Skip to content


  • Research article
  • Open Access
  • Open Peer Review

A possible association of baseline serum IL-17A concentrations with progression-free survival of metastatic colorectal cancer patients treated with a bevacizumab-based regimen

  • 1,
  • 1,
  • 1,
  • 1,
  • 1, 2,
  • 4,
  • 5,
  • 1, 3,
  • 1, 3,
  • 1, 2 and
  • 1Email author
Contributed equally
BMC Cancer201717:220

  • Received: 5 October 2016
  • Accepted: 21 March 2017
  • Published:
Open Peer Review reports



Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy.


Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models.


High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival.


In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association.

Trial registration

NCT00489697. June 20, 2007.


  • Bevacizumab
  • Vascular endothelial growth factor
  • Th17-related cytokines
  • IL-17 polymorphisms
  • Metastatic colorectal cancer
  • Survival analysis: score


Colorectal cancer is a major public health issue due to its frequency and its severity [1]. It is a major cause of death in the world [2]. The therapeutic arsenal against metastatic colorectal cancer was strengthened by the addition of monoclonal antibodies to chemotherapy. Bevacizumab (Avastin® [3]) is a humanized IgG1 that binds to the vascular endothelial growth factor (VEGF), a well known pro-angiogenic growth factor [4] which favors tumors and metastasis. Bevacizumab is widely used in the treatment of patients with advanced colorectal cancer [5].

Though bevacizumab prolongs survival of patients with metastatic colorectal cancer, some individuals do not respond to treatment [6] and it is difficult to identify at an early stage who will benefit or not from this biopharmaceutical. Our team has recently showed that antigenic burden influences bevacizumab pharmacokinetics in patients with metastatic colorectal cancer [7]. In this study, bevacizumab pharmacokinetics was also influenced by baseline VEGF and CarcinoEmbryonic Antigen (CEA) concentrations and by the number of extra-hepatic metastases. These differences in bevacizumab pharmacokinetics between patients are relevant since bevacizumab concentrations are associated with progression-free (PFS) and overall survival (OS) of patients [7]. There is however a need to identify other early biomarkers that could be predictive of response to anti-VEGF biopharmaceuticals.

Several studies suggest that interleukin-17 (IL-17A or IL-17 or cytotoxic T-lymphocyte-associated protein 8) plays a major role in colorectal cancer progression [812] and in the resistance to anti-VEGF treatment in murine models [13] or chemotherapy [14, 15]. IL-17A is a pro-inflammatory cytokine that contributes to the pathogenesis of inflammatory and auto-immune diseases [16, 17] but that also seems to be highly associated with cancer progression [18, 19]. A major source of IL-17 is a lineage of T cells known as CD4+ T helper 17 cells (Th17 cells) which differ from the Th1 and Th2 subsets [20]. IL-17 is also secreted by other cell types of the immune system including lymphocytes NKT-17, γδT-17, CD8+ Tc17, polymorphonuclear neutrophils and intestinal Paneth cells [21, 22]. IL-17 homodimers signal through the complex formed by heterodimer IL-17 Receptor (R)A/IL-17RC.

Interleukin-17 F (IL-17F) is a recently described member of the IL-17 family with a great homology to IL-17A. IL-17F is mainly secreted by T CD4+ and γδT-17 lymphocytes and acts as homodimers or heterodimers with IL-17A [23]. It signals through the same receptors as IL-17A, with a better affinity to IL-17RC. However, its role and function in inflammation and cancer, a priori close to those of IL-17A, need to be further investigated. In colon cancer, these two cytokines could have in fact opposite effects since IL-17A favors cancer development and IL-17F appears to be a protective factor against tumorigenesis [18, 24]. Notably, IL-17A polymorphisms were associated with increased risk of colorectal cancer development when comparing patients to healthy controls in Iranian and Tunisian populations [25, 26]. Interestingly IL-17F polymorphisms was observed to be mainly protective in the same populations [25, 27].

