The Role of Interleukin-17A in Colorectal Tumorigenesis

Abstract

It has been well documented that interleukin (IL)-17A mainly produced by the newly identified T cell subtype Th17 cells is an important proinflammatory cytokine that plays a vital pathogenic role in the process of human inflammatory bowel diseases. Recently, new information concerning the biological activities of IL-17A relating to the development of colorectal cancer (CRC) has also been reported. The present mini-review focuses on recent observations concerning the role of IL-17A in the development of CRCs, and it discusses the clinical significance of IL-17A as a biomarker and potential therapeutic target.

Background

Colorectal cancer (CRC) is among the most common worldwide cancers, accounting for over one million cases and about half a million deaths annually. It has long being recognized that CRC is an inflammation-related human malignance, a close association between chronic inflammation and the development of CRC as seen in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) has been widely accepted, in which chronic inflammation-induced mediators such as cytokines and chemokines appear to play an important role in the initiation of CRC in chronic inflammation.^1

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Cytokines are mainly produced by T cells. Based on the T cell differentiation in response to different stimuli, T cell-derived cytokines can be divided into Th1 and Th2 types.⁷ Th1 cytokines mediate strong cellular immune response and function as the most important anticancer factor, whereas Th2-associated cytokines mediate humoral response and favor tumor cell growth and expansion.⁷ We and others have previously shown unbalanced expression of Th1/Th2 cytokine along the colorectal adenoma-carcinoma sequence,^8,9 supporting that cytokine plays an important role in human colorectal carcinogenesis. Most recently, a novel interleukin-17 (IL-17)-expressing T cell subset has been primarily identified in CD4+T cells (named as Th17 cells)¹⁰ and other types of immune cells such as macrophages, eosinophils, neutrophils, monocytes, CD8+T cells, and T regulatory (Treg) cells.^11
–13 The differentiation and expansion of Th17 cells were stimulated by a set of cytokines that include IL-1β, IL-6, IL-21, transforming growth factor (TGF)-β, and IL-23, whereas inhibited by interferon-gamma (IFN-γ) and IL-4.¹⁰ These cytokines act as critical differentiating regulators for Th17 cell development.¹⁰ The major cytokines produced by Th17 cells are IL-17A, IL-17F, IL-21, and IL-22. The majority of studies investigating the role of Th17 cytokines in colorectal diseases have been focused on IL-17A. It has been demonstrated that IL-17A has profound effects on the processing of chronic inflammation-related human diseases such as in IBD.^14
–16 Since IBD is one of the high risk factors for CRC and accounts for roughly two-thirds of incidence of CRC, the relevance of IL-17A to CRC has become the focus of extensive investigation. Indeed, increasing evidence supports that IL-17A is involved in the development of CRCs, although the role of IL-17A as an antitumor or tumor-promoting factor in other types of human cancers is still incompletely understood.^17

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Therefore, the present mini-review focuses on certain recent observations concerning the relevance of IL-17A to the development of CRCs, and discusses the significance of IL-17A as a potential therapeutic target.

IL-17A promotes formation of precancerous adenoma and initiation of colonic cancers in animal models

It has been well known that most human CRCs develop from pre-existed precancerous lesions and chronic inflammation has been implicated in all stages of CRC development. These include CRC initiation and promotion.²² Due to its central role in colorectal chronic inflammation, IL-17A has been hypothesized to play an important role in the occurrence of CRC.

