Systemic inflammation factors as survival prognosis markers in ovarian neoplasm and the relationship with cancer-associated inflammatory mediators—a review

The relationship between the chronic inflammatory process and the appearance of neoplasia

Pathogenically, the installation and progression of carcinomas, as well as the associated inflammatory response, are favored both by the genetic predisposition and by the environmental characteristics that define, at a given moment, the properties of the area in which the tumor develops. Among these characteristics, generically called tissue homeostasis, regardless of the evolutionary stage of the cancer, an essential role belongs to the existing cell population (endothelial cells, fibroblasts, cells involved in the development of the localized inflammatory process, which later became systemic, etc.). Systemic inflammation must be interpreted as expressing the reparative response of body cells, to the signals carried by the cytokines secreted in excess, with a plurietiological determinism and over a long period of existence of the process.^15–20

Physiopathologically, in neoplasias, inflammation has a dual determinism, being involved both in the installation and evolution of cancer, but also occurring as a possible defense reaction against the existing neoplasia. The use of the three parameters/indices/ratio NLR, PLR, and LMR as markers of systemic inflammation requires the exposure of the scientific support regarding the inflammation-neoplasia interference, at least regarding the existence of inflammation as a defense process against neoplasia and only tangentially as a process which intervenes in carcinogenesis.^21,22 The appearance and development of the ovarian neoplasm, as a consequence of the existence of a chronic regional inflammation (usually located in the distal part of the Fallopian tube, or at the level of the ovarian epithelium) has as its pathogenic cause the installation of local oxidative stress, just like the evolution of any other inflammatory process, regardless of location.^23,24 At any evolutionary moment of carcinogenesis (installation, local invasion or metastasis), the inflammatory process persists, developing together with the immune system, as anti-neoplasia defense systems. Although with a protective function, these processes also lead to the disruption of redox homeostasis, exacerbating oxidative stress.^25,26 In cancers, the increase in oxidative stress is the result of the synergistic action of at least two types of histochemical processes. The first one excessively generates oxidizing species, as a result of the specificity of cancer cells to synthesize ATP macromolecules anaerobically, glycolytically, both through their own multiplication/development, and through the destructive invasion, enzymatically, of normal tissue, peri tumoral or that at the site of metastasis, a process dependent on the stage of development of the neoplasia (localized or metastatic). To these secondary or residual products of the various stages of tumor development, cumulatively, a second synthesizing source of oxidizing species is added, from the development of the associated inflammatory process. Thus, inflammation, although it occurs as a defense process, aiming to limit “tumor aggression,” constitutes a new synthesizing source of ROS/RNS, which we can generically name “redox quota generated by defense.” The process is a sequential one, unfolding in cascade, with evolution from the stage of limited, local-reactionary defense to that of systemically expressed inflammation. In the pathophysiological determination of any inflammation, two types of processes are included, derivative and independent: one alterative-destructive and another reactive-limiting.^27,28

The destructive-alterative process, which develops, is formed by the existing defense processes against the cancer cell, a non-self structure for the body. The installation of neoplasia and regional invasion induces morphological degradation both at the cellular and interstitial level, leading to areas of necrosis, with compromised tissue metabolism. Locally, the action is the consequence of the release in the matrix of the interstitium of enzymes with a destructive role, such as metalloproteinases (MMP), but also of the increase in the concentration of active biological compounds such as cytokines or chemokines.^29,30

The local development of the inflammatory process is the expression of the conjugated action of at least two categories of compounds:

- ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1), but also selectins (P, E, L), generators of chemoattraction for the figured elements that circulate lamellarly in the vessels of the normal peritumoral tissue or in those developed by angiogenesis, activated by cancer development.^31,32

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Table 2.

The main peptides that mediate inflammation.^34,35

The type of inflammation mediators		Name of mediating peptides
Cytokines	Growth factors	PDGF, FGF, VEGF, IGF, VEGH
	Pro-inflammatory factors	IL-1, IL-2, IL-6, IL-10, IL-12, IL-13, IFN-g, TNFα
	anti-inflammatory factors	TGF, IL-4, IL-10, IL-12
Chemokines		MCP, MIP, IL-8

PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; IGF: insulin-like growth factor; EGF: epithelial growth factor; IL: interleukine; IFN: interferon; TNFα: tumor necrosis factor; TGF: transforming growth factor; MCP: membrane cofactor protein; MIP: macrophage inflammatory protein.

The human body responds to the action developed by the biologically active compounds, through a set of changes, which constitute the reaction syndrome, consisting of vascular-circulatory reactions, which include permeability disorders, that allow the formation of inflammatory exudate. The recognition and targeting of cells of the mononuclear system, capable of phagocytosis (in particular, monocytes, neutrophils), by chemoattractants, is the result of their affinity/attraction to the phospholipid layer of the cell membrane.

The inflammatory process begins with the expression of adhesion molecules, responsible for the marginalization of mononuclear cells, with phagocytic capacity, and those of immune defense, and through the synergistic intervention of the cytokine VEGF (vascular endothelial growth factor), diapedesis is triggered (Figure 2).

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Figure 2.

The interface between neoplasia and chronic inflammatory process.