To our knowledge, there is no data concerning serum Th17-related cytokines concentration or Il-17-related polymorphisms that may be predictive of the clinical impact of bevacizumab in metastatic colorectal cancer or be at least implicated in the prognosis of the disease, in this particular treatment schedule. The objective of the present study was therefore to evaluate the association of individual sources of variability related to IL-17 pathway with OS and PFS of patients with metastatic colorectal cancer treated with a bevacizumab-based regimen. In addition to biomarkers previously assessed, i.e. CEA, VEGF and bevacizumab concentrations [7], we studied the influence of baseline serum Th17-related cytokines concentrations (before bevacizumab treatment initiation) and of selected IL-17A (G197A, rs2275913) and IL-17F (T7488C, rs763780) polymorphisms on clinical outcomes.


Study design

This ancillary study is part of a French multicenter non-comparative, prospective, open-label, observational study (NCT00489697, registration first received June 20, 2007). The study is also registered as ID number INCA06-FT/STIC-AVASTIN. The main study was designed to evaluate the usefulness of hepatic contrast-enhanced ultrasound sonography as predictor of response to bevacizumab-based chemotherapy in patients with metastatic colorectal cancer. Briefly, patients enrolled between January 2007 and December 2010 received 5 mg/kg bevacizumab intravenously with two-week intervals in combination with chemotherapy. Tumor response was assessed by RECIST criteria (response evaluation criteria in solid tumors [28]) using spiral Computed Tomography (CT) before treatment and at day 60 after the beginning of the treatment. The end of follow-up was December 2012. Finally, 122 patients received at least the four bevacizumab infusions.

This study was designed in accordance with legal requirements and the Declaration of Helsinki and was approved by the ethics committee of Tours University Hospital, France. All patients gave written informed consent to participate in this study, including constitutional genetic analyses. Eligible patients (18–80 years old) had histologically confirmed metastatic colorectal cancer with at least one hepatic metastasis detected by ultrasonography, a life expectancy of more than two months, a World Health Organization performance status of two or less and were mostly treated as first line treatment with a bevacizumab-based chemotherapy.

Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)

Genomic DNA was extracted from peripheral blood leukocytes. Patients were genotyped using specific primers. 100 ng/μl DNA was amplified with Taq Polymerase solution (Life Technologies, Saint-Aubin, France), including MgCl2 (2.5 mM) and dNTP (5 nM). PCR reactions were performed in 35 cycles of denaturation at 95 °C for 5 s and primer annealing and extension at 60 °C for 45 s.

IL-17A rs2275913 (G197A) sequence was amplified with the following primers previously validated by Wu et al. [29]:



Il-17F rs763780 (A7488G) was amplified with the following primers previously validated by Wrobel et al. [30]:



PCR products were digested overnight at 37 °C with FastDigest XagI (EcoNI, Fermentas, Illkirch, France) for rs2275913 variant and with FastDigest NlaIII (Hin1II, Fermentas) for rs763780 variant. The fragments were then separated on 8% TBE polyacrylamide gels (Invitrogen) and visualized after staining with ethidium bromide under UV light. The visualized DNA products for rs2275913 were 102 bp (AA genotype), 102 + 68 + 34 bp (AG genotype) and 68 + 34 bp (GG genotype). The visualized products for rs763780 were 412 bp (GG genotype), 412 + 288 + 124 bp (AG genotype) and 288 + 124 bp (AA genotype).


Baseline concentrations of Th17-related cytokines were measured in serum samples using multiplex assay following manufacturer’s protocol (Bio-Plex Pro™ Human Th17 Cytokine Assays, Bio-Rad, Marnes-la-Coquette, France). This magnetic bead–based immunoassay allows to measure 15 proteins involved in the Th17 immune response pathway: IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFNγ, TNF-α and sCD40L.

