Thymic stromal lymphopoietin: Next research hotspot of carcinogenesis?

doi:10.4236/abb.2012.326086

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Advances in Bioscience and Biotechnology, 2012, 3, 665-668 ABB

http://dx.doi.org/10.4236/abb.2012.326086 Published Online October 2012 (http://www.SciRP.org/journal/abb/)

Thymic stromal lymphopoietin: Next research hotspot of

carcinogenesis?

Tong Wu, Juan Wang, Lihua Jia, Bin Cheng*

Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China

Email: *[email protected]

Received 2 August 2012; revised 8 September 2012; accepted 19 September 2012

ABSTRACT

Thymic stromal lymphopoietin (TSLP) is an epithet-

lial cell derived cytokine which has been reported to

be a master regulator in T helper (Th) 2 driven in-

flammation. Through acting on dentritic cells (DCs),

granulocytes, natural killer T cells or directly on

CD4+ T cells, TSLP plays significant roles in the

pathogenesis of atopic diseases consisting of the triad

of asthma, allergic rhinitis and atopic dermatitis. Re-

cently mounting evidence demonstrated that cancer-

related inflammation play decisive roles at different

stages of tumor development, including initiation,

promotion, malignant conversion, invasion, and me-

tastasis. As a crucial regulator of Th2 driven inflam-

mation, the involvement of TSLP in carcinogenesis

have attracted researchers’ attention. However, the

mechanisms of TSLP’s involvement in carcinogenesis

are still largely unknown. In this review we first out-

line the roles of TSLP involved in allergic inflamma-

tion and then we further focus on the recent findings

on TSLP’s tumor promoting activities hoping to pro-

vide hints on elucidation of the TSLP implication in

carcinogenesis in future studies.

Keywords: Thymic Stromal Lymphopoietin;

Inflammation; Cancer; Carcinogenesis

1. INTRODUCTION

Thymic stromal lymphopoietin (TSLP), an epithelially

derived cytokine initially identified as a bioactive factor

secreted in the supernatants of a murine thymic stromal

cell line in 1994 [1]. TSLP is now known to have im-

pacts on hematopoietic and nonhematopoietic cell in-

cluding B cells, basophils, eosinophils, mast cells, DCs,

CD4, CD8, and NK T cells, and epithelial cells. As a

master regulator of T helper (Th) 2 driven inflammation,

TSLP is capable of activating dendritic cells to promote

T helper (Th) 2 immune responses and directly promote

Th2 differentiation of naïve CD4+ T cell and Th2 cyto-

kine-associated inflammation. [2-6]. TSLP-induced Th2

responses are associated with the pathogenesis of allergic

inﬂammatory diseases, including atopic dermatitis, asth-

ma, and rhinitis. Recently mounting evidence demon-

strated that cancer-related inflammation play decisive

roles at different stages of tumor development, including

initiation, promotion, malignant conversion, invasion,

and metastasis [7-9]. So as a strong mediator in inflame-

mation, the role of TSLP in cancer development has

aroused a great deal of interests [10-12]. However, the

mechanisms of TSLP’s involvement in carcinogenesis

are still largely unknown. In this review we outline the

roles of TSLP involved in allergic inflammation and then

we further focus on the recent finding on TSLP’s tumor

promoting activities.

2. TSLP AND ITS RECEPTOR

Thymic stromal lymphopoietin (TSLP), an epithelially

derived cytokine is predominantly expressed by epithet-

lial cells in thymus, lung, skin, intestine and tonsils as

well as stromal cells and mast cells [1,13]. The mouse

TSLP gene is located on chromosome 18, while the hu-

man TSLP gene is located on chromosome 5q22.1 next

to the atopic cytokine cluster on 5q31 [14]. TSLP origin-

nated from both mouse and human exert their biological

activities by binding to a heterodimeric receptor that

consists of the IL-7 receptor α-chain (IL-7Rα) and the

TSLP receptor chain (TSLPR), which has low affinity

for TSLP, but in combination with IL-7Rα generates a

high affinity binding site for TSLP and triggers signaling

[15]. TSLP, which is constitutively expressed in human

thymus, is responsible for the differentiation of T regu-

latory (Treg) cells by modulating the activity of thymic

DCs. In contrast to the restricted expression of TSLP,

TSLPR is more widely detected on many immune cell

types, including dendritic cells (DCs), T cells, B cells,

mast cells, natural killer T cells (NKT) and monocytes as

well as in tissues from heart, skeletal muscle, kidney and

liver which suggests that TSLP can function on a broad

*Corresponding author.

