Impact of Chemokine Axes on Survival and Tumor Progression in Ovarian Cancer

Chemokines, by binding to specific G protein-coupled receptors, orchestrate cell migration critical for development, inflammation, and immune responses. In cancer, chemokines regulate tumor cell proliferation, angiogenesis, stem-like cell traits, and metastasis, significantly influencing tumor immunity and disease progression. The chemokine profile within the tumor microenvironment shapes immune cell composition and intercellular interactions via distinct chemokine axes, thereby affecting cancer prognosis. Ovarian cancer primarily spreads within the peritoneal cavity through peritoneal dissemination, differently from hematogenous metastasis through blood and lymph vessel spread observed in other cancer types. This review synthesizes the multifaceted roles of chemokines in ovarian cancer, the deadliest gynecologic malignancy with poor survival rates. By integrating evidence from cell lines, animal models, and clinical studies, this work elucidates the pivotal role of chemokines in driving ovarian cancer progression and peritoneal metastasis. It highlights the differential impacts of specific chemokine axes on patient survival: CCL7/8-CCR2 and CXCL13-CXCR5 axes associated with improved outcomes; CXCL7-CXCR2, CXCL14, and CXCL12-CXCR7 axes linked to poorer survival; XCL1/2-XCR1, CCL15/16/23-CCR1, CCL11/15/26-CCR3, CCL4/11/16-CCR5, CCL27-CCR10, CXCL6-CXCR1, and CXCL17-CXCR8 axes showing no significant effect; and the CCL18 and CXCL11-CXCR3 axes yielding controversial results.

- ovarian cancer - chemokines - tumor microenvironment - peritoneal metastasis - overall survival 1. Introduction Ovarian cancer is the most lethal gynecological malignancy, primarily due to late-stage diagnosis and nonspecific early symptoms. This heterogeneous disease encompasses epithelial (~90% of cases, originating from the ovaries, fallopian tubes, or peritoneum), germ cell, and sex cord-stromal tumors [1]. Epithelial subtypes include high-grade serous carcinoma (HGSC; 70%), endometrioid carcinoma (10%), clear cell carcinoma (10%), mucinous carcinoma (3%), and low-grade serous carcinoma (<5%) [2]. Malignant ascites, a hallmark of advanced disease, promotes peritoneal dissemination, therapeutic resistance, and poor clinical outcomes [3]. Ascites and omental tumor microenvironments create a premetastatic niche and immunosuppressive milieu by secreting cytokines and chemokines, thereby driving tumor proliferation, metastasis, and immune evasion [4]. Chemokines are chemoattractant cytokines that recruit immune cells to the tumor microenvironment by interacting with specific receptors, shaping the immune contexture, and influencing cancer progression and prognosis [5]. They are classified into four groups based on the number of amino acids between the first cysteine (C) motifs: C (XCL1-2), CC (CCL1-28), CXC (CXCL1-17), and CX3C (CX3CL1). Each chemokine binds to specific chemokine receptors (XCR1, CCR1-10, CXCR1-8, and CX3CR1), regulating angiogenesis, immune networks, and cellular functions, thus forming distinct chemokine axes as follows: the XCL-XCR axis, the CCL-CCR axis, the CXCL-CXCR axis, and the CX3CL-CX3CR axis (Table 1). | Chemokine axis family | Chemokine axis subfamily | |---|---| | The XCL-XCR axis | The XCL1/2-XCR1 axis | | The CCL-CCR axes | The CCL3/5/7/8/14/15/16/23-CCR1 axis | | The CCL2/7/8/13/16-CCR2 axis | | | The CCL5/7/11/13/14/15/24/26/28-CCR3 axis | | | The CCL17/22-CCR4 axis | | | The CCL3/4/5/8/11/14/16-CCR5 axis | | | The CCL20-CCR6 axis | | | The CCL19/21-CCR7 axis | | | The CCL1/16-CCR8 axis | | | The CCL25-CCR9 axis | | | The CCL27/28-CCR10 axis | | | The CXCL-CXCR axes | The CXCL6/7/8-CXCR1 axis | | The CXCL1/2/3/5/6/7/8-CXCR2 axis | | | The CXCL4/9/10/11-CXCR3 axis | | | The CXCL12-CXCR4 axis | | | The CXCL13-CXCR5 axis | | | The CXCL16-CXCR6 axis | | | The CXCL11/12-CXCR7 axis | | | The CXCL17-CXCR8 axis | | | The CX3CL-CX3CR axis | The CX3CL1-CX3CR1 axis | Chemokines bind to specific G protein-coupled receptors (GPCRs) on target cell surfaces, initiating intracellular signaling cascades, including PLC, PI3K, MAPK, and JAK pathways. These cascades drive diverse cellular responses, such as migration, adhesion, survival, proliferation, and differentiation (Figure 1). The chemokine signaling axis orchestrates the peritoneal tumor microenvironment in ovarian cancer by facilitating communication among cancer, immune, and stromal cells (Figure 