Skip to main content
Top
Published in: Tumor Biology 6/2015

01-06-2015 | Research Article

Interpretation of immunohistochemistry data of tumor should consider microenvironmental factors

Authors: Huan Bian, Shuai Zhang, Huanhuan Wu, Yixiang Wang

Published in: Tumor Biology | Issue 6/2015

Login to get access

Abstract

The influence of tumor surrounding microenvironment is often neglected when immunohistochemistry is performed to investigate tumor properties and search biomarkers of cancer. This study was designed to evaluate whether the influence of tumor microenvironment on biological features of tumor cells should be taken into account for interpretation of the immunohistochemistry data of tumor specimens. In this study, we showed an example by using three tumor cell lines (HeLa, WSU-HN6, and Tca83) to establish tumor-caused bone destruction models in nude mice and then to investigate the influence of bone marrow microenvironment (BMM) on biological features of tumor cells. Immunohistochemistry results showed that, compared with tumor cells located outside of BMM, tumor cells located inside of BMM presented huge differences in the expression of inflammation-related proteins including tumor necrosis factor-α (TNF-α), TNF receptor-associated factor protein-6 (TRAF-6), phosphorylated-NF-κB p65 (p-p65), interleukin (IL)-6 and IL-11, matrix metalloproteinases including MMP-1, MMP-2, MMP-9, and MMP-13; and osteogenesis-related proteins including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), and osteocalcin (OCN) in all the models. However, when we compared the cell line pair derived from different sites (outside and inside of BMM, respectively) of the same HeLa tumor sample by real-time PCR, Western blot, and immunocytochemistry, the differences aforementioned in tumor tissues were not found. In addition, we verified that normal human bone marrow could not cause the above changes detected in vivo. Our results suggested that tumor-modified microenvironment could give the new biological features of the invaded tumor cells. Therefore, we should consider the influence of the surrounding microenvironment on tumor cells when we analyze tumor properties using immunohistochemistry.
Literature
1.
go back to reference Ordonez-Moran P, Huelsken J. Complex metastatic niches: already a target for therapy? Curr Opin Cell Biol. 2014;31C:29–38.CrossRef Ordonez-Moran P, Huelsken J. Complex metastatic niches: already a target for therapy? Curr Opin Cell Biol. 2014;31C:29–38.CrossRef
2.
go back to reference Erin N, Kale S, Tanriover G, Koksoy S, Duymus O, Korcum AF. Differential characteristics of heart, liver, and brain metastatic subsets of murine breast carcinoma. Breast Cancer Res Treat. 2013;139:677–89.CrossRefPubMed Erin N, Kale S, Tanriover G, Koksoy S, Duymus O, Korcum AF. Differential characteristics of heart, liver, and brain metastatic subsets of murine breast carcinoma. Breast Cancer Res Treat. 2013;139:677–89.CrossRefPubMed
3.
go back to reference Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 2014;40:558–66.CrossRefPubMed Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 2014;40:558–66.CrossRefPubMed
4.
go back to reference Rahim F, Hajizamani S, Mortaz E, Ahmadzadeh A, Shahjahani M, Shahrabi S, et al. Molecular regulation of bone marrow metastasis in prostate and breast cancer. Bone Marrow Res. 2014;2014:405920.CrossRefPubMedPubMedCentral Rahim F, Hajizamani S, Mortaz E, Ahmadzadeh A, Shahjahani M, Shahrabi S, et al. Molecular regulation of bone marrow metastasis in prostate and breast cancer. Bone Marrow Res. 2014;2014:405920.CrossRefPubMedPubMedCentral
5.
go back to reference Rondeau G, Abedinpour P, Desai P, Baron VT, Borgstrom P, Welsh J. Effects of different tissue microenvironments on gene expression in breast cancer cells. PLoS One. 2014;9:e101160.CrossRefPubMedPubMedCentral Rondeau G, Abedinpour P, Desai P, Baron VT, Borgstrom P, Welsh J. Effects of different tissue microenvironments on gene expression in breast cancer cells. PLoS One. 2014;9:e101160.CrossRefPubMedPubMedCentral
6.