OPEN ACCESS

T. Wu et al. / Advances in Bioscience and Biotechnology 3 (2012) 665-668

666

range of cell types [16]. Although cross-species homol-

ogy for human and mouse TSLP and its receptor is rela-

tively low, both TSLP-TSLPR interactions activate simi-

lar signaling pathways such as the transcription factor

signal transducer and activator of transcription 3 (STAT3)

in human and STAT5 in mouse and human [1].

3. TSLP AND ALLERGIC

INFLAMMATION

TSLP has been reported to play a critical role in CD4+ T

cell homeostasis in the peripheral mucosa-associated

lymphoid tissues and in the positive selection and/or ex-

pansion of regulatory T cells in the thymus under normal

physiological conditions [17]. In pathological condition,

TSLP plays significant roles both at the induction phase

of the Th2 response via polarization of DCs to drive Th2

cell differentiation and at the effector phase of the re-

sponse by promoting the expansion of activated T cells

and their secretion of Th2 cytokines [1]. This Th2 skew-

ing properties of TSLP are strongly associated with the

pathogenesis of atopic diseases consisting of the triad of

asthma, allergic rhinitis and atopic dermatitis, which are

characterized Th2 cytokine-dominanted inflammatory.

In skin inflammatory conditions such as atopic derma-

titis, TSLP expression in the epidermis of lesional skin is

higher than that in uninvolved skin or skin of nonallergic

people. Further more the skin-resident DCs in patients

with atopic dermatitis have a more activated phenotype,

which may migrate toward the draining lymph node to

prime CD4+ T cells. TSLP can induce OX40L expres-

sion on DCs, after primed by TSLP-activated DCs via

OX40-OX40L interaction, CD4+ T cells differentiate

into inflammatory Th2 effecter and memory cells, and

thus initiate the adaptive phase of allergic immune re-

sponses [18,19]. In mouse models, only the increasing

TSLP concentrations in the epidermis can induce the

onset of Th2 cytokine-associated inflammation, which

has all the cardinal features of human atopic dermatitis

[20].

TSLP has recently been proved to be a key pro-aller-

gic cytokine in chronic airway diseases, such as asthma

and chronic obstructive pulmonary disease (COPD) for

the detection of high levels expression of TSLP in bron-

chial mucosa [21]. The animal experiment demonstrated

that TSLP is both necessary and sufficient for the devel-

opment of Th2 cytokine-associated inflammation of the

airways. Mice expressing a TSLP transgene in the airway

epithelium develop a spontaneous, progressive inflame-

matory disease with all the characteristics of human

asthma, TSLP was capable of activating bone marrow-

derived dendritic cells to upregulate costimulatory mole-

cules and produce the T helper type 2 cell-attracting

chemokine CCL17 [22]. On the contrary, TSLP receptor-

deficient mice failed to develop asthma in response to

inhaled antigen [23].

4. TSLP AND CARCINOGENESIS

Recently researches have demonstrated that immune

responses have involved and play a vital role in several

stages of tumor development, such as initiation, promo-

tion, malignant conversion, invasion, and metastasis [7-

9]. As a crucial regulator of Th2 driven inflammation,

the involvement of TSLP in carcinogenesis have at-

tracted researchers’ attention. The available researches

shown that TSLP is associated with several cancer in-

cluding lung, pancreatic and breast cancer [10-12]. How-

ever, the possible regulatory mechanisms of TSLP un-

derlying these cancers are not clear and varied in dif-

ferent tumor.

4.1. Cellular Source and Target of TSLP in

Tumor Microenvironment

Similar to normal skin, lung epithelium, breast epithelial

cells, lung cancer cell and breast cancer cells have the

capacity to express TSLP [10,12]. In contrast with breast

cancer in which TSLP expression is specific to epithelial

cells and no staining can be found in tumor-infiltrating

fibroblasts [12]. One recent research on pancreatic can-

cer demonstrated that cancer-associated fibroblasts

(CAFs) secreted TSLP were an important tumor pro-

moter in cancer progression [11]. These experiments

shown that TSLP expression is up-regulated in pancre-

atic cancer and released by CAFs under the influence of

TNF-α and IL-1β that are secreted by tumor cells. So in

tumor microenvironment, the ability of tumor epithelium

and stroma to secrete TSLP varied according to tumor

content dependent manner. The cellular target of TSLP

include DCs and T cells which induce carcinogenesis

through different mechanisms subsequently [10-12,24].

