Around 15% of all malignancies are caused due to chronic or persistent inflammation (Kuper et al., 2000). Persistent inflammation can perpetuate tumor progression and in turn, tumor-induced inflammation promotes cancer growth. Developing tumors disrupt normal tissue, producing DAMPs that activate receptors on local granulocytes, triggering inflammatory processes. Tumors compress the blood and lymphatic arteries, detaching oxygen and nutrition delivery, leading to hypoxia, which signals the production of cytokines and angiogenic growth factors, recruiting macrophages and immune cells to the inflammation site (Munn, 2017).

Tumor cells secrete a variety of inflammatory mediators and cytokines/chemokines to recruit circulating immune cells to the tumor site. After infiltrating the tumor, myeloid, lymphoid, and mesenchymal cells activate various autocrine/paracrine signaling pathways and amplify the inflammatory reaction. Infiltrating cells can produce a plethora of potent soluble factors like cytokines, tumor necrotic factors, RONS, proteases like MMPs, leading to neoplastic progression (Munn, 2017) (Figure 1). Tumor-associated macrophages (TAMs), a major component of the tumor microenvironment, can generate a variety of angiogenic growth factors and proteases (Nowak and Klink, 2020). TAMs facilitate the progression of ovarian cancer at many stages of the disease development, including immune evasion of tumor cells and invasion of cancer cells. TAMs induce the invasive potential of ovarian cancer cells by secreting IL-6 and TGF-β, along with the production of MMPs (Nowak and Klink, 2020). TAMs upregulate MMP-2, -9, and -10 productions, through activating NF-κB, MAPK, and TLR signaling pathways in ovarian cancer (Ke et al., 2016).

The major inflammatory route implicated in gynecological carcinogenesis is the activation of the Cyclooxygenase-2 (COX-2)-Prostaglandin E2 (PGE2) pathway. Among the two COX isoforms, COX-1 helps in tissue integrity, proper platelet aggregation, and renal function, whereas COX-2 is predominantly expressed in inflammatory conditions and contributes to cancer development and metastasis. Upregulation of COX-2/PGE2 has been identified in many human cancers, including gynecological cancers (Liu et al., 2015; Ye et al., 2020). In early-stage uterine cervical cancer, greater levels of COX-2 expression are associated with a higher incidence of invasion and lymph node metastases (Parida and Mandal, 2014). For the cervical cancer cells to metastasize the malignant cells must have the capacity to move and infiltrate, disrupt intercellular connections, lyse extracellular matrix (ECM), and promote migration of endothelial cells and capillary lumen formation. MMP-9, and -2, and urokinase plasminogen activators play a crucial role in degrading the ECM and enabling metastatic cells to enter the vasculature and move into the target organ, resulting in tumor metastasis of cervical malignancies (Ye et al., 2020). Pentraxin 3 (PTX3), also known as the TNF-α inducible gene, is an inflammatory molecule involved in the immunological response, inflammation, and cancer. PTX3 has been known to have an essential role in tumor-associated inflammation. Positive expression of MMP-9 is linked with PTX3 expression in lung adenocarcinoma, suggesting an association of PTX3 with tumor grade and severity of malignancies (Ying et al., 2016). In human cervical cancer cells, knockdown of PTX3 reduced the tumorigenic and metastatic potential by downregulating MMP-2 and -9 activities. Furthermore, PTX-3 knockdown in mice showed reduced tumorigenicity and lung metastasis, indicating a crucial oncogenic role of PTX-3 (Ying et al., 2016).

G-coupled protein receptors (GCPR) associated with chemokine signaling are implicated in cancer migration, invasion, and metastasis (Bar-Shavit et al., 2016). Several inflammatory chemokines CCL2, CCL5, CXCL1, and CXCL12 have been implicated in gynecological cancer progression. In ovarian cancer cells, CXCL12 and its receptor CXCR4 increased the production of integrin-1β and vascular endothelial growth factor-C (VEGF-C), activating tumor vasculature in ovarian cancer (Predescu et al., 2019). In another report, CXCL5/CXCR2 axis promotes proliferation and migration of uterine cervix cells by regulating ERK and AKT pathways, contributing to its oncogenic potential (Feng et al., 2018). TAMs induce cancer cell migration by upregulating CCL20 production, activating CCR6 reception, and promoting EMT in ovarian cancer (Liu et al., 2020b). Upregulation of CXCR7 led to enhanced MMP-9 expression and cell adhesion and invasion in ovarian cancer (Yu et al., 2014).

