Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

GRP78 is Overexpressed in Non-small Cell Lung Cancer Tissues and is Associated with High VEGF Expression in Squamous Cell Carcinoma: A Pilot Study

Author(s): Maha Al-Keilani*, Mohammad A. Alqudah, Basima Almomani, Moath M. Alrjoub, Batool A. Shhabat and Karem Alzoubi

Volume 23, Issue 10, 2023

Published on: 06 June, 2023

Page: [805 - 816] Pages: 12

DOI: 10.2174/1568009623666230418111020

Price: $65

Abstract

Background: Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various cancers and has been suggested as a proangiogenic factor.

Purpose: This study aimed to investigate the expression levels of GRP78 and to test for significant relationships with the angiogenic markers, VEGF, and CD31.

Methods: In this study, paraffin-embedded NSCLC tissue samples (71 adenocarcinomas and 23 squamous cell carcinoma) were retrospectively collected from 94 patients with NSCLC. The expressions of VEGF, CD31, and GRP78 were determined by immunohistochemistry.

Results: High expression levels of VEGF and GRP78 were observed in 65 and 74 cases, respectively. Thirty-six patients expressed high CD31 levels. Adenocarcinomas expressed higher levels of the three proteins than squamous cell carcinomas (p-value < 0.05). Moreover, a statistically significant association was found between the expression levels of VEGF and CD31 (p-value = 0.001) and VEGF and GRP78 (p-value=0.028).

Conclusion: GRP78 overexpression was revealed in most of the investigated samples. The positive association between VEGF and GRP78 may indicate the proangiogenic role of GRP78 in lung cancer. Moreover, the positive association between VEGF and CD31 expression levels suggests that VEGF may cooperate with CD31 to promote angiogenesis in NSCLC.