Most recently, the pathological role of IL-17A in promoting the development of CRC has been demonstrated in animals. Nam and colleagues have revealed that IL-17A is a major mediator for TGF-β-related colonic tumorigenesis in mice. They found that anti-TGF-β monoclonal antibody alone does not affect proliferation or survival of tumor cells. However, knock down of IL-17 receptor can remarkably decrease the cancer cell growth in vivo. ²³ More recently, direct evidence of IL-17A in promoting cancer development has been documented in a mouse colon cancer model.²⁴ Chae and colleagues are able to show that colon cancer develops via the activation of Th17 cells and then the production of IL-17, where the blockade of IL-17A could significantly inhibit hyperplasia and cancer formation in mice.²⁴ This suggests that the activation of Th17 cells and production of IL-17A play a critical role in the development of precancerous lesions and cancerous lesions in the colorectum. More recently, researchers from a Korean group has also provided the evidence to support that IL-17A is a major factor in promoting the development of colitis-associated CRC.²⁵ They have found that the incidence of chemical-induced colon cancer in IL-17A knockout mice was significantly reduced as compared with wild-type mice, supporting that IL-17A is involved in the development of colitis-associated CRC.²⁵

IL-17A is elevated in both colorectal precancerous lesions and cancerous lesions in humans

CRC has different types of DNA alterations, including mismatch repair (MMR)-proficient (MSS) colon cancers. Majority of CRCs belong to MSS phenotype and immune gene expression profiles display different patterns according to MMR status. Le Gouvello and colleagues have reported that increased expression of IL-17A is a particular determinant in MMR-proficient human CRCs and associated with poor prognosis.²⁶ Th17 cell is one of the main cellular sources for IL-17A and the production of IL-17A from Th17 cells is stimulated by a set of cytokines including IL-1β, IL-6, IL-21, TGF-β, and IL-23.¹⁰ These cytokines act on different stages of Th17 cell differentiation and expansion. IL-1β, IL-6, IL-21, and TGF-β are important in inducing naïve T cell differentiation into early stages of Th17 cell differentiation, whereas IL-23 is for the last stage Th17 cell expansion. Thus, the determination of Th17 cell-stimulating factors (cytokines) in the tumor microenvironment may reflect the Th17 cell activation status. It has been previously reported that Th17-stimulating factors (cytokines) like IL-6 and TGF-β were high in patients with CRCs, and they stimulate the growth of CRC cancer cells in vitro and are related to the progression of CRC.^27,28 In addition to the Le Gouvello's report,²⁶ another study from China²⁹ has also suggested that the expression level of IL-17A may be a predicator for the poor prognosis of human CRCs. The CRC patient with a low level of IL-17A level may have a longer 5-year survival rate than those with a high level of IL-17.²⁹

Many changes including genetic, molecular, and histological alterations have been observed along the progression from human colorectal adenoma to CRC,³⁰ we have therefore examined that the expression level of IL-17A and Th17 cell-stimulating factors (cytokines) both at the precancerous stage and cancerous stage.³¹ We have found that the expression level of IL-17A is significantly elevated from the adenoma stage and throughout to the cancer stage.³¹ At the adenoma stage, the expression level of IL-17A in the microenvironment is associated with the severity of dysplasia that has been recognized as one of the histological hallmark for cancer risk in patients with adenoma. IL-17A is continuously increased at the cancer stage, but is not associated with CRC patients' clinical pathological features.³¹ In addition, we are also able to show that the stimulator factors (cytokines) for Th17 differentiation and expansion are also increased in the same patterns as IL-17A along the whole sequence,³¹ indicating that increased IL-17A is probably from the activated Th17 cells. Thus, our findings suggest that the activation of Th17 cells may affect both the adenoma stage and cancer stage. Previously, Wågsäter et al. have reported an unchanged IL-17 protein level in human CRC tissues.³² Such a discrepancy may be explained by the technique difference. They used ELISA method to measure IL-17A at a translational level, whereas most recent studies utilized quantitative real-time PCR to quantify IL-17A at a transcriptional level, which is the most sensitive quantitative technique. In addition, in the previous study adjacent normal morphological mucosa was used as controls,³² but it has been demonstrated that adjacent mucosa is abnormal in several aspects including immune response.^33
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Currently, whether all the Th17-derived cytokines function as the promoting factors on colorectal carcinogenesis is still elusive. Some studies have reported an anticancer effect of IL-17 in other types of tumors. For example, IL-17F is another member of the IL-17 family and also functions as a proinflammatory cytokine.^36,37 However, a recent study has revealed that Th17-associated cytokine IL-17F plays an inhibiting role on colonic carcinogenesis in mice, possibly via inhibiting tumor angiogenesis.³⁸ In addition, in other types of tumors, the antitumor effect of IL-17 has also been reported.^20,39 For example, Kryczek and colleagues showed that tumor growth and lung metastasis were enhanced in IL-17-deficient mice, associated with decreased IFN-γ(+) natural killer cells and tumor-specific IFN-γ(+) T cells in the tumor-draining lymph nodes and tumors.²⁰ These conflicting results may implicate that Th17 cytokines may have a different effect on colonic carcinogenesis, which could be dependent on the tumor cell types and inflammation microenvironment conditions.¹⁷