Survival analysis

Overall survival (OS) was defined as the time from first bevacizumab infusion to death from any cause, and progression-free survival (PFS) was defined as the time from first bevacizumab infusion to documented disease progression. OS and PFS were assessed using Cox semi-parametric (univariate and multivariate) proportional hazard regression models. This analysis aimed at testing and quantifying the association of circulating Th17-related cytokines concentrations (IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFNγ, TNF-α and sCD40L) and gene polymorphisms (IL-17A, GG vs AA + AG carriers; IL-17F, AA vs AG) as covariates of Cox models. The association between these covariates and OS or PFS, was assessed using forward and backward stepwise procedures. The relationship between survival and the following variables was also examined: age at inclusion, gender, bevacizumab trough concentrations before the second injection (Ctrough; <15.5 mg/L (median) vs ≥15.5 mg/L), and baseline concentrations of VEGF and CEA. For interleukin concentration measurements, values below the limit of detection (LOD) were replaced by the LOD value. Hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) were estimated. The association between covariates and survival functions was tested using Wald’s test, with alpha risk (p) <0.05. Cox survival analyses were performed using R Software version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria).


Demographic data and clinical features (Table 1)

One hundred and thirty patients were included but we analyzed only the 122 patients who received at least the four bevacizumab infusions. Median age was 65 years and patients were predominantly men (77%). The majority of patients were diagnosed for a colon cancer (72%), surgically resected (63%) with hepatic metastases only (58%). Bevacizumab associated with FOLFIRI was mostly used as first-line treatment (66%). The Table 1 below sums up the demographic data of patients and baseline measures (notably CEA, VEGF and bevacizumab concentrations), previously assessed [7].
Table 1

Demographic data of patients and baseline measures (n = 122)

Baseline patients’ characteristics (n = 122)

Age, years


65 [58–72]

Weight, kg


68 [60–77]

Height, cm (n = 121)


170 [163–174]

Body surface area, m2 (n = 121)


1.75 [1.64–1.93]

Carcinoembryonic antigen, μg/L (n = 111)


68.6 [11.8–271.3]]

Vascular endothelial growth factor, ng/L (n = 119)


169.6 [61.9–334.5]

Ctrough bevacizumab, mg/L


15.5 [11.7–22.8]

Time to progression, months


10.6 [7.4–16.1]

Follow-up period, months


23.9 [14.7–35.3]



77 (63%)



45 (37%)

World Health Organization Performance Status (n = 116)


63 (52%)



51 (42%)



2 (2%)

Primary tumor site


85 (70%)



37 (30%)

Combined chemotherapy


81 (66%)



21 (17%)



8 (7%)



12 (10%)

Results are expressed as median [interquartile range] for continuous variables or number (%) for categorical variables.

Abbreviations: n number of patients, FOLFIRI oxaliplatin, 5-fluorouracil, and leucovorin, FOLFOX irinotecan, 5-fluorouracil, and leucovorin, LV5FU2 leucovorin and 5-fluorouracil


For rs2275913 IL-17A polymorphism, genotypes were distributed as follows (Table 2): homozygous AA 10.9%, heterozygous AG 51.1% and homozygous GG 38%. For rs763780 IL-17F polymorphism, genotypes were distributed as follows (Table 2): homozygous AA 92.6% and homozygous AG 7.4%. There were no homozygous GG for this polymorphism in our study.
Table 2

Distribution and frequencies of IL-17A and IL-17F genotypes in metastatic colorectal cancer patients (n = 122)




IL-17A (rs2275913)










IL-17F (rs763780)










There was no association between the genotypes and serum cytokine levels in this cohort.

Cytokine concentrations

The concentrations of cytokines involved in the Th17 immune response pathway are summarized in Table 3. IFNγ was detected in none of the included patients. The distribution of IL-17A concentrations was shown in Fig. 1 since it was the only Th17-related cytokine associated with PFS (see below the detailed Cox multivariate analysis, Table 5). For this cytokine, the range of values was similar to previous studies [11, 31].
Table 3

Baseline concentrations of serum Th17-related cytokines (n = 122)


Median concentration (pg/ml)















































Fig. 1
Fig. 1

Distribution of baseline serum IL-17A concentrations of patients with metastatic colorectal cancer

There was no association between chemotherapy backbone and outcomes or Th17-related cytokines levels in this cohort.