Rapid tumor growth produces a tissue environment with low oxygen concentrations. Tumor hypoxia is known to have a role in tumor inflammation by regulating inflammatory mediator signals in both cancer and adjacent cells in the microenvironment (Jing et al., 2019). Under normoxic conditions, hydroxylation of the proline residues within the prolyl-hydroxylases of the HIF-1α takes place. This alteration enables the von Hippel-Lindau (VHL) to ubiquitinate suppressor protein that directs the proteasomal degradation of HIF-1/-2 subunits. In the absence of oxygen, HIF subunits stabilize and form heterodimers of HIF-1 and/or HIF-2 may then bind to hypoxia response element (HRE) of the target genes including ECM degrading enzymes, oncogenic growth factors, and macrophage-recruiting growth factors (DiGiacomo and Gilkes, 2018). MMP-13 is upregulated in ovarian cancer by HIF-1and leads to increased invasion and migration in vitro (Zhang et al., 2019).

In the early days, ovarian cancer treatment was mostly based on observations and opportunities, and there hasn’t been a randomized study comparing the effectiveness of debulking surgery with no surgery in advanced ovarian cancer. To this day, there is no effective therapy for HPV persistence. Cervical cancer prevention is based on the use of expensive HPV vaccinations and frequent cervical screenings, posing an economic burden on women in developing countries. (Hu and Ma, 2018). Development of precision medicine based on novel variations of conventional medicines and innovative therapeutic methods, including anti-angiogenic medicines, poly-ADP-ribose polymerase (PARP) inhibitors, growth factor signaling inhibitors, or folate receptor inhibitors, as well as numerous immunotherapeutic methods, are being trialed for use (Cortez et al., 2018).

The study of cancer risk among long-term users of non-steroidal anti-inflammatory drugs (NSAIDs) provides the strongest evidence supporting the importance of inflammation during neoplastic development. Overexpression of COX-2 and PGE2 has been seen in numerous human malignancies and pre-cancerous lesions, and COX inhibitory medications have been shown to protect against colorectal cancer and breast cancer (Eberhart et al., 1994; Sheng et al., 1997; Dirix et al., 2008). NSAIDs and selective COX-2 inhibitors delay the development of endometrial cancer, ovarian cancer, and cervical cancer (Daikoku et al., 2005; Hasegawa et al., 2005; Kim et al., 2013). Combined treatment of celecoxib (a COX-2 inhibitor) and rapamycin (a mammalian target of rapamycin complex one inhibitor, a mTORC1 inhibitor) reduces endometrial cancer (EC) progression in mouse models of EC and human EC cell lines (Daikoku et al., 2014) (Figure 1). However, in ovarian cancer, SC-560 (a COX-1 inhibitor) can suppress the production of PGE2 whereas while NS-398 and rofecoxib (COX-2 inhibitors) cannot, which suggests the COX-1 is the primary enzyme for producing PGE2 instead of COX-2 in ovarian cancer cells (Kino et al., 2005).

TNF- α is a major cytokine constitutively expressed in most malignant ovarian carcinomas and is responsible for cell proliferation, invasion, stemness by secreting cytokines, angiogenic factors, and MMPs (Madhusudan et al., 2005). Etanercept, a recombinant TNF receptor that binds to TNF- α and inactivates it, has shown therapeutic efficacy in recurrent ovarian cancer patients (Madhusudan et al., 2005). Since TNF- α exerts its effects primarily via modulating the NF-κB pathway, selective inhibitors of the NF-κB pathway, e.g., Bortezomib, have been tested in prostate cancer, myeloma, and ovarian cancer (Richardson et al., 2003; Bruning et al., 2009) (Figure 1). NF-κB/IκB signaling is an essential step for cancer cell survival and has been implicated in ovarian cancer development (De Simone et al., 2015; Tian et al., 2019). Resistance of cancer cells to chemotherapeutic agents has been associated with deregulated NF-κB activation (Zerbini et al., 2011).

IL-6 is produced in response to local proinflammatory cytokines such as TNF-α, within the tumor microenvironment and can activate JAK/STAT3, MAPK, and PI3K/AKT pathways (Johnson et al., 2018). Siltuximab, the monoclonal antibody with a high binding affinity for IL-6, showed therapeutic activity in patients with platinum-resistant ovarian cancer in Phase II clinical trial (Nowak and Klink, 2020) (Figure 1). IL-6 induced activation of JAK/STAT3 pathway via IL-6R dimerization leads to JAK2 recruitment, followed by activation and translocation of STAT3 into the nucleus, where it alters expression of genes involved in proliferation, migration, differentiation, angiogenesis, stemness, and chemoresistance (Jin, 2020; Sreenivasan et al., 2020). Targeted gene therapy using a cationic solid lipid nanoparticle system encapsulating STAT3 decoy oligonucleotides has shown to inhibit cell invasion by modulating E-cadherin and SNAI1 transcription factors and MMP-9 expression, suppressing growth and causing cell death through apoptosis and autophagy (Ma et al., 2015).