The mechanisms of IL-17 as a promoter for colorectal carcinogenesis

The possible mechanisms for IL-17A in promoting the formation of adenomas and CRCs have been postulated. It has been suggested that the effect of IL-17 on carcinogenesis is via an enhancing production of IL-6^40,41 while IL-6 signal has been confirmed to play a critical role in promoting colorectal tumorigenesis.²⁷

Angiogenesis is a critical step for the growth, expansion, and metastasis of human cancers. One of the potential mechanisms for IL-17A in stimulating tumor growth is its proangiogenic effect. As we have known that vascular endothelial growth factor (VEGF) is a stronger proangiogenic factor for many types of human cancers.⁴² The reagents of anti-VEGF receptors have been approved to be used in treating patients with CRC and shown in a great clinical adventure.⁴² It has been shown that IL-17A promotes the angiogenesis¹⁸ via an enhancing production of VEGF, basic fibroblast growth factor (bFGF), and hematopoietic growth factor (HGF).⁴³ Indeed, in patients with CRC, it has also been shown that elevation of IL-17A is associated with the production of VEGF in blood.²⁹ IL-8 is another potent proangiogenic factor in many types of human cancers. In renal cancer cells, IL-17 secreted from T cells can induce IL-8 released from renal cancer cells.⁴⁴ It is unknown whether IL-17 can enhance the production of IL-8 from CRC cells, however, both IL-17 and IL-8 have been found to be increased in patients with CRC.^5,31,45,46 It is necessary to further investigate whether IL-17A can stimulate IL-8 released from CRC cells in patients with CRC.

Another possible mechanism for IL-17A in promoting tumorigenesis is its effect on stem cells.

Recently, the effect of IL-17 on the tumorigenesis has also been found to be via an action on the stem cells;⁴⁵ the effect of IL-17 on cancer-initiating (stem) cells has also been confirmed in human CRCs by a study.^47,48

Although several mechanisms for IL-17 on promoting colonic tumorigenesis has been postulated, the precise role and mechanisms of IL-17A/TH17 in human CRCs still need further studies.

Clinical Implications: IL-17 as a biomarker of colorectal adenomas and cancers and as a therapeutic target

Since the elevation of IL-17A is throughout the precancerous stage and cancerous stage, the clinical relevance of IL-17A in the development of colorectal carcinogenesis is investigated. Radosavljevic et al. have shown that it might act as a valuable tumor marker in patients with CRC by measuring IL-17A levels in the serum samples from CRC patients.⁴⁶ In the investigation of IL-17A's effect along human adenoma-carcinoma sequence, we have found that the elevation of IL-17A starts from the adenoma stage, and is related to the severity of dysplasia. Although the expression level of IL-17A at the cancer is even higher, it is not related to the TNM parameters of CRC.³¹ Our findings may raise an interesting possibility that the dominant role of IL-17A in regulating the development of CRC is on the precancerous stage. However, it remains further studied and confirmed.

Anti-angiogenesis has become one of therapeutic targets. As mentioned above, it has been previously demonstrated that IL-17A can stimulate tumor growth¹⁸ via an enhanced production of proangiogenic factors such as VEGF, bFGF, and HGF.⁴³ In CRC patients, the increased IL-17A level has been associated with the production of VEGF.²⁹ Thus, the target of IL-17A may benefit the anti-angiogenic therapeutics.

