, 李丹丹, 杨占民, 孔凡龙. 大细胞肺癌移植瘤组织中HIF-1α、VEGF、Ki67、血清蛋白的表达及其与功能性血管数目的关系[J]. 癌变·畸变·突变, 2022, 34(6): 439-444.

WU Bao, BAI Yuqin, LI Dandan, YANG Zhanmin, KONG Fanlong. Expression of HIF-1α, VEGF, Ki67 and serum proteins in large-cell lung cancer cell line xenografts and their relationship with numbers of functional blood vessels[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(6): 439-444.

参考文献

[1] LIN G, QI K, LIU B, et al. A nomogram prognostic model for large cell lung cancer:analysis from the Surveillance, Epidemiology and End Results Database[J]. Transl Lung Cancer Res, 2021, 10(2):622-635.
[2] ASAMURA H, KAMEYA T, MATSUNO Y, et al. Neuroendocrine neoplasms of the lung:a prognostic spectrum[J]. J Clin Oncol, 2006, 24(1):70-76.
[3] GOLLARD R, JHATAKIA S, ELLIOTT M, et al. Large cell/neuroendocrine carcinoma[J]. Lung Cancer, 2010, 69(1):13-18.
[4] GIATROMANOLAKI A, KOUKOURAKIS M I, SIVRIDIS E, et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival[J]. Br J Cancer, 2001, 85(6):881-890.
[5] MASON D Y, BIBERFELD P. Technical aspects of lymphoma immunohistology[J]. J Histochem Cytochem, 1980, 28(8):731-745.
[6] OHNO S, TERADA N, FUJII Y, et al. Dynamic structure of glomerular capillary loop as revealed by an in vivo cryotechnique[J]. Vichows Archiv A Pathol Anat, 1996, 427(5):519-527.
[7] BAI Y Q, OHNO N, TERADA N, et al. Immunolocalization of serum proteins in xenografted mouse model of human tumor cells by various cryotechniques[J]. HistolHistopathol, 2009, 24(6):717-728.
[8] OHNO N, TERADA N, BAI Y Q, et al. Application of cryobiopsy to morphological and immunohistochemical analyses of xenografted human lung cancer tissues and functional blood vessels[J]. Cancer, 2008, 113(5):1068-1079.
[9] BAI Y Q, OHNO N, TERADA N, et al. Differential distribution of blood-derived proteins in xenografted human adenocarcinoma tissues by in vivo cryotechnique and cryobiopsy[J]. Med Mol Morphol, 2011, 44(2):93-102.
[10] NAKAMURA N, MIYAGI E, MURATA S I, et al. Expression of thyroid transcription factor-1 in normal and neoplastic lung tissues[J]. Mod Pathol, 2002, 15(10):1058-1067.
[11] HWANG D H, SZETO D P, PERRY A S, et al. Pulmonary large cell carcinoma lacking squamous differentiation is clinicopathologically indistinguishable from solid-subtype adenocarcinoma[J]. Arch Pathol Lab Med, 2014, 138(5):626-635.
[12] RUBIN E, FARBER J L. Neoplasia[M]//WINTERS R, MURPHY MB, MONROE K. Pathology. 3rd ed. Lippincottand Raven, 1999:172.
[13] ZHONG H, HANRAHAN C, POEL H, et al. Hypoxia-inducible factor 1α and 1β proteins share common signaling pathways in human prostate cancer cells[J]. Biochem Biophys Res Commun, 2001, 284(2):352-356.
[14] LEKAS A, LAZARIS A C, DELIVELIOTIS C, et al. The expression of hypoxia-inducible factor-1alpha (HIF-1αlpha) and angiogenesis markers in hyperplastic and malignant prostate tissue[J]. Anticancer Res, 2006, 26(4B):2989-2993.
[15] HUANG M, DU H X, ZHANG L, et al. The association of HIF-1α expression with clinicopathological significance in prostate cancer:a meta-analysis[J]. Cancer Manag Res, 2018, 10:2809-2816.
[16] NIE C Y, LV H F, BIE L Y, et al. Hypoxia-inducible factor 1-alpha expression correlates with response to neoadjuvant chemotherapy in women with breast cancer[J]. Medicine, 2018, 97(51):e13551.
[17] BHASKAR A, TIWARY B N. Hypoxia inducible factor-1 alpha and multiple myeloma[J]. Int J Adv Res, 2016, 4(1):706-715.
[18] KUMAR V, GABRILOVICH D I. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment[J]. Immunology, 2014, 143(4):512-519.
[19] 白玉勤, 吴宝, 张龙, 等. 非小细胞肺癌移植瘤侵袭组织中血清蛋白的分布[J]. 癌变·畸变·突变, 2018, 30(2):132-135, 139.
[20] 王徽, 白玉勤. 肺腺癌移植瘤裸鼠模型侵袭组织中酪氨酸蛋白激酶受体A7、表皮生长因子受体和Ki67蛋白表达及意义[J]. 陕西医学杂志, 2021, 50(9):1060-1063.
[21] GAYED B A, O'MALLEY K J, PILCH J, et al. Digoxin inhibits blood vessel density and HIF-1α expression in castration-resistant C4-2 xenograft prostate tumors[J]. Clin Transl Sci, 2012, 5(1):39-42.
[22] SHI L Y, TERADA N, SAITOH Y, et al. Immunohistochemical distribution of serum proteins in living mouse heart with In vivo cryotechnique[J]. Acta Histochem Cytochem, 2011, 44(2):61-72.

大细胞肺癌移植瘤组织中HIF-1α、VEGF、Ki67、血清蛋白的表达及其与功能性血管数目的关系

Expression of HIF-1α, VEGF, Ki67 and serum proteins in large-cell lung cancer cell line xenografts and their relationship with numbers of functional blood vessels

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