Keywords: NSCLC, angiogenesis, GRP78, CD31, VEGF, cancer.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[2]
Duma, N.; Santana-Davila, R.; Molina, J.R. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin. Proc., 2019, 1623-1640.
[http://dx.doi.org/10.1016/j.mayocp.2019.01.013] [PMID: 31378236]
[3]
Zhan, P.; Wang, J.; Lv, X.; Wang, Q.; Qiu, L.; Lin, X.; Yu, L.; Song, Y. Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: A systematic review with meta-analysis. J. Thorac. Oncol., 2009, 4(9), 1094-1103.
[http://dx.doi.org/10.1097/JTO.0b013e3181a97e31] [PMID: 19687765]
[4]
Kim, M.S.; Park, T.I.; Lee, Y.M.; Jo, Y.M.; Kim, S. Expression of Id-1 and VEGF in non-small cell lung cancer. Int. J. Clin. Exp. Pathol., 2013, 6(10), 2102-2111.
[PMID: 24133588]
[5]
Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.; Dvorak, H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 1983, 219(4587), 983-985.
[http://dx.doi.org/10.1126/science.6823562] [PMID: 6823562]
[6]
Cébe-Suarez, S.; Zehnder-Fjällman, A.; Ballmer-Hofer, K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell. Mol. Life Sci., 2006, 63(5), 601-615.
[http://dx.doi.org/10.1007/s00018-005-5426-3] [PMID: 16465447]
[7]
Ferrara, N.; Hillan, K.J.; Gerber, H.P.; Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov., 2004, 3(5), 391-400.
[http://dx.doi.org/10.1038/nrd1381] [PMID: 15136787]
[8]
Mineo, T.C.; Ambrogi, V.; Baldi, A.; Rabitti, C.; Bollero, P.; Vincenzi, B.; Tonini, G. Prognostic impact of VEGF, CD31, CD34, and CD105 expression and tumour vessel invasion after radical surgery for IB-IIA non-small cell lung cancer. J. Clin. Pathol., 2004, 57(6), 591-597.
[http://dx.doi.org/10.1136/jcp.2003.013508] [PMID: 15166262]
[9]
Zhang, Y.Y.; Kong, L.Q.; Zhu, X.D.; Cai, H.; Wang, C.H.; Shi, W.K.; Cao, M.Q.; Li, X.L.; Li, K.S.; Zhang, S.Z.; Chai, Z.T.; Ao, J.Y.; Ye, B.G.; Sun, H.C. CD31 regulates metastasis by inducing epithelial–mesenchymal transition in hepatocellular carcinoma via the ITGB1-FAK-Akt signaling pathway. Cancer Lett., 2018, 429, 29-40.
[http://dx.doi.org/10.1016/j.canlet.2018.05.004] [PMID: 29746931]
[10]
Usuda, K.; Iwai, S.; Funasaki, A.; Sekimura, A.; Motono, N.; Ueda, Y.; Shimazaki, M.; Uramoto, H. Expression and prognostic impact of VEGF, CD31 and αSMA in resected primary lung cancers. Anticancer Res., 2018, 38(7), 4057-4063.
[http://dx.doi.org/10.21873/anticanres.12695] [PMID: 29970531]
[11]
Sandler, A.; Gray, R.; Perry, M.C.; Brahmer, J.; Schiller, J.H.; Dowlati, A.; Lilenbaum, R.; Johnson, D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med., 2006, 355(24), 2542-2550.
[http://dx.doi.org/10.1056/NEJMoa061884] [PMID: 17167137]
[12]
Alshangiti, A.; Chandhoke, G.; Ellis, P.M. Antiangiogenic therapies in non-small-cell lung cancer. Curr. Oncol., 2018, 25(11)(Suppl. 1), 45-58.
[http://dx.doi.org/10.3747/co.25.3747] [PMID: 29910647]
[13]
Xia, S.; Duan, W.; Liu, W.; Zhang, X.; Wang, Q. GRP78 in lung cancer. J. Transl. Med., 2021, 19(1), 118.
[http://dx.doi.org/10.1186/s12967-021-02786-6] [PMID: 33743739]
[14]
Dong, D.; Stapleton, C.; Luo, B.; Xiong, S.; Ye, W.; Zhang, Y.; Jhaveri, N.; Zhu, G.; Ye, R.; Liu, Z.; Bruhn, K.W.; Craft, N.; Groshen, S.; Hofman, F.M.; Lee, A.S. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res., 2011, 71(8), 2848-2857.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3151] [PMID: 21467168]
[15]
Dong, D.; Ni, M.; Li, J.; Xiong, S.; Ye, W.; Virrey, J.J.; Mao, C.; Ye, R.; Wang, M.; Pen, L.; Dubeau, L.; Groshen, S.; Hofman, F.M.; Lee, A.S. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res., 2008, 68(2), 498-505.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-2950] [PMID: 18199545]
[16]
Ghosh, R.; Lipson, K.L.; Sargent, K.E.; Mercurio, A.M.; Hunt, J.S.; Ron, D.; Urano, F. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One, 2010, 5(3), e9575.
