Cancer Letters

Cancer Letters

Volume 345, Issue 2, 10 April 2014, Pages 157-163
Cancer Letters

Mini-review
Inflammatory cytokines in human pancreatic cancer

https://doi.org/10.1016/j.canlet.2013.07.014Get rights and content

Highlights

  • Pancreatic cancer remains one of the most lethal types of cancer with poor prognosis.

  • Current treatments provide very limited benefits with urgent need for new approaches.

  • Pancreatic tumor microenvironment supports tumor growth and immune evasion.

  • Up-regulation of cytokines plays an important role in the tumor progression.

  • Targeting cytokine pathways may have therapeutic benefits.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with poor prognosis. Despite extensive efforts, the current treatment methods have limited success. Therefore, novel therapeutic approaches are required. The pancreatic tumor microenvironment is rich in growth factors and inflammatory cytokines that support tumor growth, and it is highly immunosuppressive. Up-regulation of cytokine pathways has been shown to modulate PDAC progression and immune evasion; therefore targeting cytokines may have therapeutic benefits. In this review we provide an overview of current understanding of pro- and anti-inflammatory cytokines in pancreatic cancer and their potential as therapeutic targets.

Introduction

Pancreatic cancer is the fifth most common cause of cancer related death in the Western world. At present, it accounts for over 70,000 deaths in Europe per year [1], [2]. Pancreatic ductal adenocarcinoma (PDAC) accounts for >80% of all pancreatic neoplasms diagnosed [3]. The only curative treatment option for pancreatic cancer is surgical resection with approximately 15% of patients deemed suitable [4]. Unfortunately, the vast majority of patients diagnosed with pancreatic cancer present at an advanced stage, often with distant metastases, and are not amenable to curative surgery. As a result, the prognosis for these patients is very poor with an overall 5-year survival rate of <5% [5]. Most patients are treated with standard Gemcitabine-containing chemotherapy with palliative intent. Life expectancy in patients treated with Gemcitabine is still very poor at approximately 6 months [6]. Recent use of combination chemotherapy FOLFIRINOX (including 5-Fluorouracil, Leucovorin, Irinotecan, and Oxaliplatin) has shown an improvement in overall survival in advanced pancreatic cancer patients when compared to standard Gemcitabine based regimens (11.1 months vs. 6.8 months) [7]. Although this represents an overall survival benefit, in practical terms, the survival is less than a year.

In recent years, there have been significant advances in our understanding of pancreatic tumor biology as well as a clearer understanding of the important role that the tumor microenvironment plays in tumor development and growth. Attempts at using targeted therapeutic agents in combination with standard chemotherapy have proved clinically meaningless with negligible improvements in survival. For these reasons, considerable challenges still remain in the treatment of patients with pancreatic cancer and as such, novel therapeutic approaches are urgently required.

Section snippets

Inflammation and pancreatic cancer

Epidemiological and experimental evidence indicates that inflammation plays a significant role in the development and progression of pancreatic cancer [8], [9]. Chronic pancreatitis increases the risk of developing pancreatic cancer [10]. Common mediators have been shown to regulate both inflammatory and oncogenic pathways involved in the development and progression of pancreatic cancer, suggesting that similar mechanisms may link chronic inflammation of the pancreas to the increased risk of

Cytokines in pancreatic cancer

Cytokines regulate many biological processes including cell growth and differentiation, immunity, inflammation and metabolism [20]. Both pro- and anti-inflammatory cytokines have been found to be over expressed in pancreatic cancer. It has been shown that cytokines promote pancreatic tumor cell progression by modulating the tumor microenvironment as well as directly acting on cancer cells [21], [22], [23], [24], [25] (Fig. 1). Cytokine expression also correlates negatively with clinical

IL-6

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a major role in regulating responses to injury and infection, inflammation, cell proliferation and differentiation [42]. The engagement of IL-6 receptor leads to the activation of the JAK tyrosine kinase family members. The activation of JAK stimulates various pathways such as MAPKs, PI3Ks, STATs, which are the main pathways involved in the regulation of cell proliferation, survival and metabolism, hence indicating that IL-6 can play

Immunosuppressive mediators in the pancreatic cancer microenvironment

Escaping immune recognition is now a recognized hallmark of cancer [77]. Chemokines and cytokines can play a critical role in this immune evasion [78], [79]. Tumor cells can escape host immunity by producing immunosuppressive cytokines as well as by recruiting regulatory immune cells with immunosuppressive functions, such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs), which in turn can produce cytokines with immunosuppressive functions [78]. As mentioned previously

Conclusion

Inflammatory cytokines play a critical role in orchestrating the dynamic and complex tumor microenvironment of pancreatic cancer. Over the past few years, interest in the role of cytokines in pancreatic cancer has grown rapidly acknowledging the significant involvement of these molecules in nearly every aspect of cancer pathophysiology. Given the urgent need for new approaches in treating pancreatic cancer, study of the role of the tumor microenvironment for the purpose of targeting,

Conflict of Interest

None.

Acknowledgements

The authors wish to thank Dr. Cristina Ghirelli and Juliana Candido for their review and editing of the manuscript.

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      In the meantime, as a typical cold tumor, patients can barely benefit from immune checkpoint inhibitors like the classic programmed death protein-1 (PD-1) and its ligand (PD-L1) antibody therapies [15,16]. Since TME can recruit immunosuppressive cells like regulatory T cells (Tregs) [17], myeloid-derived suppressor cells (MDSCs) [18], and M2 tumor-associated macrophages (TAMs) [19] to restrict immune effector cells, like dendritic cells (DCs) [20], natural killer cells (NKs) and CD8+ cytotoxic T cells by secreting cytokines such as IL-6, IL-10, and TGF-β [21,22]. In the clinic, albumin bound paclitaxel was employed to eliminate the tumor ECM, aiming to recruit gemcitabine into the deep tumor and to obstruct the immunosuppressive TME [23].

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