Most studies concerning the target of IL-17A were done in animal models; several studies have demonstrated that deficient IL-17A significantly inhibits the development of colon cancer in mice. Chae et al. have found that the deletion of IL-17A abrogated the initiation and stabilization of an IL-17A-mediated inflammatory environment and then the development of colon cancer.²⁴ In addition, Hyun and colleagues have found that the occurrence of colitis-associated colon cancer in IL-17A-deficient mice is remarkably reduced as compared with that in wild-type mice.²⁵ Those data suggest that target of IL-17A may result in a reduction of CRC occurrence and could be a potential novel therapeutic target for the treatment of CRCs.

Conclusion Marker

It seems clear that Th17 cell activation and IL-17A are implicated in the pathogenesis of precancerous lesion formation and CRC development. Increased IL-17A may be a potential biomarker for the evaluation of cancer risk in adenomas and assessing of disease prognosis in CRCs. Target therapy directed against IL-17A pathway may have significance in designing biotherapeutic strategies for the prevention of colorectal tumorigenesis and/or treatment of CRCs in the future.

Footnotes

Acknowledgments

This work is financially supported by grants from the National Nature Science Foundation of China (81071969) and Medical Research Program, Northern Norway Regional Health Authority (SFP-44-04) to Cui G, and Shanghai Science and Technology Commission (No. 12XD1404000) to Liu Z.

Disclosure Statement

The authors have no conflict of interest.

References

Atreya

, Neurath

. Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol, 2005; 28:187.

Fantini

, Pallone

. Cytokines: From gut inflammation to colorectal cancer. Curr Drug Targets, 2008; 9:375.

Chung

, Chang

. Significance of inflammatory cytokines in the progression of colorectal cancer. Hepatogastroenterology, 2003; 50:1910.

Wilson

, Balkwill

. The role of cytokines in the epithelial cancer microenvironment. Semin Cancer Biol, 2002; 12:113.

Yuan

, Chen

, Yao

et al. The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci, 2005; 10:853.

Waldner

, Neurath

. Colitis-associated cancer: The role of T cells in tumor development. Semin Immunopathol, 2009; 31:249.

Kidd

. Th1/Th2 balance: The hypothesis, its limitations, and implications for health and disease. Altern Med Rev, 2003; 8:223.

Contasta

, Berghella

, Pellegrini

et al. Passage from normal mucosa to adenoma and colon cancer: Alteration of normal sCD30 mechanisms regulating TH1/TH2 cell functions. Cancer Biother Radiopharm, 2003; 18:549.

Cui

, Goll

, Olsen

et al. Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother, 2007; 56:985.

10.

Korn

, Bettelli

, Oukka

et al. IL-17 and Th17 Cells. Annu Rev Immunol, 2009; 27:485.

11.

Hinrichs

, Kaiser

, Paulos

et al. Type 17 CD8+T cells display enhanced antitumor immunity. Blood, 2009; 114:596.

12.

Kryczek

, Wu

, Zhao

et al. IL-17+regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol, 2011; 186:4388.

13.

Weaver

, Hatton

, Mangan

et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol, 2007; 25:821.

14.

Fujino

, Andoh

, Bamba

et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut, 2003; 52:65.

15.

Olsen

, Rismo

, Cui

et al. TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation. Cytokine, 2011; 56:633.

16.

Liu

, Yadav

, Xu

et al. The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J Leukoc Biol, 2011; 89:597.

17.

Murugaiyan

, Saha

. Protumor vs antitumor functions of IL-17. J Immunol, 2009; 183:4169.

18.

Numasaki

, Fukushi

, Ono

et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood, 2003; 101:2620.

19.

Martin-Orozco

, Dong

. The IL-17/IL-23 axis of inflammation in cancer: Friend or foe? Curr Opin Investig Drugs, 2009; 10:543.

20.

Kryczek

, Wei

, Szeliga

et al. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood, 2009; 114:357.