Over the years, several MMP inhibitors (MMPIs) have been discovered and trialed for use as therapeutic strategies in various cancers. Batimastat, one of the first MMPIs synthesized, had a broad range of inhibition against most MMPs and early clinical trials showed a low oral availability. Marimastat, a next-generation drug, was taken for phase 2 and 3 trials for metastatic solid tumors in lung, breast, brain, colorectal cancers. Other more specific MMPIs, such as tanomastat, a small molecule inhibitor of MMP-2, -3, -8, -9, and -13, prinomastat, which inhibits MMP-2, -3, -9, -13, and -14, and rebimastat, an inhibitor of MMP-1, -2, -3, -8, -9, -13, and -14, were then tested, in cancers (Winer et al., 2018). Ovarian carcinoma patients with platinum/paclitaxel chemotherapy were treated with BAY 12-9566 (tanomastat), showed no impact on overall survival (Hirte et al., 2006). Inhibition of non-specific targets of MMPIs, such as ADAMs and other MMPs, was the main reason behind severe side-effects, e.g., musculoskeletal syndrome, of these drugs. The advent of a new generation of MMPIs preferentially targets MMP ‘exosites’ rather than the conserved catalytic area, thereby blocking the unique function of a single MMP, showed promise in several diseases (Levin et al., 2017). In the mouse models of colorectal cancer, humanized selective monoclonal antibodies against MMP-9 (AB0041, GS-5745) were found to be effective. DX-2400 is a high-affinity, highly specific inhibitor of MMP-14 that inhibits tumor development and metastasis in vivo animal models of breast cancer and melanoma (Winer et al., 2018). D1 (A12), a therapeutic monoclonal anti-ADAM17 antibody, was tested in a mice model of ovarian showed inhibition of tumor growth (Richards et al., 2012). Computational approaches to design very specific, small-molecule inhibitors and testing their efficacy in gynecological malignancies are also being conducted via high-throughput screens (Bursavich and Rich, 2002). Together these drugs show promise for future use by preventing side effects and by minimizing inhibition of protective MMPs. In future, personalized anticancer therapies targeting individual metalloproteinases upregulated in tumors should be adopted for a better success of such inhibitors.

Metalloproteinases play a crucial role in ECM remodeling in both the normal physiological condition as well as in pathological conditions including various gynecological disorders like polycystic ovary syndrome (PCOS), preeclampsia, spontaneous abortions, and cancer. An increase in MMP-2 and -9 is seen during normal pregnancy to support vasodilation, placentation, and uterine expansion. However, a higher MMP-9 expression level can cause spontaneous abortions. The expression of MMPs gets altered during the complications in pregnancy and a decreased MMP-2 and -9 leads to vasoconstriction, hypertensive pregnancy, and preeclampsia (Chen and Khalil, 2017; Balci and Ozdemir, 2019). MMPs and their inhibitors are said to be involved in the pathogenesis and follicular development of PCOS. A higher MMP-9/TIMP-1 ratio and a decreased ADAMTS-1 have been found in PCOS patients therefore might be involved in their pathogenesis (Xiao et al., 2014; Ranjbaran et al., 2016). Metalloproteinases are key regulators for many of the changes in the tumor microenvironment, inflammation, and metastasis. The major source of MMPs, ADAMs, as well as TIMPs, is from the stromal cells that infiltrated the tissue, although cancerous cells can also express them (Egeblad and Werb, 2002). Depending on the tumor types different stromal cells secrete different metalloproteinases and their inhibitors into the extracellular matrix for the specific alteration of the milieu around the tumor. These secreted metalloproteinases show some major consequences on their activity and function; for example, neutrophil-derived MMP-9 easily gets activated due to the absence of a bound TIMP-1 molecule (Ardi et al., 2007). Metalloproteinases are regulated at different stages such as at their gene expression level, their localization, while converting from their pro-active zymogen to its active form, or by the expression of their inhibitors; and the specific context is needed while studying their pathophysiological relevance. Few of the MMPs such as MMP-2, -3, -7, -9, and -12 might provide a negative feedback loop as well. The complexity of the MMP regulation is important considering that the activity of the MMPs that are secreted from the inflammatory cells can damage the tissue and prolong the inflammatory response in chronic inflammatory diseases and cancer (Parks et al., 2004). This inflammatory response leads to the production of a large amount of ROS by the macrophages and neutrophils at the tumor site which further influences the function of MMPs by activating them via oxidation of the pro-domain cysteine and amino acid modification at its catalytic domain (Kessenbrock et al., 2010). Studies showed a prevalence of M1 cells subtype among the tumor-associated macrophages in epithelial serous ovarian cancer microenvironment and are also associated with increased IL-6 levels in patients with advanced stages. In the pre-clinical studies of OC models, it is seen that the M1 macrophages increased the metastatic potential of the cancerous cells by activating NF-κB whereas M2 subtypes were related to the cancer cell progression and the formation of spheroids. This change of subtype polarization in OC patients with advanced stages might be helpful in the prognosis of the disease and are likely to respond to chemotherapy (Maccio et al., 2020). The upregulation in the MMP secretion following the release of the inflammatory mediators such as chemokines or cytokines supports the presence of a feedback loop for tightly controlling the activities of the chemokines by the MMPs which further influence the immune response. This chemokine processing at N-/or C-terminus by the MMPs shows different effects on chemokine activity, the changes in the chemokine gradient, and the recruitment of the inflammatory cells in the inflammatory tissue, and can also regulate inflammation, and leukocytes transmigration from vasculature to tissue (Butler and Overall, 2013; Nissinen and Kahari, 2014).

Several MMPs play a role in both the pro-and anti-inflammatory pathways. For example, MMP-8 regulates skin inflammation whereas MMP-9 is shown to have an anti-inflammatory role in the inflammation of skin and glomerulonephritis (Nissinen and Kahari, 2014; Kapoor et al., 2016). Inflammation and cancer are interlaced with each other therefore when tumorigenicity and/or metastasis are increased by the inflammatory components in the tumor microenvironment, the MMPs also show their anti-inflammatory role to potentially decrease the tumorigenicity and metastasis interfering with the progression of cancer. For example, MMP-3 deficient animals with squamous cell carcinoma showed increased proliferation, tumor growth, and metastasis. Again, an overexpression of MMP-26 increased the survivability of the patient by the proteolytic degradation of ER-β in ductal carcinoma in situ. MMP-2 and -12 act on plasminogen to produce angiostatin, an anti-angiogenic component, which suppresses metastasis and tumor growth in lung cancer (Dufour and Overall, 2013).

There is an increase in stiffness of the tissue and interstitial fluid pressure, and an alteration in the blood flow is also seen with increased tumorigenicity in addition to the mechanical forces that further contribute to the progression of the tumor via proteolytic degradation of the ECM thereby altering the conformation of the substrates of the MMPs and empowering the easy recognition and proteolytic cleavage of the substrate proteins (Butcher et al., 2009). Von Willebrand factor (VWF) is a multimolecular complex, crucial for the regulation of blood clotting mechanism, is highly sensitive to the increased shear forces in the blood flow which is usually seen during an injury. The high shear forces of the blood unfold the VWF domain two by inducing the conformational changes of the complex which leads to an exposed cleavage site for ADAMTS-13. ADAMTS-13 then starts cleaving the complex into monomers thereby initiating the clotting of the blood (Zhang et al., 2009). Furthermore, the ADAM and ADAMTS family members are also correlated with the progression of the tumor. Therefore, the involvement of the mechanical forces in the regulation of the activity and function of the MMP is plausible in inflammation and cancer metastasis (Kessenbrock et al., 2010).

The complexity of the function of MMPs is discovered when it is seen to be doing more than only degrading the physical barriers. Metalloproteinases have a key role in multiple cellular pathways. Metalloproteinases are critically involved in the misbalance between the growth and anti-growth signals, the metastatic spread, apoptosis, and angiogenesis in cancerous tissues (Kessenbrock et al., 2010; Kapoor et al., 2016; Winer et al., 2018). The upregulated tumor proliferation can be achieved by either becoming self-sufficient in growth-promoting factors or by acquiring insensitivity to the anti-growth factors (Winer et al., 2018) (Figure 2).

The ECM is a complex compartment with multiple functions involved in various biochemical pathways both in the normal cellular condition as well as in the tumor microenvironment. ECM remodeling can greatly affect tumor growth, invasion, migration, metastasis, angiogenesis, and apoptosis via various cellular processes thereby promoting cancer progression. For example, Cancer-associated fibroblasts (CAFs) can enhance MMP expression as well as its activation which in turn cleaves type-I collagen, an ECM component, resulting in ECM degradation and remodeling allowing cancer cells to invade and migrate to a distant site (Erdogan and Webb, 2017; Di Martino et al., 2021). MMP-2, -9, and -14 TIMP-1 and -2 have been seen to be altered in cell proliferation, invasion, and metastasis in multiple types of cancers.

ADAM-8 is seen to be overexpressed in the inflammatory cell which can be used as a marker for the prediction of intra-amniotic inflammation during labor (Malamitsi-Puchner et al., 2006). An overexpression of ADAMTS-1, a member of the ADAMTS gene family of metalloproteinases, can also be seen in the cervix during labor suggesting the multiple functions of extracellular matrix proteins in modulating integrity of the tissue, differentiation, and migration of the epithelial cells and inflammation (Ruscheinsky et al., 2008). ADAMTS-1 regulates cytokine-mediated decidual ECM remodeling. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, induces ECM degradation whereas the anti-inflammatory cytokine TGF-β1 counterbalanced the effect of IL-1β thereby regulating the expression of ADAMTS-1 (Ng et al., 2006).