Overall survival (Table 4)

Median OS was 23.9 months (95% CI, 20.6–31.3 months). The univariate Cox analysis identified high baseline VEGF, IL-31 and CEA concentrations, and low bevacizumab Ctrough as risk factors of death. In the multivariate analysis, high baseline CEA concentrations (HR = 1.15; 95% CI, 1.04–1.27; P = 0.0064) and low bevacizumab Ctrough (<15.5 mg/L; HR = 1.89; 95% CI, 1.20–2.97; P = 0.0063) were independent risk factors of death.
Table 4

Cox regression analyses of potential factors associated with overall survival in patients with metastatic colorectal cancer (n = 122)



95% CI


Univariate analysis: Covariate

 Gender (female)




 Age, years




 Vascular endothelial growth factor, μg/L




 Ctrough bevacizumab <15.5 mg/L



9.9 × 10 −5

 Log(carcinoembryonic antigen), μg/L



9.8 × 10 −5

 IL17A polymorphism (A carriers)




 IL17F polymorphism (AG)




 IL-1β, pg/mL




 IL-4, pg/mL




 IL-6, pg/mL




 IL-10, pg/mL




 IL-17A, pg/mL




 IL-17F, pg/mL




 IL-22, pg/mL




 IL-31, pg/mL




 IL-33, pg/mL




 sCD40L, pg/mL




 Tumor necrosis factorα, pg/mL




Multivariate analysis: Covariate

 Ctrough bevacizumab <15.5 mg/L




 Log(CEA), μg/L




Abbreviations: HR hazard ratio, 95% CI 95% confidence interval, C trough trough concentration of bevacizumab before second infusion

Progression-free survival (Table 5)

Median PFS was 10.6 months (95% CI, 9.6–12.4 months). The univariate analysis showed that high baseline IL-17A, VEGF and CEA concentrations, and low bevacizumab Ctrough were risk factors of progression. In the multivariate analysis, high baseline concentrations of IL-17A (HR = 1.02; 95% CI, 1.00–1.04; P = 0.043) and VEGF (HR = 2.34; 95% CI, 1.31–4.20; P = 0.0041), and low bevacizumab Ctrough ((<15.5 mg/L; HR = 1.72; 95% CI, 1.17–2.53; P = 0.0059) were independent risk factors of progression. In this new set of analysis and considering the selected Th17/IL-17A-related factors, VEGF and bevacizumab concentrations remain independent risks factors as recently described by Caulet et al. [7].
Table 5

Cox regression analyses of potential factors associated with progression-free survival in patients with metastatic colorectal cancer (n = 122)



95% CI


Univariate analysis: Covariate

 Gender (female)




 Age, years




 Vascular endothelial growth factor, μg/L




 Ctrough bevacizumab <15.5 mg/L




 Log(carcinoembryonic antigen), μg/L




 IL-17A polymorphism (A carriers)




 IL-17F polymorphism (AG)




 IL-1β, pg/mL




 IL-4, pg/mL




 IL-6, pg/mL




 IL-10, pg/mL




 IL-17A, pg/mL




 IL-17F, pg/mL




 IL-22, pg/mL




 IL-31, pg/mL




 IL-33, pg/mL




 sCD40L, pg/mL




 Tumor necrosis factorα, pg/mL




Multivariate analysis: Covariate

 Vascular endothelial growth factor, μg/L




 Ctrough bevacizumab <15.5 mg/L




 IL-17A, pg/mL




Abbreviations: HR hazard ratio, 95% CI 95% confidence interval, C trough trough concentration of bevacizumab before second infusion

We next assessed whether the combination of the independent factors identified by multivariate Cox analysis would increase the predictive ability of each individual factor for PFS. A risk score was calculated for each patient, by summing-up the number of high-risk factors defined as IL-17A and VEGF concentrations above the respective median values, and bevacizumab Ctrough below the median. Median PFS was significantly longer in patients with <2 high-risk factors compared to those with ≥2 high-risk factors (12.9 vs 8.7 months, P = 0.0006 by log-rank test; Fig. 2).
Fig. 2
Fig. 2