21.

Muranski

, Boni

, Antony

et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood, 2008; 112:362.

22.

Klintrup

, Makinen

, Kauppila

et al. Inflammation and prognosis in colorectal cancer. Eur J Cancer, 2005; 41:2645.

23.

Nam

, Terabe

, Kang

et al. Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res, 2008; 68:3915.

24.

Chae

, Gibson

, Zelterman

et al. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A, 2010; 107:5540.

25.

Hyun

, Han

, Lee

et al. Role of IL-17A in the development of colitis-associated cancer. Carcinogenesis, 2012; 33:931.

26.

Le Gouvello

, Bastuji-Garin

, Aloulou

et al. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut, 2008; 57:772.

27.

Becker

, Fantini

, Wirtz

et al. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle, 2005; 4:217.

28.

Yang

, Pang

, Moses

. TGF-beta and immune cells: An important regulatory axis in the tumor microenvironment and progression. Trends Immunol, 2010; 31:220.

29.

Liu

, Duan

, Cheng

et al. 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; 407:348.

30.

Leslie

, Carey

, Pratt

et al. The colorectal adenoma-carcinoma sequence. Br J Surg, 2002; 89:845.

31.

Cui

, Yuan

, Goll

, Florholmen

. IL-17A in the tumor microenvironment of the human colorectal adenoma-carcinoma sequence. Scand J Gastroenterol, 2012; 47:1304.

32.

Wågsäter

, Lofgren

, Hugander

et al. Expression of interleukin-17 in human colorectal cancer. Anticancer Res, 2006; 26:4213.

33.

Fox

, Whalen

, Sanders

et al. Angiogenesis in normal tissue adjacent to colon cancer. J Surg Oncol, 1998; 69:230.

34.

Pandey

, Gordon

, Wang

. Expression of proliferation-specific genes in the mucosa adjacent to colon carcinoma. Dis Colon Rectum, 1995; 38:462.

35.

Cui

, Yuan

, Goll

et al. Distinct changes of dendritic cell number and IL-12 mRNA level in adjacent mucosa throughout the colorectal adenoma-carcinoma sequence. Cancer Immunol Immunother, 2007; 56:1993.

36.

Chang

, Dong

. IL-17F: Regulation, signaling and function in inflammation. Cytokine, 2009; 46:7.

37.

Yang

, Chang

, Park

et al. Regulation of inflammatory responses by IL-17F. J Exp Med, 2008; 205:1063.

38.

Tong

, Yang

, Yan

et al. A protective role by interleukin-17F in colon tumorigenesis. PLoS One, 2012; 7:e34959.

39.

Benchetrit

, Ciree

, Vives

et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 2002; 99:2114.

40.

Tartour

, Fossiez

, Joyeux

et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res, 1999; 59:3698.

41.

Wang

, Yi

, Kortylewski

et al. Y. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med, 2009; 206:1457.

42.

Sitohy

, Nagy

, Dvorak

. Anti-VEGF/VEGFR therapy for cancer: Reassessing the target. Cancer Res, 2012; 72:1909.

43.

Takahashi

, Numasaki

, Lotze

et al. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett, 2005; 98:189.

44.

Inozume

, Hanada

, Wang

et al. IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells. J Immunother, 2009; 32:109.

45.

Cui

, Yuan

, Goll

et al. Dynamic changes of interleukin-8 network along the colorectal adenoma-carcinoma sequence. Cancer Immunol Immunother, 2009; 58:1897.

46.

Radosavljevic

, Ljujic

, Jovanovic

et al. Interleukin-17 may be a valuable serum tumor marker in patients with colorectal carcinoma. Neoplasma, 2010; 57:135.

47.

Yang

, Wang

, Guan

et al. Foxp3+IL-17+T cells promote development of cancer-initiating cells in colorectal cancer. J Leukoc Biol, 2011; 89:85.

48.

Zhang

, Yamaza

, Kelly

et al. Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. PLoS One, 2009; 4:e7798.