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Review
. 2018 Jul 30;10(8):251.
doi: 10.3390/cancers10080251.

The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer

Sudha S Savant  1 , Shruthi Sriramkumar  2 , Heather M O'Hagan  3   4
Affiliations
Review

The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer

Sudha S Savant et al. Cancers (Basel). .

Abstract

Inflammation plays a role in the initiation and development of many types of cancers, including epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSC), a type of EOC. There are connections between EOC and both peritoneal and ovulation-induced inflammation. Additionally, EOCs have an inflammatory component that contributes to their progression. At sites of inflammation, epithelial cells are exposed to increased levels of inflammatory mediators such as reactive oxygen species, cytokines, prostaglandins, and growth factors that contribute to increased cell division, and genetic and epigenetic changes. These exposure-induced changes promote excessive cell proliferation, increased survival, malignant transformation, and cancer development. Furthermore, the pro-inflammatory tumor microenvironment environment (TME) contributes to EOC metastasis and chemoresistance. In this review we will discuss the roles inflammation and inflammatory mediators play in the development, progression, metastasis, and chemoresistance of EOC.

Keywords: cytokines; epithelial ovarian cancer; growth factors; inflammation; reactive oxygen species.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Sources of inflammation in the ovary and fimbriae. Ovulation, retrograde menstruation, endometriosis, infections, exposure to talc, Polycystic Ovarian Syndrome (PCOS), and obesity result in exposure of the ovary and fimbriae to reactive oxygen species (ROS), oxidative stress, cytokines, and growth factors, generating an inflammatory response that leads to additional production of ROS and cytokines in the ovary. Unresolved, chronic inflammation is a critical risk factor for tumor initiation.
Figure 2
Figure 2
Inflammatory mediators contributing to EOC progression, metastasis, and angiogenesis. EOC cells produce ROS, chemokines, cytokines, and growth factors that can: (1) Lead to recruitment of immune cells like Dentric cells (DC), Natural killer cells (NK), Tumor associated macrophages (TAMs), and T-regulatory (Treg) cells into the TME, which generate additional cytokines, ROS, and growth factors, resulting in chronic inflammation. (2) Stimulate the tumor cells themselves, the TAMs, and the surrounding fibroblasts (also known as cancer associated fibroblasts or CAFs) to proliferate and secrete growth factors like TGF-β and FGF that stimulate production of integrins and Matrix Metalloproteins (MMPs), resulting in migration of the tumor cell via degradation of the extra cellular matrix (ECM). (3) Stimulate endothelial cells (EC) to produce growth factors like PDGF and EGF and factors like VEGF that stimulate angiogenesis. The double arrows indicate that the cells are a source of the factor as well as stimulated by it.
Figure 3
Figure 3
Inflammatory mediators contribute to chemoresistance of EOC. A combination of platinum and taxane drugs is currently used as chemotherapy for OC. ROS, Lyophosphotidic Acid (LPA), cytokines, and growth factors like TGF-β and EGF increase tumor cell survival by upregulating antiapoptotic genes, by stimulating stemness and proliferation of cancer initiating cells, by increasing repair of damaged DNA, or by increasing efflux of the drug. The resistant tumor cells and the cancer initiating cells can then proliferate under the influence of growth factors and cytokines resulting in a recurrent chemoresistant tumor.
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