The consequence of the increased migration of leukocytes is the infiltration of the intra- and peritumoral tissue or, in the case of extirpation of the tumor, of the area on which it was intervened. The triggered inflammatory response is characterized by an increase in the neutrophil population that mediates a pro-carcinogenic effect, by promoting angiogenesis, cancer cell migration, with local invasion and metastasis.^36,37

In addition, neutrophils indirectly regulate the epithelial-mesenchymal transition, through the production of oncogenic cytokines and chemokines, such as interleukins (IL)-1β, IL-6, IL-12, and TNF-α, which promote the recruitment and further activation of other inflammatory cells.^38-41

However, in the leukocyte infiltrate, monocytes predominate, which, through metamorphosis, become macrophages. These macrophages, termed tumor-associated macrophages (TAMs), are phenotypically and functionally distinct from pre-existing tumor tissue macrophages (MTMs), as TAMs express the adhesion molecule VCAM1 and do not exhibit an “alternatively activated” phenotype.^28,42,43

Tissuely, they secrete numerous biologically active products, such as those in Table 2, but also myeloperoxidases (MMP),^44,45 which have a synergistic action with the released cytokines. ⁴⁶

Thus, these hemoproteins will contribute, at the tumor level, to the destruction of the extracellular matrix, facilitating the mobilization of tumor cells and metastasis.^47,48

In parallel, the released MMPs cause the exacerbation of the synthesis of pro-oxidant agents (ROS) which, reacting with NO, develop another locally destructive species, nitrogen derivatives (NOS). Excessive local synthesis of the two types of agents with pro-oxidative properties leads, through consumption, to the quantitative insufficiency of antioxidant defense systems, such as “scavenger” enzymes (superoxide dismutase (SOD), catalase, GSH-peroxidase (GSHPx), GSH-reductase and GSSG), but also by other non-enzymatic antioxidants.^49–51

Modification at the level of the tumor cell, of the way of controlling the synthesis of mediators involved in the development of inflammation, such as the activation of leukopoiesis and thrombocytopoiesis

Oxidative stress is caused by an imbalance between the production and accumulation of ROS in cells and the ability of the biological system to detoxify them. Cancer cells exhibit aberrant redox homeostasis, but while ROS are pro-tumorigenic, high ROS levels are cytotoxic. The functions of cells in the tumor microenvironment, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and T cells, are affected by oxidative stress. ⁵²

At the level of the latter, there is a change in the way of controlling the synthesis and release of cytokines, some of which have a role as mediators of inflammation and immune defense. Thus, tissue oxidative stress allows the continuation of the effect of

a. Cancer proliferation, the pathogenic mechanism promoting invasion and metastasis. ⁵³

In conditions of oxidative stress, the target of ROS/RNS is the derivative of sphingomyelin, arachidonic acid, which, through multi-enzymatic catalysis, generates most of the mediator compounds of inflammation, but also of carcinogenesis. Figure 2 predominantly highlights the effects developed by the main four groups of messenger compounds, with a role in autocrine or paracrine signaling, resulting from the enzymatic biodegradation of arachidonic acid: prostaglandins, prostacyclins, thromboxanes, and leukotrienes, molecules produced especially by leukocytes.

In a next step, the resulting compounds activate “redox signaling,” which allows a sequential and modulated process to unfold and “apply” the signals carried by them.^54–56

In order to carry out such a process, cells have both specific structures, with the role of redox sensors, as well as the mechanisms of signal transduction, respectively transcription.

In neoplasms, the impairment of hematopoiesis and the function of the immune system is the expression of the activation of membrane receptors BTL1 and BTL2, respectively, high and low affinity receptors, to which one of the most powerful pro-inflammatory cytokines (LTB4) binds. ⁵⁷

BLT1 has long been known to be a chemoattractant receptor for neutrophils, and recent studies have identified BLT1 expression on multiple cell types (macrophages, activated T cells, mast cells), greatly expanding the potential roles of LTB4. This diversity of expression has led to the current concepts of yin and yang regulation of cancer, as the activity of immune cells influencing both pro (neutrophils, myeloid-derived suppressor cells) and anti-tumor outcomes (CD8⁺ effector T cells) can be controlled by the axis LTB4/BLT1. BLT2 expression on epithelial cells has been implicated in pro-tumorigenic signaling by promoting chemotherapy resistance, angiogenesis, inflammation and metastasis. Becoming active by fixation, the information carried by LTB4 is cytosolic transduced into the nucleus, where the signals act as modulators of transcription.^58,59

The pathway that disrupts the intracellular transmission, is the phosphorylation of tyrosine, threonine, serine residues or functional-structural proteins, catalyzed by cytosolic kinases of the Janus-associated kinase family type (JAK1, JAK2, JAK3, and TYK2).^60,61 JAK1 and, in particular, JAK2 are involved in signaling through cytokines and growth factors, affecting hematopoiesis and immune system function. The control of activation at the membrane level, by JAK2, is exercised by two domains: functional JH1 and JH2, which negatively regulates the first domain. The presence of a mutation in the latter domain allows the activation of JH1 and implicitly JAK2 kinase through phosphorylation^62–64. Phosphorylated JAK2 activates the signaling pathway: STAT, MAPK, ERK (Ras-Raf-MEK-ERK pathway), and PI3/akt which, on the one hand, modulates the synthesis and release of some of the cytokines involved in inflammation, and, on the other hand, induces growth proliferation, differentiation and cell survival, including at the level of red bone marrow. ⁶⁵

The processes of multiplication and differentiation, at the hematogenous medulla level, are expressed peripherally, by changing some of the parameters of the blood count, such as platelets, neutrophils, and monocytes, figurative elements that are integrated in the calculation of systemic markers of inflammation. This constitutes the scientific foundation, which allows the practitioner to evaluate, indirectly, the dimensions of inflammation in cancer, and these parameters NLR, PLR, and LMR are potential clinical prognostic markers. NLR has been repeatedly reported as a prognostic factor in ovarian cancer patients in advanced stages of the disease,^11,66–69 in patients with other tumor locations^70,71 or may be useful in selecting patients for different types of immunotherapy.^66,72