[http://dx.doi.org/10.1371/journal.pone.0009575] [PMID: 20221394]
[17]
Li, Z.; Li, Z. Glucose regulated protein 78: A critical link between tumor microenvironment and cancer hallmarks. Biochim. Biophys. Acta, 2012, 1826(1), 13-22.
[PMID: 22426159]
[18]
Katanasaka, Y.; Ishii, T.; Asai, T.; Naitou, H.; Maeda, N.; Koizumi, F.; Miyagawa, S.; Ohashi, N.; Oku, N. Cancer antineovascular therapy with liposome drug delivery systems targeted to BiP/GRP78. Int. J. Cancer, 2010, 127(11), 2685-2698.
[http://dx.doi.org/10.1002/ijc.25276] [PMID: 20178102]
[19]
Ren, P.; Chen, C.; Yue, J.; Zhang, J.; Yu, Z. High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma. OncoTargets Ther., 2017, 10, 617-625.
[http://dx.doi.org/10.2147/OTT.S123494] [PMID: 28228658]
[20]
Fluss, R.; Faraggi, D.; Reiser, B. Estimation of the Youden Index and its associated cutoff point. Biom. J., 2005, 47(4), 458-472.
[http://dx.doi.org/10.1002/bimj.200410135] [PMID: 16161804]
[21]
Jia, M.; Jiang, P.; Hu, J.; Huang, Z.; Deng, Y.; Hu, Z. The optimal cut-off value of immunohistochemical parameter P53 for predicting recurrence of endometrial cancer. Int. J. Gynecol. Obstet., 2020, 153(2), 344-350.
[22]
Bonnesen, B.; Pappot, H.; Holmstav, J.; Skov, B.G. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: Relation to prognosis. Lung Cancer, 2009, 66(3), 314-318.
[http://dx.doi.org/10.1016/j.lungcan.2009.02.013] [PMID: 19324448]
[23]
Emmert, A.; Didilis, V.; Böhler, A.; Markus, J.; Füzesi, L.; Waldmann-Beushausen, R.; Bougioukas, I.; Schöndube, F.; Danner, B. Prognostic significance of influence of CD-31 and PDEF expression in patients with non-small-lung cancer. The Thoracic and Cardiovas. Surg., 2014, 62(SO1)
[http://dx.doi.org/10.1055/s-0034-1367089]
[24]
Emmert, A.; Oellerich, A.; Füzesi, L.; Waldmann-Beushausen, R.; Bohnenberger, H.; Schöndube, F.A.; Danner, B.C. Prognostic significance of CD31 expression in patients with non-small-cell-lung cancer. Adv. Lung Cancer , 2016, 5(3), 21-29.
[http://dx.doi.org/10.4236/alc.2016.53003]
[25]
Bačić I.; Karlo, R.; Zadro, A.Š.; Zadro, Z.; Skitarelić N.; Antabak, A. Tumor angiogenesis as an important prognostic factor in advanced non-small cell lung cancer (Stage IIIA). Oncol. Lett., 2018, 15(2), 2335-2339.
[PMID: 29434942]
[26]
Kwon, D.; Koh, J.; Kim, S.; Go, H.; Min, H.S.; Kim, Y.A.; Kim, D.K.; Jeon, Y.K.; Chung, D.H. Overexpression of endoplasmic reticulum stress-related proteins, XBP1s and GRP78, predicts poor prognosis in pulmonary adenocarcinoma. Lung Cancer, 2018, 122, 131-137.
[http://dx.doi.org/10.1016/j.lungcan.2018.06.005] [PMID: 30032821]
[27]
Uramoto, H.; Sugio, K.; Oyama, T.; Nakata, S.; Ono, K.; Yoshimastu, T.; Morita, M.; Yasumoto, K. Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance. Lung Cancer, 2005, 49(1), 55-62.
[http://dx.doi.org/10.1016/j.lungcan.2004.12.011] [PMID: 15949590]
[28]
Wang, Q.; He, Z.; Zhang, J.; Wang, Y.; Wang, T.; Tong, S.; Wang, L.; Wang, S.; Chen, Y. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect. Prev., 2005, 29(6), 544-551.
[http://dx.doi.org/10.1016/j.cdp.2005.09.010] [PMID: 16297569]
[29]
Sun, Q.; Hua, J.; Wang, Q.; Xu, W.; Zhang, J.; Zhang, J.; Kang, J.; Li, M. Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer. Mol. Biol. Rep., 2012, 39(6), 6753-6761.
[http://dx.doi.org/10.1007/s11033-012-1500-8] [PMID: 22297694]
[30]
Wu, H.M.; Jiang, Z.F.; Fan, X.Y.; Wang, T. Ke-Xu; Yan, X.B.; Ma, Y.; Xiao, W.H.; Liu, R.Y. Reversed expression of GRIM-1 and GRP78 in human non–small cell lung cancer. Hum. Pathol., 2014, 45(9), 1936-1943.
[http://dx.doi.org/10.1016/j.humpath.2014.04.023] [PMID: 25081541]
[31]
Rajesh, L.; Joshi, K.; Bhalla, V.; Dey, P.; Radotra, B.D.; Nijhawan, R. Correlation between VEGF expression and angiogenesis in breast carcinoma. Anal. Quant. Cytol. Histol., 2004, 26(2), 105-108.