go back to reference Shi H, Hayes M, Kirana C, Miller R, Keating J, Macartney-Coxson D, et al. TUFM is a potential new prognostic indicator for colorectal carcinoma. Pathology. 2012;44:506–12.CrossRefPubMed Shi H, Hayes M, Kirana C, Miller R, Keating J, Macartney-Coxson D, et al. TUFM is a potential new prognostic indicator for colorectal carcinoma. Pathology. 2012;44:506–12.CrossRefPubMed
7.
go back to reference Pei J, Fu W, Yang L, Zhang Z, Liu Y. Oxidative stress is involved in the pathogenesis of Keshan disease (an endemic dilated cardiomyopathy) in China. Oxid Med Cell Longev. 2013;2013:474203.CrossRefPubMedPubMedCentral Pei J, Fu W, Yang L, Zhang Z, Liu Y. Oxidative stress is involved in the pathogenesis of Keshan disease (an endemic dilated cardiomyopathy) in China. Oxid Med Cell Longev. 2013;2013:474203.CrossRefPubMedPubMedCentral
8.
go back to reference Cong L, Pu CQ, Shi Q, Wang Q, Lu XH. Complement membrane attack complex is related with immune-mediated necrotizing myopathy. Int J Clin Exp Pathol. 2014;7:4143–9.PubMedPubMedCentral Cong L, Pu CQ, Shi Q, Wang Q, Lu XH. Complement membrane attack complex is related with immune-mediated necrotizing myopathy. Int J Clin Exp Pathol. 2014;7:4143–9.PubMedPubMedCentral
9.
go back to reference Labelle P, Reilly CM, Naydan DK, Labelle AL. Immunohistochemical characteristics of normal canine eyes. Vet Pathol. 2012;49:860–9.CrossRefPubMed Labelle P, Reilly CM, Naydan DK, Labelle AL. Immunohistochemical characteristics of normal canine eyes. Vet Pathol. 2012;49:860–9.CrossRefPubMed
10.
go back to reference Zhu LJ, Dai L, Zheng DH, Mo YQ, Ou-Yang X, Wei XN, et al. Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis. Arthritis Res Ther. 2012;14:R133.CrossRefPubMedPubMedCentral Zhu LJ, Dai L, Zheng DH, Mo YQ, Ou-Yang X, Wei XN, et al. Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis. Arthritis Res Ther. 2012;14:R133.CrossRefPubMedPubMedCentral
11.
go back to reference Furuta H, Osawa K, Shin M, Ishikawa A, Matsuo K, Khan M, et al. Selective inhibition of NF-kappaB suppresses bone invasion by oral squamous cell carcinoma in vivo. Int J Cancer. 2012;131:E625–35.CrossRefPubMed Furuta H, Osawa K, Shin M, Ishikawa A, Matsuo K, Khan M, et al. Selective inhibition of NF-kappaB suppresses bone invasion by oral squamous cell carcinoma in vivo. Int J Cancer. 2012;131:E625–35.CrossRefPubMed
12.
go back to reference Tang CH, Chuang JY, Fong YC, Maa MC, Way TD, Hung CH. Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells. Carcinogenesis. 2008;29:1483–92.CrossRefPubMedPubMedCentral Tang CH, Chuang JY, Fong YC, Maa MC, Way TD, Hung CH. Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells. Carcinogenesis. 2008;29:1483–92.CrossRefPubMedPubMedCentral
14.
go back to reference 14 Bodnar M, Szylberg L, Kazmierczak W, Marszalek A. Tumor progression driven by pathways activating matrix metalloproteinases and their inhibitors. J Oral Pathol Med 2014. 14 Bodnar M, Szylberg L, Kazmierczak W, Marszalek A. Tumor progression driven by pathways activating matrix metalloproteinases and their inhibitors. J Oral Pathol Med 2014.
15.
go back to reference Chakravarthi BV, Pathi SS, Goswami MT, Cieslik M, Zheng H, Nallasivam S, et al. The miR-124-Prolyl Hydroxylase P4HA1-MMP1 axis plays a critical role in prostate cancer progression. Oncotarget. 2014;5:6654–69.CrossRefPubMedPubMedCentral Chakravarthi BV, Pathi SS, Goswami MT, Cieslik M, Zheng H, Nallasivam S, et al. The miR-124-Prolyl Hydroxylase P4HA1-MMP1 axis plays a critical role in prostate cancer progression. Oncotarget. 2014;5:6654–69.CrossRefPubMedPubMedCentral
16.
go back to reference Balbin M, Pendas AM, Uria JA, Jimenez MG, Freije JP, Lopez-Otin C. Expression and regulation of collagenase-3 (MMP-13) in human malignant tumors. Apmis. 1999;107:45–53.CrossRefPubMed Balbin M, Pendas AM, Uria JA, Jimenez MG, Freije JP, Lopez-Otin C. Expression and regulation of collagenase-3 (MMP-13) in human malignant tumors. Apmis. 1999;107:45–53.CrossRefPubMed
17.