Kaplan–Meier plots. Progression-free survival according to the score calculated by baseline concentrations of plasma VEGF and serum IL-17A and bevacizumab Ctrough. P = 0.0006 by log-rank test


Drugs that target the VEGF pathway, associated with chemotherapy backbone, have a significant impact in metastatic colorectal cancer therapy . Bevacizumab in combination with chemotherapy has been proven to extend OS in first-line therapy [5] and in second-line therapy [32]. A pooled analysis from seven phase II and III (3763 patients) demonstrated that the use of bevacizumab with chemotherapy was associated with statistically significant benefits in survival outcomes, compared to chemotherapy alone, in the treatment of metastatic colorectal cancer [33].

According to the literature, IL-17A is involved in colorectal cancer progression, in cancer resistance and tumor escape following anti-VEGF-based therapy [11, 13, 15, 18, 34]. In addition, IL-17A is a factor that regulates T cell plasticity and might also promote antitumor immunity [35]. In syngeneic tumor pre-clinical models, Chung et al. [13] well described how IL-17A is implicated in a network that favors tumor escape following anti-VEGF treatment, notably via an IL17/G-CSF (granulocyte colony-stimulating factor)/Bv8 (prokineticin-2) alternative pathway initiated by Th17 infiltration. To study the relevancy of their pre-clinical findings, they investigated notably tissue sections from patients with colorectal cancer. Aa strong correlation of IL-17A–positive lymphocytes and Bv8-expressing polymorphonuclear granulocytes was found. In our ancillary study, we therefore sought to investigate the influence of IL-17A-related individual factors on OS and PFS in patients with metastatic colorectal cancer treated with bevacizumab mainly associated with FOLFIRI regimen.

In addition to the risk factors of progression reported by Caulet et al. [7] and regarding this cohort of patients with advanced colorectal cancer treated with a bevacizumab-based regimen, serum IL-17A baseline concentrations were identified as an independent factor and no influence of other Th17/Il-17A-related markers was observed.

To our knowledge, this is the first report that investigates IL-17A and its related factors as potential biomarkers of response of bevacizumab-based regimen in advanced colorectal cancer. However this study has some limitations since there is no control arm without bevacizumab therapy, which means that our findings have a prognostic role and other studies are needed to validate a predictive value. We can not conclude on whether our finding is attributable to bevacizumab alone or in combination with backbone chemotherapy. A recent systematic meta-analysis showed that there was no statistically significant difference in efficacy when bevacizumab is used with both irinotecan- or oxaliplatin-based regimens [36].

Some reports indicated that IL-17A could initiate and favour the tumoral progression at early colorectal cancer stages [8, 37] so it could be interesting to evaluate the impact of IL-17A concentrations at this time in future prospective studies including bevacizumab treatment. Wang et al. measured IL-17A concentrations in serum of patients with colorectal cancer that did not receive bevacizumab infusions [31]. They showed that significantly higher IL-17A concentrations were found at early colorectal cancer stages (I/II) concomitantly with increased concentrations of Il-23, another interleukin linked to Th17 differentiation, compared to control healthy donors. Tseng et al. also found that high IL-17A concentrations at stage II were associated with shorter disease-free survival in an independent analysis [11]. Moreover, retrospectively and irrespective of bevacizumab therapy, Tosolini et al. [38] showed that colorectal cancer patients with high expression of the Th17 genes cluster, analyzed from frozen specimens, had a poor prognosis and this result was confirmed with the quantification of IL-17-positive cells in situ. To date, only one team reported that high IL-17A expression, compared to expression in adenoma and non-tumor tissue, is an independent favorable prognostic factor that predicts overall survival of colorectal cancer by quantifying RNA expression in tissues and IL-17A immunohistochemical levels [39]. All the other publications reported that IL-17A high expression (RNA, immunohistochemistry and/or serum concentration) is a negative prognostic marker of colorectal cancer progression [8, 9, 38, 40].