[PMID: 15131898]
[32]
Kapoor, P.; Deshmukh, R.; Kulkarni, V.; Kukreja, I. VEGF and CD 34: A correlation between tumor angiogenesis and microvessel density-an immunohistochemical study. J. Oral Maxillofac. Pathol., 2013, 17(3), 367-373.
[http://dx.doi.org/10.4103/0973-029X.125200] [PMID: 24574654]
[33]
Hutajulu, S.H.; Paramita, D.K.; Santoso, J.; Sani, M.I.A.; Amalia, A.; Wulandari, G.; Ghozali, A.; Kurnianda, J. Correlation between vascular endothelial growth factor-A expression and tumor location and invasion in patients with colorectal cancer. J. Gastrointest. Oncol., 2018, 9(6), 1099-1108.
[http://dx.doi.org/10.21037/jgo.2018.07.01] [PMID: 30603129]
[34]
Ni, M.; Zhang, Y.; Lee, A.S. Beyond the endoplasmic reticulum: Atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem. J., 2011, 434(2), 181-188.
[http://dx.doi.org/10.1042/BJ20101569] [PMID: 21309747]
[35]
Shin, B.K.; Wang, H.; Yim, A.M.; Le Naour, F.; Brichory, F.; Jang, J.H.; Zhao, R.; Puravs, E.; Tra, J.; Michael, C.W. Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J. Biol. Chem., 2003, 278(9), 7607-7616.
[http://dx.doi.org/10.1074/jbc.M210455200]
[36]
Vandewynckel, Y-P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S.; Heindryckx, F.; Van Vlierberghe, H. The paradox of the unfolded protein response in cancer. Anticancer Res., 2013, 33(11), 4683-4694.
[PMID: 24222102]
[37]
Binet, F.; Sapieha, P. ER stress and angiogenesis. Cell Metab., 2015, 22(4), 560-575.
[http://dx.doi.org/10.1016/j.cmet.2015.07.010] [PMID: 26278049]
[38]
Farshbaf, M.; Khosroushahi, A.Y.; Mojarad-Jabali, S.; Zarebkohan, A.; Valizadeh, H.; Walker, P.R. Cell surface GRP78: An emerging imaging marker and therapeutic target for cancer. J. Cont. Rel., 2020, 328, 932-341.
[39]
Gonzalez–Gronow, M.; Selim, M.A.; Papalas, J.; Pizzo, S.V. GRP78: A multifunctional receptor on the cell surface. Antioxid. Redox Signal., 2009, 11(9), 2299-2306.
[40]
Raiter, A.; Weiss, C.; Bechor, Z.; Ben-Dor, I.; Battler, A.; Kaplan, B.; Hardy, B. Activation of GRP78 on endothelial cell membranes by an ADAM15-derived peptide induces angiogenesis. J. Vasc. Res., 2010, 47(5), 399-411.
[http://dx.doi.org/10.1159/000281580]
[41]
Birukova, A.A.; Singleton, P.A.; Gawlak, G.; Tian, X.; Mirzapoiazova, T.; Mambetsariev, B.; Dubrovskyi, O.; Oskolkova, O.V.; Bochkov, V.N.; Birukov, K.G. GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids. Mol. Biol. Cell, 2014, 25(13), 2006-2016.
[42]
Zhang, J.; Jiang, Y.; Jia, Z.; Li, Q.; Gong, W.; Wang, L.; Wei, D.; Yao, J.; Fang, S.; Xie, K. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin. Exp. Metastasis, 2006, 23(7-8), 401-410.
[43]
Zheng, H-c.; Takahashi, H.; Li, X-h.; Hara, T.; Masuda, S.; Guan, Y-f.; Takano, Y.J. Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum. Pathol., 2008, 39(7), 1042-1049.
[http://dx.doi.org/10.1016/j.humpath.2007.11.009]
[44]
Lee, H.Y.; Jung, J-H.; Cho, H-M.; Kim, S.H.; Lee, K-M.; Kim, H-J.; Lee, J.H.; Shim, B.Y. GRP78 protein expression as prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer. Cancer Res. Treat., 2015, 47(4), 804-812.
[45]
Niu, Z.; Wang, M.; Zhou, L.; Yao, L.; Liao, Q.; Zhao, Y. Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer. Sci. Rep., 2015, 5, 16067.
[http://dx.doi.org/10.1038/srep16067]
[46]
Wang, M.; Wey, S.; Zhang, Y.; Ye, R.; Lee, A.S. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid. Redox Signal., 2009, 11(9), 2307-2316.
[47]
Kuo, L.J.; Hung, C.S.; Chen, W.Y.; Chang, Y.J.; Wei, P.L. Glucose-regulated protein 78 silencing down-regulates vascular endothelial growth factor/vascular endothelial growth factor receptor 2 pathway to suppress human colon cancer tumor growth. J. Surg. Res., 2013, 185(1), 264-272.
[48]
