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The Pro-inflammatory Milieu and Its Role in Malignant Epithelial Initiation

  • Adam Yagui-Beltrán
  • Qizhi Tang
  • David M. Jablons
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Increasing research from preclinical and clinical studies is demonstrating that inflammation with its myriad of heterogeneous mediators and cellular effectors plays a role in the malignant initiation of epithelial cells. Pre-existing inflammation may exist prior to the development of cancer, or on the other hand it may be that oncogenic changes may lead to a certain inflammatory microenvironment that in turn will promote the development of a tumor. Examples of how inflammation may lead to cancer formation include enhanced proliferation of initiated cells, through resistance to apoptosis, induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, abnormal tumor neovascularization or angiogenesis, and the promotion of metastasis among others.

At the time of malignant transformation of epithelial cells, the many components of the tumor microenvironment (TME), such as the tumor cells themselves, the stromal cells in surrounding tissue and the infiltrating leukocytes cells generate an intratumoral inflammatory state by the aberrant expression and secretion of a florid array of pro-inflammatory molecules that include chemokines, cytokines, cyclooxygenase-2, prostaglandins (PGs), iNOS, nitric oxide (NO), and a vast network of intracellular signaling molecules including upstream kinases and transcription factors that facilitate tumor promotion and progression. In this chapter, we will explore current knowledge of the various components of the pro-inflammatory milieu within the TME; we will, for example, highlight the major molecular studies that support how pro-inflammatory cytokines, chemokines, and PGs are able to regulate some of the angiogenic switches controlled by vascular endothelial growth factors inducing inflammatory angiogenesis. We will highlight some of the principal tumor cell–stroma dynamic relationships and how often these interplays are incrementally manipulated in ways that favor malignant epithelial initiation, resulting in tumor immune evasion, tumor growth, and metastasis. We hope that an increasing understanding of the specific molecular mechanisms associating inflammation, TME, and cancer will subsequently result in a better understanding of how these cancers to subvert the immune system and overcome response our wide array of chemoradiotherapeutic agents.

Keywords

Vascular Endothelial Growth Factor Reactive Nitrogen Species Ataxia Telangiectasia Mutate Acute Inflammatory Response Bone Marrow Derive Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

The authors are supported by grants from the National Institutes of Health (CA132566 and CA130980), Department of Defense Award for mesothelioma research (W81XWH-09-1-0342), an Era of Hope Scholar Award (W81XWH-06-1-0416), the Bonnie J. Addario Lung Cancer Research Foundation, the Kazan, McClain, Abrams, Fernandez, Lyons, Greenwood, Harley & Oberman Research Foundation Inc., and the Eileen D. Ludwig Endowed Chair Fund for Thoracic Oncology Research.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Adam Yagui-Beltrán
    • 1
  • Qizhi Tang
  • David M. Jablons
  1. 1.Department of Surgery, Division of Adult Thoracic Surgery, The Helen Diller Family Comprehensive Cancer Center Thoracic SurgeryUniversity of California San FranciscoSan FranciscoUSA

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