Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Correlations between immune response and vascularization qRT-PCR gene expression clusters in squamous cervical cancer

Authors: Simone Punt, Jeanine J Houwing-Duistermaat, Iris A Schulkens, Victor L Thijssen, Elisabeth M Osse, Cornelis D de Kroon, Arjan W Griffioen, Gert Jan Fleuren, Arko Gorter, Ekaterina S Jordanova

Published in: Molecular Cancer | Issue 1/2015

Login to get access

Abstract

Background

The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma.

Methods

The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level.

Results

We identified four immune response clusters: ‘T cells’ (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), ‘Macrophages’ (CD4/CD14/CD163), ‘Th2’ (IL4/IL5/IL13/IL12) and ‘Inflammation’ (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: ‘Angiogenesis’ (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and ‘Vessel maturation’ (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The ‘T cells’ module was correlated with all modules except for ‘Inflammation’, while ‘Inflammation’ was most significantly correlated with ‘Angiogenesis’ (p < 0.001). High expression of the ‘T cells’ cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010).

Conclusions

‘Inflammation’ marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.
Literature
1.
2.
3.
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.CrossRefPubMed
4.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.CrossRefPubMed
5.
Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, der Meer DM B-v, Vloon AP, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009;361:1838–47.CrossRefPubMed
6.
Jordanova ES, Gorter A, Ayachi O, Prins F, Durrant LG, Kenter GG, et al. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin Cancer Res. 2008;14:2028–35.CrossRefPubMed
7.
Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NH, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12:465–72.CrossRefPubMed
8.
Cunha LL, Morari EC, Guihen AC, Razolli D, Gerhard R, Nonogaki S, et al. Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma. Clin Endocrinol (Oxf). 2012;77:918–25.CrossRef
9.
Feng Q, Wei H, Morihara J, Stern J, Yu M, Kiviat N, et al. Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma. Gynecol Oncol. 2012;127:412–9.CrossRefPubMedCentralPubMed
10.
11.
De Vos van Steenwijk PJ, Ramwadhdoebe TH, Goedemans R, Doorduijn EM, van Ham JJ, Gorter A, et al. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. Int J Cancer. 2013;133:2884–94.PubMed
12.
Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18:349–55.CrossRefPubMed
13.
Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7:e50946.CrossRefPubMedCentralPubMed
14.
Donskov F. Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol. 2013;23:200–7.CrossRefPubMed
15.
Griffioen AW, Damen CA, Blijham GH, Groenewegen G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood. 1996;88:667–73.PubMed
16.
17.
Tjalma W, Van ME, Weyler J, Dirix L, Van DA, Goovaerts G, et al. Quantification and prognostic relevance of angiogenic parameters in invasive cervical cancer. Br J Cancer. 1998;78:170–4.CrossRefPubMedCentralPubMed
18.
Fuller T, Langfelder P, Presson A, Horvath S. Review of Weighted Gene Coexpression Network Analysis. In: Horng-Shing Lu H et al., editors. Handbook of Statistical Bioinformatics. Berlin Heidelberg: Springer-Verlag; 2011. p. 369–88.CrossRef
19.
20.
Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW, et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res. 2007;67:354–61.CrossRefPubMed
21.
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–43.CrossRefPubMedCentralPubMed
22.
Wang W, Hodkinson P, McLaren F, MacKinnon A, Wallace W, Howie S, et al. Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate. Int J Cancer. 2012;131:E928–37.CrossRefPubMed
23.
24.
Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14:e218–28.CrossRefPubMed
25.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51.CrossRefPubMed
26.
Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517–27.CrossRefPubMed
27.
Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28:2940–7.CrossRefPubMed
28.
Pahne-Zeppenfeld J, Schroer N, Walch-Ruckheim B, Oldak M, Gorter A, Hegde S, et al. Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9 expressing dendritic cells. Int J Cancer. 2013;134:2061–73.CrossRef
29.
Heusinkveld M, Heusinkveld M, DeVosvanSteenwijk PJ, Goedemans R, Ramwadhdoebe TH, Gorter A, et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol. 2011;187:1157–65.CrossRefPubMed
30.
Punt S, Fleuren GJ, Kritikou E, Lubberts E, Trimbos JB, Jordanova ES, et al. Angels and demons: Th17 cells represent a beneficial response, while neutrophil IL-17 is associated with poor prognosis in squamous cervical cancer. Oncoimmunology. 2015;4:e984539.CrossRef
31.
Cowland JB, Borregaard N. The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J Leukoc Biol. 1999;66:989–95.PubMed
32.
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–71.CrossRefPubMed
33.
Cavallaro U, Dejana E. Adhesion molecule signalling: not always a sticky business. Nat Rev Mol Cell Biol. 2011;12:189–97.CrossRefPubMed
34.
Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 1996;56:1111–7.PubMed
35.
Zijlmans HJ, Fleuren GJ, Hazelbag S, Sier CF, Dreef EJ, Kenter GG, et al. Expression of endoglin (CD105) in cervical cancer. Br J Cancer. 2009;100:1617–26.CrossRefPubMedCentralPubMed
36.
Yuan A, Yu CJ, Chen WJ, Lin FY, Kuo SH, Luh KT, et al. Correlation of total VEGF mRNA and protein expression with histologic type, tumor angiogenesis, patient survival and timing of relapse in non-small-cell lung cancer. Int J Cancer. 2000;89:475–83.CrossRefPubMed
37.
Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7.CrossRefPubMed
38.
Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19:1114–23.CrossRefPubMed
39.
Sauter ER, Nesbit M, Watson JC, Klein-Szanto A, Litwin S, Herlyn M. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 1999;5:775–82.PubMed
40.
Schmitt M, Horbach A, Kubitz R, Frilling A, Haussinger D. Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. J Hepatol. 2004;41:274–83.CrossRefPubMed
41.
Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13:134.CrossRefPubMedCentralPubMed
42.
de Boer MA, Jordanova ES, Kenter GG, Peters AA, Corver WE, Trimbos JB, et al. High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients. Clin Cancer Res. 2007;13:132–8.CrossRefPubMed
43.
Thijssen VL, Brandwijk RJ, Dings RP, Griffioen AW. Angiogenesis gene expression profiling in xenograft models to study cellular interactions. Exp Cell Res. 2004;299:286–93.CrossRefPubMed
44.
Thijssen VL, Hulsmans S, Griffioen AW. The galectin profile of the endothelium: altered expression and localization in activated and tumor endothelial cells. Am J Pathol. 2008;172:545–53.CrossRefPubMedCentralPubMed
45.
Metadata
Title
Correlations between immune response and vascularization qRT-PCR gene expression clusters in squamous cervical cancer
Authors
Simone Punt
Jeanine J Houwing-Duistermaat
Iris A Schulkens
Victor L Thijssen
Elisabeth M Osse
Cornelis D de Kroon
Arjan W Griffioen
Gert Jan Fleuren
Arko Gorter
Ekaterina S Jordanova
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0350-0

Other articles of this Issue 1/2015

Molecular Cancer 1/2015 Go to the issue

Review

p66Shc as a switch in bringing about contrasting responses in cell growth: implications on cell proliferation and apoptosis

Research

Invasion of ovarian cancer cells is induced byPITX2-mediated activation of TGF-β and Activin-A

Research

Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors

Research

Retinoic acid-induced CHD5 upregulation and neuronal differentiation of neuroblastoma

Research

BMP4 depletion by miR-200 inhibits tumorigenesis and metastasis of lung adenocarcinoma cells

Research

AduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-κB mediated uPAR activation
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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
Image Credits