4.2. TSLP in Lung Cancer

One of the important mechanisms for cancer to escape

immune surveillance is to create an immunosuppressive

microenvironment. It has been reported that Tregs, which

could suppress the activity of lymphocytes and help the

tumor cells to escape the host immune system, were in-

creased in the peripheral blood or tumor microenviron-

ment in patients with cancer [25-28]. In lung cancer, the

prevalence of Tregs in tumor microenvironment was

correlated with the expression of TSLP which was sig-

nificantly increased compared with that in benign lesion

and non-cancer lung tissue and correlated with patho-

logic type, stage, tumor size, and lymph node metastasis

[10]. Further study demonstrated that TSLP was capable

of inducing the differentiation of CD4+ CD25− T cells

T. Wu et al. / Advances in Bioscience and Biotechnology 3 (2012) 665-668 667

into CD4+ CD25+ Tregs and the subsequent migration

of Tregs to the cancer microenvironment by secreting

chemokines MDC/CCL22 and TARC/CCL17 in a DC-

dependent manner [10].

4.3. TSLP in Pancreatic Cancer

One recent research on pancreatic cancer demonstrated

that TSLP expression is up-regulated in pancreatic can-

cer and released by CAFs under the influence of TNF-α

and IL-1β that are secreted by tumor cells [11]. In vitro

study found that myeloid DCs are activated with features

of TSLP-treated DCs by the supernatant of proinflam-

matory cytokine-treated CAFs and acquire Th2-polariz-

ing capability. In vivo study shown that DCs with of

TSLP-treated and Th2-attracting features are present in

pancreatic cancer patients. Collectively, based on these

available results the authors proposed a hypothesis on

how CAFs secreted TSLP promote Th2-mediated in-

flammation in pancreatic cancer which correlated with

reduced survival in pancreatic cancer under the influence

of tumor cells. Pancreatic tumor cells release proinflam-

matory cytokines (TNF-α and IL-1β) and elicit the secre-

tion of TSLP by CAFs. These CAFs-derived TSLP acti-

vate tumor antigen-load resident DC and induce their

migration to draining lymph nodes where they activate

tumor antigen-specific CD4+ Th2 cells. Finally these

CD4+ Th2 cells home to the tumor under the influence

of tumor-derived Th2 chemoattractants to exert tumor-

promoting effecter functions.

4.4. TSLP in Breast Cancer

Besides pancreatic cancer, breast cancer which were in-

filtrated with tumor promoting inflammatory Th2 cell are

also driven by breast cancer-derived TSLP [12]. TSLP

secreted by breast cancer cells induced OX40L-ex-

pressing DCs migration to the tumor microenvironment

which can smolder type 2 inflammation that perpetuates

breast cancer. Further more, another research in mice on

breast cancer demonstrated that CD4+ T cells are also

targets of cancer-produced TSLP during cancer progress-

sion and metastasis [24]. TSLP was responsible for the

lung metastasis by inducing production of CCL17 in the

lungs and non-Treg subsets of CD4+ T cells, whereas

DCs did not appear to be critical in this process.

5. PERSPECTIVE

The evidence available to date indicates that the cancer-

promoting activity of TSLP from cancer cell or CAFs

varied in different cancers primarily required signaling

through the TSLP receptor on DCs or CD4+ T cells,

promoting Th2-skewed immune responses and produc-

tion of immunosuppressive factors. However, many de-

tails underlying effect of TSLP on cacinogenesis such as

signal transduction mechanisms are largely unknown.

Our previous study found that TSLP was expressed on

mouse oral keratinocyte under inflammation [29], and

TSLP and its receptor were detected on oral squamous

cell carcinoma cell line (unpublished data). Whether

TSLP is also involved in the carcinogenesis in other

epithelial tumor type which progression have been re-

ported to be associated with immune disregulation and

elevated Th2 cytokines expression such as head and neck

carcinoma remains to be fully elucidated in further study

[30,31]. Notably, elucidation of the TSLP implication in

carcinogesesis may offer novel therapeutic options to

complement currently available therapeutic strategies.

6. ACKNOWLEDGEMENTS

This work was supported by grants from the National Natural Science

Foundation of China (No. 91029712) and the Fundamental Research

Funds for the Central Universities of China (2009).

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ABBREVIATIONS

TSLP: Thymic Stromal Lymphopoietin

Th: T Helper

DC: Dentritic Cell

IL-7Rα: IL-7 Receptor α-Chain

TSLPR: TSLP Receptor Chain

Treg: T Regulatory Cell

NKT: Natural Killer T Cells

STAT: Signal Transducer and Activator of Transcription

COPD: Chronic Obstructive Pulmonary Disease

CAF: Cancer-Associated Fibroblast