1). Chemokine signatures in ovarian cancer reveal distinct expression profiles between cell lines and tumor tissues, driven by the heterogeneity of the tumor microenvironment [6]. In human ovarian cancer cell lines, dominant expression of chemokines CXCL1-4, CXCL8, CXCL16, and the receptor CXCR4 was observed (Figure 2). Notably, ovarian cancer exhibits a high frequency of p53 mutation compared to other cancer types [7]. These mutations correlate with distinct chemokine signatures and differential overall survival outcomes between p53 wild-type and mutant ovarian cancers [7]. This chapter compiles comprehensive literature data on chemokines in ovarian cancer, encompassing clinical characteristics in patients, in vitro findings from ovarian cancer cell models, and in vivo results from animal models for ovarian cancer. This chapter elucidates the functional roles of chemokine axes in ovarian cancer, focusing on chemokine signature, overall survival, and clinicopathologic features in patients. Additionally, it explores the molecular mechanisms of chemokines derived from ovarian cancer cells and tumor-bearing animal models. Overall survival data for serous ovarian cancer (n = 1207) were sourced from the Kaplan-Meier Plotter database ( 2. The XCL1/2-XCR axis XCL1, XCL2, and XCR1 expression levels do not significantly influence survival [7]. 3. The CCL-CCR axis 3.1 The CCL3/5/7/8/14/15/16/23-CCR1 axis High CCL3 levels correlate with improved survival in the serous subtype (HR = 0.75; 95% CI = 0.62–0.90), but show no association with TP53 mutation status (mutant vs. wild-type) [7]. CCL3 antibody reduces tumor metastasis in animal models [8]. CCL5 is associated with improved survival in the serous subtype (HR = 0.81; 95% CI = 0.68–0.97) and TP53 mutant tumors [7]. Elevated CCL5 expression correlates with tumors harboring DNA damage repair gene somatic mutations [9, 10] and T-cell infiltration [11]. Macrophage (Mφ)-derived CCL5 promotes tumor-mesothelial cell adhesion [12]. CCL5 increases cell proliferation through MEK/Erk activation and Jun, NF-κB2, and Traf2 expression [13], and stromal-secreted CCL5 induces chemoresistance via IL-6/PYK2 signaling [14]. CCL5 was elevated in cancer stem-like cells (CSCs) [15], driving endothelial differentiation and tumor angiogenesis through CCR1/3/5-dependent NF-κB and STAT3 pathways [16]. In non-CSCs, CCL5 promotes epithelial-mesenchymal transition (EMT), MMP9, and tumor invasion via NF-κB activation [17, 18]. Cisplatin-induced CCL5 secretion from cancer-associated fibroblasts (CAFs) promotes cisplatin resistance through STAT3 and Akt activation [19]. Additionally, CCL5 enrichment in immune cells (T and NK cells) may support cancer cell survival in ascites [20]. CCL5 antibodies boost the antitumor effects of PARP inhibitors in murine models [21]. CCL7 levels correlate with improved survival in the serous subtype (HR = 0.75; 95%CI = 0.63–0.90), but show no association with TP53 mutation status [7]. Peritoneal Mφs from patients exhibit increased CCL7 expression, which promotes tumor cell invasion [22]. CCL8 levels correlate with improved survival in the serous subtype (HR = 0.77; 95%CI = 0.66–0.90), but show no association with TP53 mutation status [7]. CCL14 levels are linked to poor survival in the serous subtype (HR = 1.28; 95%CI = 1.07–1.52), but show no association with TP53 mutation status [7]. Contrarily, CCL14 upregulation in tissue microarray samples is associated with better prognosis [23]. Neither CCL15 nor CCL16 impacts survival outcomes [7]. CCL23 shows no impact on survival outcomes [7], although high CCL23 levels are detected in ascites and sera of patients [24]. CCL23, secreted by Mφs, contributes to immunosuppression by inducing T-cell exhaustion [24] and promotes tumor colonization in the omentum via CCR1 by activating Erk1/2 and PI3K pathways [25]. CCR1 shows no impact on survival outcomes [7]. Blocking CCR1 reduces the invasion of CSCs [18]. 3.2 The CCL2/7/8/13/16-CCR2 axis CCL2 is associated with improved survival in the serous subtype (HR = 0.78; 95%CI = 0.65–0.94), but shows no association with TP53 mutation status [7]. CCL2 promotes cell proliferation, migration, and invasion via the MEK/Erk/MAP3K19 and PI3K/Akt/mTOR pathways [26–28]. CCL2 is expressed at higher levels in the ascites of obese mice [29]. Serum CCL2 levels are elevated in primary ovarian cancer, correlating with histological grade and age at diagnosis, but not with overall survival [30], while both the lowest and highest values of CCL-2 show poor prognosis [31]. CCL2 is highly expressed in tumors with intraepithelial T cells [11], but is downregulated in most cancer cell lines and primary adenocarcinomas [32]. Increased tumoral CCL2 expression correlates with improved survival [33]. However, low CCL2 expression in tissue microarray is a feature of HGSOC and does not correlate with survival [34]. CCL2 contributes to paclitaxel resistance via NF-κB-mediated PI3K/Akt activation, while CCR2 inhibitors enhance paclitaxel sensitivity in murine models [35]. Similarly, CCL2 antibodies improve paclitaxel and carboplatin therapy outcomes [36]. CCL2 from cancer-associated mesothelial cells drives peritoneal metastasis via the p38-MAPK pathway [37], and stromal CCL2 induces IL-6/PYK2-dependent chemoresistance [22]. Omental adipocyte-derived CCL2 enhances cell migration and metastasis via the PI3K/Akt/mTOR pathway [28]. CCL7, CCL8, and CCL16 are described within the context of the CCL3/5/7/8/14/15/16/23-CCR1 axis. CCL13 levels correlate with improved survival in the serous subtype (HR = 0.67; 95% CI = 0.57–0.79), but show no association with TP53 mutation status [7]. Conversely, high tumoral CCL13 expression is associated with shorter survival and promotes migration and invasion while inhibiting apoptosis [38]. CCL13 upregulates MMP-2, MMP-9, N-cadherin, vimentin, and Bcl2/Bax, downregulates E-cadherin, and activates the p38 MAPK pathway, thereby enhancing cancer progression [38]. CCR2 levels correlate with improved survival in the serous subtype (HR = 0.82; 95%CI = 0.69–0.97), but show no association with TP53 mutation status [7]. CCR2 facilitates leukocyte recruitment to the tumor microenvironment, and its genetic deletion reduces tumor burden [39]. CCR2 inhibitors enhance paclitaxel sensitivity in murine models [35] and, when combined with bevacizumab, sustain anticancer effects [40]. CCR2 antagonists reduce CCL2-induced cell invasion and adhesion [41]. 3.3 The CCL5/7/11/13/14/15/24/26/28-CCR3 axis CCL5, CCL7, CCL13, CCL14, and CCL15 are described within the context of the CCL3/5/7/8/14/15/16/23-CCR1 axis and the CCL2/7/8/13/16-CCR2 axis. CCL11 does not affect survival [7]. CCL11 promotes cell proliferation, migration, and invasion, effects that are inhibited by antibodies against CCR2, CCR3, and CCR5, through the activation of Erk1/2, MEK1, and STAT3 [42]. In the serous subtype, CCL24 is associated with favorable survival (HR = 0.83; 95% CI = 0.70–0.97), but shows no association with TP53 mutation status [7]. CCL26 has no survival impact [7]. Conversely, CCL28 is linked to poor survival in the serous subtype (HR = 1.39; 95% CI = 1.10–1.75). CCR3 does not impact survival [7]. CCR3 is highly expressed in ovarian cancer cells, and its specific inhibitor reduces cell invasion [22]. Additionally, CCR3 inhibition suppresses CCL11-induced proliferation, migration, and invasion of cancer cells [43], as well as the invasion of ovarian CSCs [18]. 3.4 The CCL17/22-CCR4 axis CCL17 does not significantly affect survival [7], but it improves survival in other studies using Xenabrowser [44]. CCL22 is associated with improved survival in the serous subtype (HR = 0.83; 95% CI = 0.71–0.98), but shows no association with TP53 mutation status [7]. CCL22 is present in ascitic fluid, where it promotes CCR4 + T-cell enrichment [45, 46]. Plasma CCL22 is elevated in stage IV patients compared to stages I and III [47]. CCR4 shows no survival impact [7]. In a CCL22-secreting ovarian cancer humanized mouse model, CCR4 antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs [48]. 3.5 The CCL3/4/5/8/11/14/16-CCR5 axis CCL3, CCL5, CCL8, CCL11, CCL14, and CCL16 are described within the context of the CCR1/CCR2/CCR3 axis. CCL4 shows no survival impact [7]. CCL4 levels were reduced in the sera of patients [49], but it was highly expressed in tumors with intraepithelial T cells [11]. CCR5 has no impact on survival [7]. CCR5 antagonists suppress CCL5-induced intracellular Ca2 + flux and proliferation [50]. CD4 + T cells delay the progression of MHC class II-negative ovarian cancer by secreting CCL5, which recruits CCR5 + dendritic cells [43]. While CCR5 antagonist maraviroc does not affect cell viability, it enhances apoptosis induction, cell cycle blockage, DNA damage, and ROS formation [51]. 3.6 Orphan ligand CCL18 CCL18 is associated with improved survival in the serous subtype (HR = 0.78; 95% CI = 0.67–0.90) [52], but shows no association with TP53 mutation status [7]. Serum CCL18 levels are significantly higher in ovarian cancer [52, 53]. High CCL18 expression correlates with worse FIGO staging and poor survival, which is associated with serum levels, not mRNA levels [53, 54]. ZEB1-induced CCL18 expression promotes M2-TAM aggregation and CD8 + T-cell apoptosis, aiding immune escape [55]. CCL18 increases cell migration, invasion, and adhesion, but not proliferation, and ascitic CCL18 levels are correlated with enhanced cell migration, which is attenuated by CCL18 antibodies [54, 56]. High CCL18 mRNA levels are linked to increased metastasis and worse survival, mediated partly through the mTORC2 pathway [57]. 3.7 The CCL20-CCR6 axis CCL20 shows improved survival in the serous subtype (HR = 0.84; 95% CI = 0.70–1.00) but no association with TP53 mutation status [7]. Serum CCL20 levels are elevated in ovarian cancer [58]. The CCL20-CCR6 axis drives metastasis by promoting migration and invasion in high-CCR6 cancer cells, with effects reversed by CCR6 blockade [59]. CCL20 upregulates N-cadherin and versican while downregulating E-cadherin, with CCR6 knockout blocking these changes [59]. Cisplatin-stimulated Mφs increase CCL20 production, activating CCR6 on ovarian cancer cells and inducing EMT to enhance cell migration [60]. CCL20 promotes paclitaxel resistance in CD44 + CD117 + cells via Notch1 signaling [61] and doxorubicin resistance by regulating ABCB1 expression [62]. NF-κB-mediated CCL20, potentiated by CXCR2, is a key chemokine network in the peritoneal dissemination of ovarian cancer [6]. CCR6 has no impact on survival in the serous subtype [7], while high CCR6 correlates with increased metastasis and poor prognosis in TP53 mutant tumors [60]. 3.8 The CCL19/21-CCR7 axis CCL19 has no overall survival impact [7]. CCL21 has no overall survival impact [7]. However, CCL21 is associated with poor survival in TP53 wild-type tumors [7]. Serum CCL21 levels are elevated in ovarian cancer patients [63]. CCR7 is associated with improved survival in serous ovarian cancer (HR = 0.84; 95% CI = 0.70–1.00), but shows no association with TP53 mutation status [7]. CCR7 is overexpressed in ovarian cancer, correlating with advanced FIGO stage and lymph node metastasis [64]. 3.9 The CCL1/16-CCR8 axis CCL1 has no overall survival impact [7]. CCL16 is described within the context of the CCL3/5/7/8/14/15/16/23-CCR1 axis. CCR8 is associated with improved survival in serous ovarian cancer (HR = 0.78; 95% CI = 0.67–0.91), but shows no association with TP53 mutation status [7]. The CCL1-CCR8 axis promotes the migration and infiltration of CD4 + CCR8 + Tregs into ovarian tumors [65]. 3.10 The CCL25-CCR9 axis CCL25 is associated with improved survival in the serous subtype (HR = 0.78; 95% CI = 0.66–0.91), but shows no association with TP53 mutation status [7]. CCL25 is linked to a decreased risk of ovarian cancer [44]. High CCL25 and CCR9 expressions are observed in serous adenocarcinoma [66]. CCR9 has no impact on survival [7]. The CCR9-CCL25 axis reduces cisplatin-induced apoptosis by enhancing anti-apoptotic signaling, including Akt activation, as well as GSK-3β and FKHR phosphorylation [67]. CCR9 antibody inhibits CCL25-induced migration and invasion of cancer cells [66]. 3.11 The CCL27/28-CCR10 axis CCL27 and CCR10 have no overall survival impact [7]. CCL28 is described within the context of the CCL5/7/11/13/14/15/24/26/28-CCR3 axis. 4. The CXCL-CXCR axis 4.1 The CXCL6/7/8-CXCR1 axis CXCL6 has no overall survival impact [7]. CXCL7 is associated with poor survival in the serous subtype (HR = 1.19; 95%CI = 1.01–1.40), but shows no association with TP53 mutation status [7]. CXCL8 is highly expressed in ovarian cancer cells (Figure 2) and is associated with improved survival in the serous subtype (HR = 0.81; 95% CI = 0.69–0.96), but shows no association with TP53 mutation status [7]. Consistently, high CXCL8 expression correlates with better prognosis [68]. CXCL8 is significantly elevated in cancerous tissue, ascites, serum, and recurrent tumors, and is associated with ovarian cancer stage, grade, and lymph node metastasis [69–71]. Proinflammatory cytokines (IL-1, TNF) induce CXCL8 via NF-κB signaling, while IFNγ upregulates it through JAK1/STAT1 and NF-κB pathways, promoting proliferation, migration, and invasion [72–74]. TAMs-derived CXCL8 enhances invasion via Wnt/β-catenin-mediated TRIM46 upregulation [75]. It drives EMT, metastasis, and angiogenesis by acting on endothelial CXCR1/2 receptors, activating the Erk pathway, and promoting endothelial cell proliferation, tube formation, and migration [70, 76, 77]. CXCL8 contributes to paclitaxel resistance via GSK-3β/p70S6K1 signaling and reduces bortezomib effectiveness, which is improved by IKK inhibition [78–80]. Proteasome inhibition increases CXCL8 expression, contributing to resistance [78]. CXCL8 knockdown reduces tumor growth and M2 Mφ infiltration [81]. CXCR1 has no impact on survival [7]. CXCR1 is upregulated in advanced cancer tissues and correlates with stage, grade, and lymph node metastasis [70]. 4.2 The CXCL1/2/3/5/6/7/8-CXCR2 axis CXCL1 is highly expressed in ovarian cancer cells (Figure 2) [6, 68, 72]. Serum CXCL1 levels are significantly elevated in patients, increasing with disease stage [82]. High CXCL1 expression in ascites is notable in undifferentiated cancers [83]. CXCL1 promotes tumor progression by: 1) enhancing angiogenesis through CXCR1/2 receptor-mediated endothelial cell proliferation, tube formation, and migration [76]; 2) driving cancer cell proliferation via EGFR transactivation and p38 activation in ovarian fibroblasts [84, 85]. Despite its tumorigenic roles, high serum CXCL1 expression is associated with improved survival [52]. However, CXCL1 mRNA levels have no impact on survival in the serous subtype, with no association with TP53 mutation status [7]. In obese mice, higher circulating CXCL1 levels correlate with earlier ovarian cancer onset, increased peritoneal metastasis, and a trend toward shorter survival [29]. CXCL2 exhibits high expression in ovarian cancer cells (Figure 2) and is significantly upregulated in platinum-resistant epithelial ovarian cancer, promoting cisplatin resistance [86]. CXCL2 knockdown or antibody treatment enhances cisplatin sensitivity [86]. CXCL2 is highly expressed in epithelial cancer tissues, correlating with tumor differentiation, stage, and metastasis [87]. However, high CXCL2 expression does not independently predict prognosis [87] and has no impact on survival [7]. CXCL3 expression is high in ovarian cancer cells (Figure 2) but significantly reduced in ovarian cancer patients [68]. High CXCL3 expression is associated with better prognosis in the serous subtype (HR = 0.82, 95% CI = 0.70–0.97) and improved outcomes [68], but shows no association with TP53 mutation status [7]. CXCL5 has no impact on survival [7]. Elevated CXCL5 levels are observed in ascites [83]. Bevacizumab combined with paclitaxel and platinum-based chemotherapy reduces serum CXCL5 levels in post-tumor debulking surgery, correlating with improved survival [88]. CXCL6, CXCL7, and CXCL8 are described within the context of the CXCL6/7/8-CXCR1 axis. CXCR2 expression is elevated in advanced serous ovarian cancer tissues, correlating with higher tumor stage, grade, and lymph node metastasis [70]. High CXCR2 expression is associated with poor survival in TP53-mutant tumors [7] and serves as a prognostic and immunological biomarker, as well as a potential immunotherapeutic target [89]. CXCR2 knockdown reduces tumor growth and M2-Mφ infiltration [81]. Increased CXCR2 levels in peritoneal fluid, but not serum or tumor tissue, correlate with histological differentiation stage [69]. CXCR2 inhibition re-sensitizes ovarian cancer to cisplatin [90], enhances antitumor and antiangiogenic responses [91], and promotes mitotic catastrophe in both chemo-sensitive and chemo-resistant ovarian cancer cells, independent of p53 status [92]. The CXCL1/8-CXCR2 axis drives progression by upregulating proinflammatory chemokines via EGFR-transactivated Akt and NF-κB signaling [93]. CXCR2 also negatively regulates p21 via Akt-mediated Mdm2 in a p53-independent manner [94] and enhances metastatic potential through the TAK1/NF-κB cascade [95]. CXCR2 blockade reduces tumor growth by decreasing tumor-associated neutrophils and increasing CD8 + T cell activity [96]. CXCR2 promotes ovarian cancer progression through dysregulated cell cycle, reduced apoptosis, and enhanced angiogenesis [97]. 4.3 The CXCL4/9/10/11-CXCR3 axis CXCL4 expression is high in ovarian cancer cells (Figure 2) with no impact on survival [7]. CXCL9 is downregulated in ovarian cancer tissues [98]. However, high CXCL9 levels are observed in epithelial ovarian cancer [99] and correlate with tumor stage [100]. High CXCL9 expression is associated with improved overall survival in the serous subtype (HR = 0.76; 95% CI = 0.63–0.92) [68] and TP53-mutant tumors, but not in TP53 wild-type tumors [7]. CXCL9 inhibits tumor growth and enhances anti-PD–L1 therapy in preclinical ovarian cancer models [101]. CXCL9’s angiostatic properties may suppress epithelial ovarian cancer progression [102]. CXCL10 expressions are significantly upregulated in ovarian cancer, particularly in serous epithelial tumors and HRD tumors [9, 68, 99]. High CXCL10 expression is associated with longer overall survival in the serous subtype (HR = 0.77; 95% CI = 0.66–0.90) [100] and prolonged prognosis, correlating with increased infiltration of immune cells [103]. Low CXCL10 expression is linked to poor prognosis and reduced immune infiltration [44, 103]. No difference in survival is observed between TP53-mutant and wild-type tumors [7]. CXCL10 inhibits epithelial ovarian cancer progression by enhancing cytotoxic T cell activity and suppressing angiogenesis [104]. It is produced by M1-type TAMs in immune-infiltrated high-grade serous carcinoma [105]. Dendritic cell-derived CXCL10 restrains tumor growth and metastasis by activating cytotoxic T lymphocytes [106]. In contrast, adipocyte-derived CXCL10 in obesity promotes cell migration and invasion [107], and omentum-derived adipose stem cells in ovarian cancer patients are a novel CXCL10 source [108]. CXCL10 overexpression reduces tumor burden and malignant ascites in syngeneic murine high-grade serous carcinoma models, while reduced CXCL10 expression increases ascites and disease progression [109]. Intraperitoneal CXCL10 administration inhibits tumor growth [110]. In BRCA2 wild-type epithelial ovarian cancer, treatment with the CXCL10/CXCR3 antagonist AMG487 attenuates Treg induction and IL10 production [111]. CXCL11 is upregulated in ovarian cancer [68, 104]. High CXCL11 expression is linked to improved survival in the serous subtype (HR = 0.73; 95% CI = 0.61–0.88) and TP53-mutant tumors, but not in wild-type tumors [7]. CXCL11 is associated with reduced ovarian cancer risk [44] and correlates with tumor stage and longer survival [68, 100]. Conversely, high CXCL11 expression in tissue microarray predicts worse survival in HGSOC [112]. CXCL11 promotes M1 Mφ polarization via the Jak2-Stat1 signaling pathway, acting as a favorable prognostic biomarker [113]. It mediates Twist1-induced angiogenesis in epithelial ovarian cancer [114]. CAFs-derived CXCL11 promotes cell proliferation and migration via CXCR3, which is expressed in malignant cells [115]. CXCR3 expression does not significantly impact overall survival [7]. However, a high CXCR3 immunohistochemistry score in advanced cancer is linked to reduced survival [116], although it is associated with higher tumor grade and lymph node metastasis [115]. CXCR3 mediates cell migration toward malignant ascites, which can be inhibited by CXCR3 antibody [116]. In a p53-negative epithelial ovarian cancer mouse model, CXCR3 antibody treatment reduced tumor ascites and extended survival [111]. 4.4 The CXCL12-CXCR4 axis CXCL12 expression is elevated in tumor tissues [68], in ascites [83], and in obese mouse models [29]. Plasma CXCL12 levels are significantly higher in FIGO stage III patients compared to stage I [117]. High CXCL12 expression is linked to poor survival in the serous subtype (HR = 1.32; 95% CI = 1.13–1.55) [68] and TP53 wild-type tumors [7]. Primary and recurrent serous carcinoma, including CXCL12-positive immune cells, correlate with chemosensitivity and improved overall survival [118]. CXCL12-positive CAFs are linked to poor prognosis and chemotherapy resistance in HGSOC [119]. The CXCL12-3’A polymorphism is associated with poor chemotherapy response and reduced survival rates [120]. CXCL12 promotes cell proliferation, migration, and invasion by activating Erk1/2, Akt [121, 122], αvβ6 integrin [123], and MMP-9/MMP-2 [124], and through EGF receptor transactivation [125]. CXCL12 suppresses ARHGAP10 expression, enhancing cell invasion [126], and elicits intracellular calcium flux, migration, and integrin expression changes [127]. CAF-derived CXCL12 promotes peritoneal metastasis by inducing EMT [128]. CXCL12 knockdown reduces cell proliferation and tumor growth [129]. CXCR4 is highly expressed in ovarian cancer cells (Figure 2). High CXCR4 immunohistochemistry score is associated with unfavorable prognosis and reduced chemosensitivity, correlating with lower overall survival [130]. However, some studies link high CXCR4 mRNA expression to better prognosis [131]. CXCR4 expression is linked to improved survival in TP53-mutant tumors [7]. The CXCL12-CXCR4 axis promotes cell proliferation, migration, invasion, and metastasis by activating Erk1/2, Akt [121], integrin β1/β3 [132], RhoA, Rac-1/Cdc42 [133], and NF-κB pathways, and inducing EMT [134]. CXCR4 mediates peritoneal dissemination via Sp1-dependent CXCL12 signaling and extracellular matrix-directed spheroid formation [135]. CXCL12-stimulated growth is abrogated by CXCR4 antibodies [136], while cisplatin-induced CXCR4 expression promotes proliferation of CSCs [137]. The Notch pathway enhances tumor growth and metastasis via the CXCL12-CXCR4 axis [138]. CXCR4 antagonists (e.g., AMD3100) inhibit CXCL12-induced proliferation, migration, and EMT [121, 134], enhance paclitaxel chemotherapy [139], and reduce tumor burden, metastasis, and angiogenesis [140]. They also increase tumor apoptosis/necrosis while reducing Treg infiltration [129]. CXCR4 blockade inhibits tumor growth and metastasis by enhancing CD8 + T cell infiltration and reducing immunosuppression [141]. CXCR4 knockdown inhibits proliferation, invasion, and metastasis, promotes apoptosis via ASK1/c-Jun activation, and enhances chemosensitivity by reducing RhoA, Rac-1/Cdc42, Wnt, vimentin, and Slug expression [130, 133, 140, 142]. 4.5 The CXCL13-CXCR5 axis Ovarian cancer cells typically exhibit low CXCL13 expression [68, 104]. High CXCL13 levels in ascites are observed in obese mice [29] and are linked to improved survival in the serous subtype and TP53 mutant tumors [7, 68, 143]. CXCL13 is generally associated with a decreased risk of ovarian cancer [44], though one study reported an increased risk [144]. The positive association with CXCL13 is stronger in non-HGSOC, overweight/obese women, and postmenopausal women [144]. High CXCL13 expression correlates with increased infiltration of CXCR5-expressing CD8 + T cells, enhancing the immune response [143]. CXCL13 expression is associated with tumor stage and longer overall survival [100]. CXCR5 expression levels are linked to tumor stages [145]. High CXCR5 expression is associated with improved survival in the serous subtype [145], but shows no association with TP53 mutation status [7]. 4.6 Orphan ligand CXCL14 CXCL14 expression is upregulated in ovarian cancer tissues [68, 104], while healthy controls have higher serum CXCL14 levels [146]. High CXCL14 expression is linked to poor survival in the serous subtype (HR = 1.26; 95%CI = 1.08–1.48) [68, 147] but shows no association with TP53 mutation status [7]. Upregulated CXCL14 promotes cell proliferation and metastasis by activating the Wnt/β-catenin signaling pathway [147]. 4.7 The CXCL16-CXCR6 axis CXCL16 is highly expressed in ovarian cancer cells (Figure 2) and tumor tissues [68]. CXCL16 expression does not affect survival [7, 68]. Elevated serum CXCL16 independently predicts poor survival [148]. However, low CXCR6 expression is associated with shorter survival [145]. High CXCL16 levels are linked to aggressive ovarian cancer, promoting disease progression through CXCR6 activation and MMP modulation [149]. TAMs enhance cisplatin resistance in ovarian cancer cells via the CXCL16-CXCR6 axis by increasing RNA methylation [150]. CXCL16 knockdown in TAMs or CXCR6 in ovarian cancer cells reduces cisplatin resistance [150]. High CXCR6 expression is associated with improved survival in the serous subtype (HR = 0.83; 95%CI = 0.70–1.00) but shows no association with TP53 mutation status [7]. 4.8 The CXCL11/12-CXCR7 axis CXCL11 and CXCL12 are discussed within the CXCL4/9/10/11-CXCR3 and CXCL12-CXCR4 axes, respectively. CXCR7 levels are high in ovarian cancer tissues [145]. High CXCR7 expression is associated with poor survival in the serous subtype (HR = 1.26; 95%CI = 1.06–1.50) [145] but shows no association with TP53 mutation status [7]. The CXCL11-CXCR7 axis, under ERα control, promotes EMT and metastasis in ovarian cancer cells [151]. The CXCL12-CXCR7 axis enhances cell invasion by upregulating MMP-9 expression via the p38 MAPK pathway [152]. 5. The CX3CL1-CX3CR1 axis CX3CL1 is elevated in the sera of advanced ovarian cancer patients [82]. High CX3CL1 expression correlates with worse survival in advanced HGSOC [153]. However, it shows a better survival in the serous subtype (HR = 0.84; 95% CI = 0.71–0.99), but shows no association with TP53 mutation status [7]. Through binding to CX3CR1, CX3CL1 promotes Akt activation and cell proliferation, driving intraperitoneal tumor growth despite increased T-cell recruitment [153]. CX3CR1 expression is associated with poor survival in the serous subtype (HR = 1.26; 95% CI = 1.06–1.50) [154], but shows no association with TP53 mutation status [7]. Hypoxia-inducible factor-1α upregulates CX3CR1 expression, promoting EMT in ovarian cancer cells [155]. 6. Summary/conclusion Chemokines significantly influence ovarian cancer progression by modulating the peritoneal tumor microenvironment through immune cell recruitment, cell-to-cell communication, metastasis, chemoresistance, and tumor growth, ultimately affecting prognosis and survival. Chemokine axes primarily drive cell migration and invasion over proliferation, altering the immune contexture and overall survival. They regulate EMT genes, immune cell infiltration, tumor size, grade, and stage, while some promote tumor growth and angiogenesis by enhancing cell viability and angiogenic gene expression. Certain chemokines also contribute to cancer recurrence and chemoresistance, reducing therapeutic efficacy. In ovarian cancer, survival outcomes vary by chemokine-receptor axis (Figure 3A): The XCL-XCR axis shows unchanged survival. Survival outcomes in the CCL-CCR axis are as follows: good survival in CCL3, CCL5, CCL7, CCL8, CCL20, CCL22, CCL24, CCL25, CCR2, CCR7, and CCR8; poor survival in CCL28; unchanged survival in CCL1, CCL4, CCL11, CCL15, CCL16, CCL19, CCL23, CCL26, CCL27, CCR1, CCR3, CCR4, CCR5, CCR9, and CCR10; controversial survival in CCL2, CCL13, CCL14, CCL17, CCL18, CCL21, and CCR6. Survival in the CXCL-CXCR axis are as follows: good survivals in CXCL3, CXCL8, CXCL9, CXCL10, CXCL13, CXCR5, and CXCR6; poor survivals in CXCL7, CXCL12, CXCL14, CXCR2, CXCR7, and CX3CR1; unchanged survival in CXCL2, CXCL4, CXCL5, CXCL6, CXCL17, CXCR1, and CXCR8; controversial survival in CXCL1, CXCL11, CXCL16, CXCR3, and CXCR4. Orphan chemokines CCL18 and CXCL14 have controversial and poor survival, respectively. Survival in the CX3CL1-CX3CR1 axis shows controversial survival for CX3CL1 and poor survival for CX3CR1. Chemokine axes associated with patient survival are summarized as follows (Figure 3B): CCL7/8-CCR2 and CXCL13-CXCR5 correlate with improved survival; CXCL7-CXCR2, CXCL14, and CXCL12-CXCR7 with poor survival; XCL1/2-XCR1, CCL15/16/23-CCR1, CCL11/15/26-CCR3, CCL4/11/16-CCR5, CCL27-CCR10, CXCL6-CXCR1, and CXCL17-CXCR8 show no significant association; while CCL18 and CXCL11-CXCR3 display conflicting associations. Mechanistically, CCL7/8-CCR2 and CXCL13-CXCR5 likely enhance survival by recruiting leukocytes and cytotoxic CD8⁺ T cells into the tumor microenvironment [39, 143], thereby suppressing tumor progression. In contrast, CXCL7-CXCR2 promotes tumor growth and poor survival by increasing M2-Mφ infiltration, activating Akt and NF-κB, and reducing CD8⁺ T cell infiltration and p21 expression [81, 93, 94, 96]. CXCL14 appears to decrease survival by promoting proliferation and metastasis via Wnt/β-catenin activation [147]. Similarly, CXCL12-CXCR7 likely induces ERK1/2 and Akt activation and upregulates MMP-9, enhancing migration and invasion, and leading to poor survival [121, 122, 124, 152]. Conflicts in survival outcomes reported across studies may arise from methodological differences, variations in patient cohorts, or inconsistencies in sample measurement, underscoring the need for additional research. Although a single chemokine may exert a dominant effect in isolated cell models, its influence can vary dramatically when interacting with other cell types within the tumor microenvironment. In the peritoneal tumor microenvironment of ovarian cancer, distinct chemokine expression profiles among tumor cells, stromal cells, immune cells, and adipocytes reveal intricate cell-to-cell communication networks that cannot be explained by any one chemokine alone. Despite extensive study of CXCL12 and CXCR4, the roles of many other chemokines in ovarian cancer remain poorly understood, warranting further investigation. Chemokines drive ovarian cancer progression through specific receptor interactions, modulating the peritoneal tumor microenvironment by recruiting immune cells, facilitating cell-to-cell crosstalk, promoting metastasis and chemoresistance, and enhancing tumor growth, ultimately influencing patient prognosis and survival. Acknowledgments This work was supported, in whole or in part, by research funds from the National Institutes of Health (NIH) and the American Cancer Society (ACS) as follows: U54MD007586, U54CA163069, and ACS DICRIDG-21-071-01-DICRIDG.

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