Mini-reviewCancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement
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.
References (142)
- et al.
Interleukin-6 signaling pathway in targeted therapy for cancer
Cancer Treat. Rev
(2012) - et al.
Microbial amphiphiles: a class of promising new-generation anticancer agents
Drug Discov. Today
(2015) - et al.
AhR- and NF-kappaB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-alpha in human mammary MCF-7 cells
Chem. Biol. Interact
(2013) - et al.
IL6-mediated suppression of miR-200c directs constitutive activation of inflammatory signaling circuit driving transformation and tumorigenesis
Mol. Cell
(2012) - et al.
Tumor-derived jagged1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells
Cancer Cell
(2011) - et al.
The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma
Mol. Oncol
(2013) - et al.
Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK-NF-kappa B signaling pathway
Biochem. Bioph. Res. Co
(2014) - et al.
Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells
Cytokine
(2012) - et al.
Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment
Eur. J. Cancer
(2013) - et al.
Zerumbone inhibits interleukin-6 and induces apoptosis and cell cycle arrest in ovarian and cervical cancer cells
Int. Immunopharmacol
(2012)
IL-6 induces MUC4 expression through gp130/STAT3 pathway in gastric cancer cell lines
Biochim. Biophys. Acta
Identification of Liver Cancer Progenitors Whose Malignant Progression Depends on Autocrine IL-6 Signaling
Cell
Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression
Cell
Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-beta signaling by IL-6
Lung Cancer
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer (vol 15, pg 103, 2009)
Cancer Cell
gp130-mediated stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis
Cancer Cell
STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma
Cancer Lett
Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer
Cancer Cell
Elevated expression of APE1/Ref-1 and its regulation on IL-6 and IL-8 in bone marrow stromal cells of multiple myeloma
Clin. Lymphoma Myeloma Leuk
IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development
Cancer Cell
Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu
Exp. Cell Res
Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells
Cell. Signal
Bone marrow-derived myofibroblasts promote colon tumorigenesis through the IL-6/JAK2/STAT3 pathway
Cancer Lett
An epigenetic switch involving NF-kappa B, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation
Cell
An HNF4 alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis
Cell
Retinoic acid inhibits pancreatic cancer cell migration and EMT through the downregulation of IL-6 in cancer associated fibroblast cells
Cancer Lett
Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells
Toxicol. Appl. Pharm
Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+breast cancer by expanding the cancer stem cell population
Mol. Cell
Role of crosstalk between interleukin-6 and transforming growth factor-beta 1 in epithelial-mesenchymal transition and chemoresistance in biliary tract cancer
Eur. J. Cancer
Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1
Mol. Cell. Endocrinol
Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2
J. Mol. Med
Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine
Cancer Res
Interleukin-6: an angiogenic target in solid tumours
Crit. Rev. Oncol. Hematol
Targeting interleukin-6 in inflammatory autoimmune diseases and cancers
Pharmacol. Ther
Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma
Oncogene
Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer
Breast Cancer Res
Diacerein-mediated inhibition of IL-6/IL-6R signaling induces apoptotic effects on breast cancer
Oncogene
Inflammation and prostate cancer: the role of interleukin 6 (IL-6)
BJU Int
IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma
Histopathology
Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8
Cancer Res
Constitutively active stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of cten
Cancer Res
Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells
Cancer Res
Hyperactivated NF-kappa B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells
Mol. Cell. Biol
Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer
FASEB J.
Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation
Breast Cancer Res
The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis
Neoplasia
Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner
Cancer Res
Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction
Brit. J. Cancer
Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration
J. Cell. Biochem
Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells
Int. J. Cancer
Cited by (189)
Co-culture models for investigating cellular crosstalk in the glioma microenvironment
2024, Cancer Pathogenesis and TherapyLocalized delivery of Erlotinib using liposomal gel formulations for the treatment of oral squamous cell carcinoma
2023, International Journal of PharmaceuticsEnhancers of mesenchymal stem cell stemness and therapeutic potency
2023, Biomedicine and PharmacotherapyRole of COL6A2 in malignant progression and temozolomide resistance of glioma
2023, Cellular SignallingResveratrol suppresses lung cancer by targeting cancer stem-like cells and regulating tumor microenvironment
2023, Journal of Nutritional BiochemistryEpigentic signaling: regulation of cancer stem cells in colorectal cancer
2023, Cancer Stem Cells and Signaling Pathways