go back to reference McDonald L, Ferrari N, Terry A, Bell M, Mohammed ZM, Orange C, et al. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis Model Mech. 2014;7:525–34.CrossRefPubMedPubMedCentral McDonald L, Ferrari N, Terry A, Bell M, Mohammed ZM, Orange C, et al. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis Model Mech. 2014;7:525–34.CrossRefPubMedPubMedCentral
18.
go back to reference Baniwal SK, Khalid O, Gabet Y, Shah RR, Purcell DJ, Mav D, et al. Runx2 transcriptome of prostate cancer cells: Insights into invasiveness and bone metastasis. Mol Cancer. 2010;9:258.CrossRefPubMedPubMedCentral Baniwal SK, Khalid O, Gabet Y, Shah RR, Purcell DJ, Mav D, et al. Runx2 transcriptome of prostate cancer cells: Insights into invasiveness and bone metastasis. Mol Cancer. 2010;9:258.CrossRefPubMedPubMedCentral
19.
go back to reference Pratap J, Lian JB, Javed A, Barnes GL, van Wijnen AJ, Stein JL, et al. Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev. 2006;25:589–600.CrossRefPubMed Pratap J, Lian JB, Javed A, Barnes GL, van Wijnen AJ, Stein JL, et al. Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev. 2006;25:589–600.CrossRefPubMed
20.
go back to reference Zhang JH, Wang J, Tang J, Barnett B, Dickson J, Hahsimoto N, et al. Bone sialoprotein promotes bone metastasis of a non-bone-seeking clone of human breast cancer cells. Anticancer Res. 2004;24:1361–8.PubMed Zhang JH, Wang J, Tang J, Barnett B, Dickson J, Hahsimoto N, et al. Bone sialoprotein promotes bone metastasis of a non-bone-seeking clone of human breast cancer cells. Anticancer Res. 2004;24:1361–8.PubMed
21.
go back to reference Waltregny D, Bellahcene A, de Leval X, Florkin B, Weidle U, Castronovo V. Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. J Bone Miner Res. 2000;15:834–43.CrossRefPubMed Waltregny D, Bellahcene A, de Leval X, Florkin B, Weidle U, Castronovo V. Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. J Bone Miner Res. 2000;15:834–43.CrossRefPubMed
22.
go back to reference Ogbureke KU, Nikitakis NG, Warburton G, Ord RA, Sauk JJ, Waller JL, et al. Up-regulation of SIBLING proteins and correlation with cognate MMP expression in oral cancer. Oral Oncol. 2007;43:920–32.CrossRefPubMed Ogbureke KU, Nikitakis NG, Warburton G, Ord RA, Sauk JJ, Waller JL, et al. Up-regulation of SIBLING proteins and correlation with cognate MMP expression in oral cancer. Oral Oncol. 2007;43:920–32.CrossRefPubMed
23.
go back to reference Salem AM, Zohny SF, Abd EM, Hamdy R. Predictive value of osteocalcin and beta-CrossLaps in metastatic breast cancer. Clin Biochem. 2007;40:1201–8.CrossRefPubMed Salem AM, Zohny SF, Abd EM, Hamdy R. Predictive value of osteocalcin and beta-CrossLaps in metastatic breast cancer. Clin Biochem. 2007;40:1201–8.CrossRefPubMed
24.
go back to reference Gardner TA, Lee SJ, Lee SD, Li X, Shirakawa T, Kwon DD, et al. Differential expression of osteocalcin during the metastatic progression of prostate cancer. Oncol Rep. 2009;21:903–8.PubMed Gardner TA, Lee SJ, Lee SD, Li X, Shirakawa T, Kwon DD, et al. Differential expression of osteocalcin during the metastatic progression of prostate cancer. Oncol Rep. 2009;21:903–8.PubMed
25.
go back to reference Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LW. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase a signaling pathway. Cancer Res. 2005;65:2303–13.CrossRefPubMed Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LW. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase a signaling pathway. Cancer Res. 2005;65:2303–13.CrossRefPubMed
26.
go back to reference Moskaluk CA, Baras AS, Mancuso SA, Fan H, Davidson RJ, Dirks DC, et al. Development and characterization of xenograft model systems for adenoid cystic carcinoma. Lab Invest. 2011;91:1480–90.CrossRefPubMedPubMedCentral Moskaluk CA, Baras AS, Mancuso SA, Fan H, Davidson RJ, Dirks DC, et al. Development and characterization of xenograft model systems for adenoid cystic carcinoma. Lab Invest. 2011;91:1480–90.CrossRefPubMedPubMedCentral
27.
go back to reference Krishna M. Diagnosis of metastatic neoplasms: an immunohistochemical approach. Arch Pathol Lab Med. 2010;134:207–15.PubMed Krishna M. Diagnosis of metastatic neoplasms: an immunohistochemical approach. Arch Pathol Lab Med. 2010;134:207–15.PubMed