The rs2275913 polymorphism can promote production of high levels of IL-17A and lead to enhanced IL-17-mediated immune responses. The rs763780 polymorphism leads to a Histidine-to-Arginine substitution and therefore antagonizes the function of wild-type IL-17F [41]. In our study we observed no influence of IL-17A and IL-17F polymorphisms on OS and PFS of our bevacizumab-treated group of patients with metastatic colorectal cancer.

Among individual Th17-related potential biomarkers, only baseline serum IL-17A concentrations are herein associated with PFS in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. We can extrapolate that the clinical response could be influenced by or associated with other individual Th17-related biomarkers in larger panels or at early stages of the disease, e.g. IL-6 and IL-23 as markers of Th17 maturation or IL-17 and TNF-α as the main secreted factors. The fact that Il-17A was the only significant Th17-related factor associated with PFS must be reproducibly analyzed in other prospective studies. Moreover, it is important to distinguish the impact of IL-17A and the infiltration of Th17 cells. A recent meta-analysis following Prisma guidelines emphasizes the fact that high IL-17A quantities were correlated with poor prognosis in cancer and notably in colorectal cancer but the impact of high Th17 cell frequencies is very controversial and depends on the cancer type [42].


To conclude, we think that evaluation of serum IL-17A concentration alone is probably not clinically relevant and IL-17A concentration should be assessed as an additional risk factor, along with baseline VEGF concentration and bevacizumab Ctrough. It could help to stratify patients with metastatic colorectal cancer receiving bevacizumab as first-line treatment according to their risk of disease progression (see Fig. 2). Considering the range of hazard ratios and p values in the Cox regression multivariate analysis, serum Il-17A concentrations play a significant role in the risk score but to a lesser degree than plasma VEGF and bevacizumab trough concentrations. But this significant result is highly dependent on one case which, if left out, weakens the data. Therefore the association should be confirmed in other clinical studies. And the determination of IL-17A concentrations at baseline, along with baseline VEGF concentrations and bevacizumab Ctrough, could also be embedded in the design strategy for future prospective clinical trials. In a near future, it would be interesting to target IL-17A, concomitantly or sequentially to VEGF inhibition, to overcome resistance to anti-VEGF-based therapy in metastatic colorectal cancer.


95% CI: 

95% confidence interval


Carcinoembryonic antigen


Trough concentration of bevacizumab before second infusion


Granulocyte colony-stimulating factor


Hazard ratio


Interleukin-17 A


Overall survival


Progression-free survival


Vascular endothelial growth factor



The authors wish to thank Laurence Talbot (BIO-RAD) for technical assistance and critical analysis of multiplex assay.


The grant from Société Nationale Française de Gastro-Entérologie (« Fonds d’Aide à la Recherche et à l’Evaluation en Hépato-gastroentérologie », FARE SNFGE 2013–2014) allows to perform multiplex analysis and genotyping of patients. This publication has been logistically supported by the French National Research Agency under the program “Investissements d’avenir” Grant Agreement LabEx MAbImprove: ANR-10-LABX-53. AG is supported by a postdoctoral fellowship from Fondation de France.

Availability of data and materials

The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.

Authors’ contributions

EL, AG and NB performed the experiments, analyzed the data and reviewed the manuscript. MT, MC and DT analyzed, interpreted the patient data and wrote the manuscript. CB, OB and TL participated in patients’ inclusion, critically interpreted the data and reviewed the manuscript. GP, TL and WR designed the study, analyzed the data and wrote the manuscript. All authors have read and approved the final version of this manuscript.

Competing interests

Olivier Bouché reports receiving personal fees from Roche, Merck Serono, and Lilly. Christophe Borg reports grants from Roche and grants and personal fees from Sanofi. Gilles Paintaud reports grants from Novartis, Roche Pharma, Genzyme, MSD, Servier, and Pfizer.

Consent for publication

Not applicable.