Visioli, F.; Wang, Y.; Alam, G.N.; Ning, Y.; Rados, P.V.; Nör, J.E.; Polverini, P.J. Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress. PLoS One, 2014, 9(6), e101053.
[http://dx.doi.org/10.1371/journal.pone.0101053] [PMID: 24964091]
[49]
Liu, Y.; Cox, S.R.; Morita, T.; Kourembanas, S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells: Identification. Circ. Res., 1995, 77(3), 638-643.
[50]
Weigand, M.; Hantel, P.; Kreienberg, R.; Waltenberger, J.J.A. Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis, 2005, 8(3), 197-204.
[51]
Su, J.C.; Mar, A.C.; Wu, S.H.; Tai, W.T.; Chu, P.Y.; Wu, C.Y.; Tseng, L.M.; Lee, T.C.; Chen, K.F.; Liu, C.Y. Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis. Sci. Rep., 2016, 6, 28888.
[http://dx.doi.org/10.1038/srep28888]
[52]
Qiao, Y.; Dsouza, C.; Matthews, A.A.; Jin, Y.; He, W.; Bao, J.; Jiang, F.; Chandna, R.; Ge, R.; Fu, L. Discovery of small molecules targeting GRP78 for antiangiogenic and anticancer therapy. Eur. J. Med. Chem., 2020, 193, 112228.
[http://dx.doi.org/10.1016/j.ejmech.2020.112228] [PMID: 32199134]
[53]
Chen, M.; Zhang, Y.; Yu, V.C.; Chong, Y-S.; Yoshioka, T.; Ge, R. Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction. Cell Death Differ., 2014, 21(5), 797-810.
[http://dx.doi.org/10.1038/cdd.2014.3] [PMID: 24464222]
[54]
Liu, R.; Li, X.; Gao, W.; Zhou, Y.; Wey, S.; Mitra, S.K.; Krasnoperov, V.; Dong, D.; Liu, S.; Li, D.; Zhu, G.; Louie, S.; Conti, P.S.; Li, Z.; Lee, A.S.; Gill, P.S. Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth, and metastasis. Clin. Cancer Res., 2013, 19(24), 6802-6811.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1106] [PMID: 24048331]
[55]
Imai, H.; Kaira, K.; Yazawa, T.; Shimizu, A.; Nagashima, T.; Ohtaki, Y.; Obayashi, K.; Asao, T.; Oyama, T.; Shimizu, K. Endoplasmic reticulum stress sensor GRP78/BiP expression in lung adenocarcinoma: Correlations and prognostic significance. Int. J. Clin. Exp. Pathol., 2017, 10(3), 3315-3326.
[56]
El-Gohary, Y.M.; Silverman, J.F.; Olson, P.R.; Liu, Y.L.; Cohen, J.K.; Miller, R.; Saad, R.S. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am. J. Clin. Pathol., 2007, 127(4), 572-579.
[http://dx.doi.org/10.1309/X6NXYE57DLUE2NQ8] [PMID: 17369132]
[57]
Poncelet, C.; Fauvet, R.; Feldmann, G.; Walker, F.; Madelenat, P.; Darai, E. Prognostic value of von Willebrand factor, CD34, CD31, and vascular endothelial growth factor expression in women with uterine leiomyosarcomas. J. Surg. Oncol., 2004, 86(2), 84-90.
[http://dx.doi.org/10.1002/jso.20055] [PMID: 15112250]
[58]
Biswas, S.; Charlesworth, P.J.S.; Turner, G.D.H.; Leek, R.; Thamboo, P.T.; Campo, L.; Turley, H.; Dildey, P.; Protheroe, A.; Cranston, D.; Gatter, K.C.; Pezzella, F.; Harris, A.L. CD31 angiogenesis and combined expression of HIF-1α and HIF-2α are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFα transcriptional products are not: Implications for antiangiogenic trials and HIFα biomarker studies in primary CC-RCC. Carcinogenesis, 2012, 33(9), 1717-1725.
[http://dx.doi.org/10.1093/carcin/bgs222] [PMID: 22777959]
[59]
Tokumo, K.; Kodama, J.; Seki, N.; Nakanishi, Y.; Miyagi, Y.; Kamimura, S.; Yoshinouchi, M.; Okuda, H.; Kudo, T. Different angiogenic pathways in human cervical cancers. Gynecol. Oncol., 1998, 68(1), 38-44.
[http://dx.doi.org/10.1006/gyno.1997.4876] [PMID: 9454658]
[60]
Mattern, J.; Koomägi, R.; Volm, M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br. J. Cancer, 1996, 73(7), 931-934.
[http://dx.doi.org/10.1038/bjc.1996.166] [PMID: 8611409]
[61]
Tonino, P.; Abreu, C. Microvessel density is associated with VEGF and α-SMA expression in different regions of human gastrointestinal carcinomas. Cancers, 2011, 3(3), 3405-3418.
[http://dx.doi.org/10.3390/cancers3033405] [PMID: 24212960]

Rights & Permissions Print Cite
Article Metrics
30
3
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy