Cancer and inflammation

Abstract

The relationship between inflammation and cancer has been recognized since the 17^th century,¹ and we now know much about the cells, cytokines and physiological processes that are central to both inflammation and cancer.^2-9 Chronic inflammation can induce certain cancers,^10-17 and solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination.⁵ ,^18-20 Consequently, inflammatory pathways have been targeted in attempts to control cancer.^21-23 Inflammation is a central aspect of the innate immune system's response to tissue damage or infection, and also facilitates the recruitment of circulating cells and antibodies of the adaptive immune response to the tissue. Components of the innate immune response carry out a robust, but sometimes overly-conservative response, sacrificing specificity for the sake of preservation. Thus, when innate immunity goes awry, it can have profound implications. How the innate and adaptive immune systems cooperate to neutralize pathogens and repair damaged tissues is still an area of intense investigation. Further, how these systems can respond to cancer, which arises from normal 'self' cells that undergo an oncogenic transformation, has profound implications for cancer therapy. Recently, immunotherapies that activate adaptive immunity have shown unprecedented promise in the clinic, producing durable responses and dramatic increases in survival rate in patients with advanced stage melanoma.^24-26 Consequently, the relationship between cancer and inflammation has now returned to the forefront of clinical oncology. WIREs Syst Biol Med 2017, 9:e1370. doi: 10.1002/wsbm.1370 For further resources related to this article, please visit the WIREs website.

Figure 1

Differences in the progression of acute and cancer-induced inflammation. While many of the cells and processes are common, acute inflammation resolves after the pathogen is eliminated and/or tissue architecture has been stabilized. In cancer-induced inflammation, there is continuous mechanical disruption, cytokine and growth factor production and cell recruitment, so inflammation persists.

Figure 2

Inflammation induced by tissue insult or pathogens. a) Tissue damage produces cell and matrix debris (damage-associated molecular patterns, DAMPs) that binds to receptors on resident granuloctyes (mast cells, eosinophils, basophils). Similarly, pathogens release substances (pathogen -associated molecular patterns, PAMPs) that bind to receptors on these cells. b Activation of the granulocytes releases cytokines and chemokines that act on pain receptors and vascular cells. c) In response, blood vessels dilate and become leaky. The extravasating plasma carries proteins that modify the ECM, and the changes in blood flow and EC adhesion molecules facilitate the infiltration of circulating neutrophils, monocytes and other myeloid cells into the tissue. d) Macrophages and neutrophils clean up debris, attack any pathogens and fortify the extracellular matrix. e) In the case of pathogenic response, the cells and antibodies produced in the adaptive immune response arrive and help clear the infection. f) Tissue architecture is restored by macrophages and fibroblasts, which contract the wound and normalize the ECM. Angiogenic vessels re-perfuse the tissue. g) Remodeling of the tissue continues for weeks/months as blood vessels and matrix structures are refined.

Figure 3

Involvement of inflammatory processes during tumor development and progression. a) After mutagenesis, cancer cells proliferate, disrupting the surrounding tissue, drawing the attention of resident macrophages and fibroblasts. Cancer cell-produced cytokines and growth factors may also play a role in this early stage. Resident granulocytes may also respond to DAMPs released by damaged cells and matrix as the tumor disrupts normal tissue. b) As the tumor expands, macrophages and fibroblasts are recruited to the area, and matrix production is increased. Oxygen diffusion limitations cause hypoxia in the tumor core, and angiogenic growth factors such as VEGF are produced by the tumor. c) The growth factors act on nearby blood vessels, causing dilation and leakiness. d) The growth factor environment, modified ECM and fluid flow through the tissue all encourage formation of new vessels that enter and feed the tumor. e) This environment, and the new vasculature, accelerates the infiltration of innate immune cells, which produce additional inflammatory cytokines that further affect the blood vessels and recruit more cells. f) Without specific anti-tumor immunity, these events amplify out of control, and the abundant/modified ECM provides pathways for cancer invasion. g) Immunotherapies can activate the adaptive immune response, allowing cytotoxic T-cells to kill the cancer cells.