Cancer Letters

Cancer Letters

Volume 375, Issue 1, 28 May 2016, Pages 51-61
Cancer Letters

Mini-review
Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement

https://doi.org/10.1016/j.canlet.2016.02.048Get rights and content

Highlights

  • IL-6 is a critical cytokine involved in malignant transformation and progression.

  • IL-6 regulates cancer stem cell and mesenchymal stem cell formation.

  • IL-6 induces epithelial to mesenchymal transition (EMT) in cancer.

  • Overexpression of IL-6 is the contributing factor for chemoresistance.

Abstract

Interleukin-6 (IL-6) is a cytokine present in tumor microenvironment. Elevated level of IL-6 is associated with cancer cell proliferation, angiogenesis and metastasis through fueling STAT3, MAPK and Akt signaling. It promotes epithelial to mesenchymal transition (EMT) through altered expression of N-cadherin, vimentin, snail, twist and E-cadherin leading to cancer metastasis. IL-6 boosts mammosphere formation, self-renewal of stem cells, stemness properties of cancer cells and recruitment of mesenchymal stem cells. IL-6 is also a contributing factor for multidrug resistance in cancer due to gp130/MAPK/STAT3 mediated activation of transcription factors C/EBPβ/δ, overexpression of p-glycoprotein, EMT transition and expansion of stem cells. The in-depth investigation of IL-6 mediated cellular effects and its signaling pathway can provide the new window for future research and clinical development of IL-6 targeted therapy in cancer. Thus, an overview is delivered in this review deciphering the emerging aspect of the predominant influence of IL-6 in malignant transformation, EMT, cancer-associated stem cells and chemoresistance.

Introduction

Cancer is a unique and dynamic chromosomal chaos characterized by altered orientation of a large number of genes expression. Over the decades, numerous cancer-associated genes and their functions have been discovered providing an innovative platform, which aids in understanding of the tumor biology and discovery of next generation cancer therapeutics. Exaggerated level of cytokines, growth factors and their receptors, estrogen receptors and amplification HER2/neu are the widespread molecular transformations in many types of cancer onset. Among the cytokines, Interleukin-6 (IL-6) particularly plays a critical role in number of biological and pathobiological events. IL-6 is 26KDa molecular weight protein containing 185 amino acids. Different cancer cells, cancer-associated cells, resistant cancer cells and cancer stem cells overexpress and secrete IL-6 in tumor microenvironment [1], [2], [3]. Secreted IL-6 couples to the binding domains of IL-6 receptor (IL-6R) which employs a different transmembrane glycoprotein gp130 also known as CD130 [4]. IL-6/IL-6R/gp130 complex activates distinct pathways to enforce its oncogenic consequence. These pathways include JAK/STAT, MAPK and PI3K/Akt [5], [6], [7]. This cytokine is hugely reported to be involved in many inflammatory conditions. Recently, a growing number of publications showed that IL-6 is a key player in molecular abnormality, chemoresistance, epithelial to mesenchymal transition and stem cell formation in various types of malignant states.

Here, we are trying to make an effort to present the current trends of the involvement of IL-6 in development/ progression, chemoresistance and stem cell maintenance in cancer. We also endeavor to capture the latest profile of IL-6 mediated molecular action in cancer progression, chemoresistance and stem cells.

Section snippets

IL-6 as triggering factor in cancer development and progression

Tumor microenvironment is composed with highly heterogeneous populations. Inflation of IL-6 in this microenvironment triggers many oncogenic factors creating a suitable atmosphere that promotes tumor survival, proliferation, metastasis and angiogenesis. Significantly high level of IL-6 has been detected in serum samples of patients suffering from breast, colon, pancreatic, esophageal, gastric, hepatic, pancreatic, non-small cell lung, renal cancer and multiple myeloma [8], [9]. Apoptosis is

IL-6 and cancer-associated stem cells

Steady and dynamic populations of cancer stem cells are crucial component in tumor. These cells have the ability to self-renew and differentiate into other cells. These stem cell population cause metastasis, chemoresistance and relapse of many cancers. Recently, a number of research findings showed predominant function of IL-6 in regulation and maintenance of different type of cancer-associated stem cells. IL-6 secreted from different type of cancer-associated stem cells also affects tumor

IL-6 and epithelial mesenchymal transition (EMT)

EMT is a crucial biological event that is involved in cellular transformation, tumorigenesis and metastasis in many cancers. EMT is characterized by loss of epithelial features and gain of mesenchymal features of the epithelial cells. Decreased expression of E-Cadherin and increased profile of N-Cadherin, Vimentin, Snail and Twist are the major hallmarks of EMT phenomena.

EMT induction was promoted by EGF, PI3K-Akt, TGF-β, FGF, hedgehog, Wnt/beta-catenin and NF-кB signaling pathway. Recently,

Involvement of IL-6 and micro RNA in EMT and chemoresistance

Micro RNAs (miRs) are small non-coding RNAs (~22 nucleotides) that regulate wide number of biological process including tumor invasion, metastasis, EMT and development of multidrug resistance in cancer cells. These miRs bind with target mRNA in complementary base pair and suppress the post-translational gene expression. A number of miRs were identified that regulate tumor promotion or suppression. Recent findings suggested that IL-6 and miRs co-operatively modulate EMT and chemoresistance in

Concluding remarks

A global epidemic state of cancer-associated disease is expected to take place in the coming decades. The understanding of molecular interaction in cancer related pathobiological state may lead to new fundamental concept to understand the cancer progression and discovery of new therapeutic targets. Many tumor promoting factors have been detected in cancer microenvironment opening new windows of cancer mystery. Cytokines, which are mainly involved in inflammatory conditions, are also found to be

Conflict of interest

There is no conflict of interest.

Acknowledgements

Authors acknowledge the financial support from Ministry of Earth Sciences (Grant no: MoES/16/48/09/RDEAS; Date: 15-07-2010). Rashmi Bharti is thankful to Indian Institute of Technology Kharagpur for providing Institute fellowship (MHRD). Goutam Dey acknowledges CSIR, India for fellowship.

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