Ethics approval and consent to participate

This study was designed in accordance with legal requirements and the Declaration of Helsinki and was approved by the ethics committee of Tours University Hospital, France. All patients gave written informed consent to participate in this study, including constitutional genetic analyses.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

Université François-Rabelais de Tours, CNRS, GICC UMR 7292, UFR de médecine, BP 3223, 10, boulevard Tonnellé, 37032 Tours Cedex 01, France
CHRU de Tours, Department of Hepato-Gastroenterology and Digestive Oncology, Tours, France
CHRU de Tours, Laboratory of Pharmacology-Toxicology, Tours, France
INSERM, UMR 1098, Department of Medical Oncology, University Hospital, Besançon, France
Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Robert Debré, Reims, France


  1. Jooste V, Remontet L, Colonna M, Belot A, Launoy G, Binder F, Faivre J, Bouvier AM. Trends in the incidence of digestive cancers in France between 1980 and 2005 and projections for the year 2010. Eur J Cancer Prev. 2011;20(5):375–80.View ArticlePubMedGoogle Scholar
  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.View ArticlePubMedGoogle Scholar
  3. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.View ArticlePubMedGoogle Scholar
  4. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.View ArticlePubMedGoogle Scholar
  5. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.View ArticlePubMedGoogle Scholar
  6. Temraz S, Mukherji D, Alameddine R, Shamseddine A. Methods of overcoming treatment resistance in colorectal cancer. Crit Rev Oncol Hematol. 2014;89(2):217–30.View ArticlePubMedGoogle Scholar
  7. Caulet M, Lecomte T, Bouché O, Rollin J, Gouilleux-Gruart V, Azzopardi N, Léger J, Borg C, Douillard J, Manfredi S, et al. Bevacizumab pharmacokinetics influences overall and progression-free survival in metastatic colorectal cancer patients. Clin Pharmacokinet. 2016; in pressGoogle Scholar
  8. Cui G, Yuan A, Goll R, Florholmen J. IL-17A in the tumor microenvironment of the human colorectal adenoma-carcinoma sequence. Scand J Gastroenterol. 2012;47(11):1304–12.View ArticlePubMedGoogle Scholar
  9. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, Lin Z, Zhu B. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011;407(2):348–54.View ArticlePubMedGoogle Scholar
  10. Shi Y, Lin H, Cui J, Qi H, Florholmen J, Liu Z, Cui G. The role of interleukin-17A in colorectal tumorigenesis. Cancer Biother Radiopharm. 2013;28(6):429–32.View ArticlePubMedGoogle Scholar
  11. Tseng JY, Yang CY, Liang SC, Liu RS, Yang SH, Lin JK, Chen YM, Wu YC, Jiang JK, Lin CH. Interleukin-17A modulates circulating tumor cells in tumor draining vein of colorectal cancers and affects metastases. Clin Cancer Res. 2014;20(11):2885–97.View ArticlePubMedGoogle Scholar
  12. Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J. Interleukin-17: a promoter in colorectal cancer progression. Clin Dev Immunol. 2013;2013:436307.PubMedPubMed CentralGoogle Scholar
  13. Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19(9):1114–23.View ArticlePubMedGoogle Scholar
  14. Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, Gantt Jr GA, Sukhdeo K, DeVecchio J, Vasanji A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210(13):2851–72.View ArticlePubMedPubMed CentralGoogle Scholar
  15. Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, Zhang W, Zhong Z, Sanchez-Lopez E, Wu LW, et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity. 2014;41(6):1052–63.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28(4):454–67.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13(2):139–45.View ArticlePubMedGoogle Scholar
  18. Yang B, Kang H, Fung A, Zhao H, Wang T, Ma D. The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediat Inflamm. 2014;2014:623759.Google Scholar
  19. Zou W, Restifo NP. T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol. 2010;10(4):248–56.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11(10):763–76.View ArticlePubMedGoogle Scholar
  21. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149–62.View ArticlePubMedGoogle Scholar