28.
go back to reference Pu Y, Wang L, Wu H, Feng Z, Wang Y, Guo C. High MMP-21 expression in metastatic lymph nodes predicts unfavorable overall survival for oral squamous cell carcinoma patients with lymphatic metastasis. Oncol Rep. 2014;31:2644–50.PubMed Pu Y, Wang L, Wu H, Feng Z, Wang Y, Guo C. High MMP-21 expression in metastatic lymph nodes predicts unfavorable overall survival for oral squamous cell carcinoma patients with lymphatic metastasis. Oncol Rep. 2014;31:2644–50.PubMed
29.
go back to reference Sakashita T, Homma A, Suzuki S, Hatakeyama H, Kano S, Mizumachi T, et al. Prognostic value of cyclin D1 expression in tumor-free surgical margins in head and neck squamous cell carcinomas. Acta Otolaryngol. 2013;133:984–91.CrossRefPubMed Sakashita T, Homma A, Suzuki S, Hatakeyama H, Kano S, Mizumachi T, et al. Prognostic value of cyclin D1 expression in tumor-free surgical margins in head and neck squamous cell carcinomas. Acta Otolaryngol. 2013;133:984–91.CrossRefPubMed
30.
go back to reference Liao CT, Wallace CG, Lee LY, Hsueh C, Lin CY, Fan KH, et al. Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area. Oral Oncol. 2014;50:721–31.CrossRefPubMed Liao CT, Wallace CG, Lee LY, Hsueh C, Lin CY, Fan KH, et al. Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area. Oral Oncol. 2014;50:721–31.CrossRefPubMed
31.
go back to reference Luo Y, Yu M, Grady WM. Field cancerization in the colon: a role for aberrant DNA methylation? Gastroenterol Rep (Oxf). 2014;2:16–20.CrossRef Luo Y, Yu M, Grady WM. Field cancerization in the colon: a role for aberrant DNA methylation? Gastroenterol Rep (Oxf). 2014;2:16–20.CrossRef
32.
33.
go back to reference 33 Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 2014. 33 Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 2014.
35.
go back to reference Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451–8. Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451–8.
37.
go back to reference Ji RC. Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. Cancer Lett. 2014;346:6–16.CrossRefPubMed Ji RC. Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. Cancer Lett. 2014;346:6–16.CrossRefPubMed
38.
go back to reference Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, et al. Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 2013;73:3235–47.CrossRefPubMedPubMedCentral Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, et al. Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 2013;73:3235–47.CrossRefPubMedPubMedCentral
39.
go back to reference Zeng W, Liu P, Pan W, Singh SR, Wei Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett 2014 Zeng W, Liu P, Pan W, Singh SR, Wei Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett 2014
40.
go back to reference Hasmim M, Messai Y, Noman MZ. Chouaib S [Tumor hypoxia: a key player in the regulation of stromal and anti-tumor responses]. Med Sci (Paris). 2014;30:422–8.CrossRef Hasmim M, Messai Y, Noman MZ. Chouaib S [Tumor hypoxia: a key player in the regulation of stromal and anti-tumor responses]. Med Sci (Paris). 2014;30:422–8.CrossRef
42.
go back to reference Ren Y, Hao P, Dutta B, Cheow ES, Sim KH, Gan CS, et al. Hypoxia modulates A431 cellular pathways association to tumor radioresistance and enhanced migration revealed by comprehensive proteomic and functional studies. Mol Cell Proteomics. 2013;12:485–98.CrossRefPubMed Ren Y, Hao P, Dutta B, Cheow ES, Sim KH, Gan CS, et al. Hypoxia modulates A431 cellular pathways association to tumor radioresistance and enhanced migration revealed by comprehensive proteomic and functional studies. Mol Cell Proteomics. 2013;12:485–98.CrossRefPubMed
Metadata
Title
Interpretation of immunohistochemistry data of tumor should consider microenvironmental factors
Authors
Huan Bian
Shuai Zhang
Huanhuan Wu
Yixiang Wang
Publication date
01-06-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3088-9

Other articles of this Issue 6/2015

Tumor Biology 6/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine