Review
Inflammation: Gearing the journey to cancer

https://doi.org/10.1016/j.mrrev.2008.03.002Get rights and content

Abstract

Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis.

Section snippets

Chronic inflammation as a predisposing factor for malignant transformation of cells

Chronic inflammation represents a major pathologic basis for the majority of human malignancies. The role of inflammation in carcinogenesis has first been proposed by Rudolf Virchow in 1863, when he noticed the presence of leukocytes in neoplastic tissues [1]. Since the Virchow's early observation that linked inflammation and cancer, accumulating data have supported that tumors can originate at the sites of infection or chronic inflammation [2]. Approximately, 25% of all cancers are somehow

Major mediators linking inflammation and cancer

Chronic inflammation is implicated in all stages of carcinogenesis, i.e., initiation, promotion and progression. In a persistently inflamed tissue, excessive generation of ROS can cause genomic instability which leads to initiation of cancer [3], [61]. A single initiated cell undergoes proliferation to produce a clone of mutated cells which form premalignant mass, the event generally termed tumor promotion. Some of the preneoplastic cells encounter additional mutations and become malignant.

Inflammatory angiogenesis in cancer

The role of inflammation in angiogenesis has been evolutionarily recognized in physiological processes, such as development of uterine and intestinal vasculature [206]. Angiogenesis is also essential for the growth and survival of solid tumors, and their progression to invasive phenotypes. The concept of angiogenesis as a mechanism of growth and survival of tumor cells was first introduced by Folkman et al., who proposed that tumor cells could sense their distance from the normal vasculature

Role of miRNA in cancer

In the field of epigenetics, microRNAs (miRNAs or miR) have emerged as a novel class of gene expression regulators. The miRNAs constitute a large family of non-coding-, small size- (19–22 oligonucleotides), and gene-silencing RNAs, which negatively regulate gene expression via translational repression and/or mRNA degradation. miRNAs are transcribed by RNA polymerase II forming a long primary transcript (pri-miRNA), which is processed into a short hairpin structure (pre-miRNA) by nuclear RNase

Components of inflammatory signaling cascades as targets for chemoprevention

Chemoprevention is a practical approach of preventing cancer by using relatively non-toxic chemical entities to halt, reverse or delay the carcinogenic process [119]. One of the promising strategies for chemoprevention is to alleviate inflammatory responses, which is implicated in all stages of tumorigenesis [255]. Numerous synthetic and natural compounds with anti-inflammatory properties have been identified as attractive chemopreventive arsenal [119], [255]. At the molecular level, the

Conclusion

Despite enormous effort to conquer cancesur over the last few decades, the outcome of conventional strategies, such as chemotherapy and radiotherapy, to combat cancer appears unsatisfactory as the incidence and the mortality of cancer, in general, are not decreasing worldwide. The concept of chemoprevention, therefore, appears to be a realistic and fundamental approach to fight cancer. Illuminating an inflammation-cancer link corroborates that chemoprevention can be achieved, partly, by

Acknowledgements

This work was supported by the grants for 21C Frontier Functional Human Genome Project (grant number FG07-21-21), the Innovative Drug Research Center (grant number: R11-2007-107-0000-0) and the National Research Laboratory from Korea Science and Engineering Foundation, from the Ministry of Science and Technology, Republic of Korea. Joydeb Kumar Kundu is a recipient of Brain Korea-21 (BK-21) post-doctoral fellowship.

References (284)

  • W.G. Deng et al.

    Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators

    Blood

    (2004)
  • M. Philip et al.

    Inflammation as a tumor promoter in cancer induction

    Semin. Cancer Biol.

    (2004)
  • Y.-J. Surh et al.

    Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation

    Mutat. Res.

    (2001)
  • Y.D. Jung et al.

    Role of P38 MAPK, AP-1, and NF-κB in interleukin-1β-induced IL-8 expression in human vascular smooth muscle cells

    Cytokine

    (2002)
  • F. Burke et al.

    A cytokine profile of normal and malignant ovary

    Cytokine

    (1996)
  • W. Cozen et al.

    IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma

    Blood

    (2004)
  • M.R. Schneider et al.

    Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells

    Cancer Lett.

    (2000)
  • C. Becker et al.

    TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling

    Immunity

    (2004)
  • F.R. Greten et al.

    IKK-β links inflammation and tumorigenesis in a mouse model of colitis-associated cancer

    Cell

    (2004)
  • S. Kobayashi et al.

    Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells

    Gastroenterology

    (2005)
  • E. Stylianou et al.

    Interleukin 1 induces NF-κB through its type I but not its type II receptor in lymphocytes

    J. Biol. Chem.

    (1992)
  • D. Giri et al.

    Interleukin-1α is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia

    Am. J. Pathol.

    (2000)
  • M.M. Mueller et al.

    Friends or foes—bipolar effects of the tumour stroma in cancer

    Nat. Rev. Cancer

    (2004)
  • S. Perwez Hussain et al.

    Inflammation and cancer: an ancient link with novel potentials

    Int. J. Cancer

    (2007)
  • L. Jackson et al.

    Chronic inflammation and pathogenesis of GI and pancreatic cancers

    Cancer Treat. Res.

    (2006)
  • D. Schottenfeld et al.

    Chronic inflammation: a common and important factor in the pathogenesis of neoplasia

    CA Cancer J. Clin.

    (2006)
  • S.H. Itzkowitz et al.

    Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation

    Am. J. Physiol. Gastrointest. Liver Physiol.

    (2004)
  • W.G. Nelson et al.

    The role of inflammation in the pathogenesis of prostate cancer

    J. Urol.

    (2004)
  • K.J. O’Byrne et al.

    Chronic immune activation and inflammation as the cause of malignancy

    Br. J. Cancer

    (2001)
  • D.C. Whitcomb

    Inflammation and cancer V. Chronic pancreatitis and pancreatic cancer

    Am. J. Physiol. Gastrointest. Liver Physiol.

    (2004)
  • K. Matsuzaki et al.

    Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma

    Hepatology

    (2007)
  • L. Herszenyi et al.

    Carcinogenesis in inflammatory bowel disease

    Dig. Dis.

    (2007)
  • D.N. Seril et al.

    Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models

    Carcinogenesis

    (2003)
  • J. Eaden et al.

    Colorectal cancer prevention in ulcerative colitis: a case–control study

    Aliment Pharmacol. Ther.

    (2000)
  • S. Strano et al.

    Mutant p53: an oncogenic transcription factor

    Oncogene

    (2007)
  • M.S. Cooke et al.

    Oxidative DNA damage: mechanisms, mutation, and disease

    FASEB J.

    (2003)
  • L.J. Marnett

    Oxyradicals and DNA damage

    Carcinogenesis

    (2000)
  • M. Jaiswal et al.

    Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism

    Cancer Res.

    (2000)
  • Y. Hoki et al.

    iNOS-dependent DNA damage in patients with malignant fibrous histiocytoma in relation to prognosis

    Cancer Sci.

    (2007)
  • H. Xu et al.

    Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis

    Cancer Res.

    (2004)
  • N. Babbar et al.

    Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis

    Cancer Res.

    (2006)
  • H. Ohshima et al.

    8-Nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species: formation, occurrence, and implications in inflammation and carcinogenesis

    Antioxid. Redox Signal.

    (2006)
  • V. Yermilov et al.

    Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro

    Carcinogenesis

    (1995)
  • S. Kawanishi et al.

    Oxidative and nitrative DNA damage as biomarker for carcinogenesis with special reference to inflammation

    Antioxid. Redox Signal.

    (2006)
  • S. Pinlaor et al.

    Nitrative and oxidative DNA damage in intrahepatic cholangiocarcinoma patients in relation to tumor invasion

    World J. Gastroenterol.

    (2005)
  • W. Hu et al.

    The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma

    Carcinogenesis

    (2002)
  • L. Ying et al.

    Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation

    Cancer Res.

    (2007)
  • L.J. Hofseth et al.

    Nitric oxide-induced cellular stress and p53 activation in chronic inflammation

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • K.D. Kroncke

    Nitrosative stress and transcription

    Biol. Chem.

    (2003)
  • P.A. Cerutti et al.

    Inflammation and oxidative stress in carcinogenesis

    Cancer Cells

    (1991)
  • Cited by (712)

    View all citing articles on Scopus
    1

    On leave from Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh.

    View full text