  22. Hirota K, Ahlfors H, Duarte JH, Stockinger B. Regulation and function of innate and adaptive interleukin-17-producing cells. EMBO Rep. 2011;13(2):113–20.View ArticlePubMed CentralGoogle Scholar
  23. Chang SH, Dong C. IL-17F: regulation, signaling and function in inflammation. Cytokine. 2009;46(1):7–11.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Tong Z, Yang XO, Yan H, Liu W, Niu X, Shi Y, Fang W, Xiong B, Wan Y, Dong C. A protective role by interleukin-17F in colon tumorigenesis. PLoS One. 2012;7(4):e34959.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Nemati K, Golmoghaddam H, Hosseini SV, Ghaderi A, Doroudchi M. Interleukin-17FT7488 allele is associated with a decreased risk of colorectal cancer and tumor progression. Gene. 2015;561(1):88–94.View ArticlePubMedGoogle Scholar
  26. Omrane I, Marrakchi R, Baroudi O, Mezlini A, Ayari H, Medimegh I, Stambouli N, Kourda N, Bouzaienne H, Uhrhammer N, et al. Significant association between interleukin-17A polymorphism and colorectal cancer. Tumour Biol. 2014;35(7):6627–32.View ArticlePubMedGoogle Scholar
  27. Omrane I, Baroudi O, Bougatef K, Mezlini A, Abidi A, Medimegh I, Stambouli N, Ayari H, Kourda N, Uhrhammer N, et al. Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer. Immunol Lett. 2014;158(1–2):189–94.View ArticlePubMedGoogle Scholar
  28. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.View ArticleGoogle Scholar
  29. Wu X, Zeng Z, Chen B, Yu J, Xue L, Hao Y, Chen M, Sung JJ, Hu P. Association between polymorphisms in interleukin-17A and interleukin-17F genes and risks of gastric cancer. Int J Cancer. 2010;127(1):86–92.View ArticlePubMedGoogle Scholar
  30. Wrobel T, Gebura K, Wysoczanska B, Jazwiec B, Dobrzynska O, Mazur G, Kuliczkowski K, Bogunia-Kubik K. IL-17F gene polymorphism is associated with susceptibility to acute myeloid leukemia. J Cancer Res Clin Oncol. 2014;140(9):1551–5.View ArticlePubMedPubMed CentralGoogle Scholar
  31. Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G, Yuan BZ. The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers. BMC Cancer. 2012;12:418.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson 3rd AB, Eastern Cooperative Oncology Group Study E. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(12):1539–44.View ArticleGoogle Scholar
  33. Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, Waterkamp D, Tabernero J. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist. 2013;18(9):1004–12.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, Wang Z, Wang C, Zhang Z, Xia W, et al. gammadeltaT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014;40(5):785–800.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol. 2009;183(7):4169–75.View ArticlePubMedGoogle Scholar
  36. Chan DL, Pavlakis N, Shapiro J, Price TJ, Karapetis CS, Tebbutt NC, Segelov E. Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature. PLoS One. 2015;10(8):e0135599.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Wang K, Karin M. Tumor-Elicited Inflammation and Colorectal Cancer. Adv Cancer Res. 2015;128:173–96.View ArticlePubMedGoogle Scholar
  38. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, 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(4):1263–71.View ArticlePubMedGoogle Scholar
  39. Lin Y, Xu J, Su H, Zhong W, Yuan Y, Yu Z, Fang Y, Zhou H, Li C, Huang K. Interleukin-17 is a favorable prognostic marker for colorectal cancer. Clin Transl Oncol. 2015;17(1):50–6.View ArticlePubMedGoogle Scholar
  40. Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette MT, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, et al. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut. 2008;57(6):772–9.View ArticlePubMedGoogle Scholar
  41. Dai ZM, Zhang TS, Lin S, Zhang WG, Liu J, Cao XM, Li HB, Wang M, Liu XH, Liu K, et al. Role of IL-17A rs2275913 and IL-17F rs763780 polymorphisms in risk of cancer development: an updated meta-analysis. Sci Rep. 2016;6:20439.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Punt S, Langenhoff JM, Putter H, Fleuren GJ, Gorter A, Jordanova ES. The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review. Oncoimmunology. 2015;4(2):e984547.View ArticlePubMedPubMed CentralGoogle Scholar


© The Author(s). 2017