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Open access peer-reviewed chapter

Integrins in Ovarian Cancer: Survival Pathways, Malignant Ascites and Targeted Photochemistry

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Mustafa Kemal Ruhi, Brittany P. Rickard, William J. Polacheck and Imran Rizvi

Submitted: 10 July 2022 Reviewed: 22 July 2022 Published: 22 August 2022

DOI: 10.5772/intechopen.106725

Recent Advances, New Perspectives and Applications in the Treatment of Ovarian Cancer IntechOpen
Recent Advances, New Perspectives and Applications in the Treatme... Edited by Michael Friedrich

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Recent Advances, New Perspectives and Applications in the Treatment of Ovarian Cancer

Edited by Michael Friedrich

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Abstract

Integrins are surface adhesion molecules that, upon binding to ligands, cluster to form adhesion complexes. These adhesion complexes are comprised of structural and regulatory proteins that modulate a variety of cellular behaviors including differentiation, growth, and migration through bidirectional signaling activities. Aberrant integrin expression and activation in ovarian cancer plays a key role in the detachment of cancer cells from primary sites as well as migration, invasion, and spheroid formation. An emerging area is the activation or rearrangement of integrins due to mechanical stress in the tumor microenvironment, particularly in response to fluid shear stress imparted by currents of malignant ascites. This chapter describes the role of integrins in ovarian cancer with an emphasis on crosstalk with survival pathways, the effect of malignant ascites, and discusses the literature on integrin-targeting approaches in ovarian cancer, including targeted photochemistry for therapy and imaging.

Keywords

  • ovarian cancer
  • integrins
  • ascites
  • photodynamic therapy
  • targeted photochemistry

1. Introduction

High-grade serous ovarian carcinoma (HGSOC, ovarian cancer) is the most common and most fatal type of gynecologic malignancy. HGSOC accounts for 75% of all epithelial ovarian cancers and for 5% of all cancer deaths [1, 2]. In most cases, HGSOC develops without symptoms and is diagnosed at an advanced stage, when malignant cells are already disseminated within the peritoneal cavity [2, 3]. Metastasis in ovarian cancer commonly occurs via transcoelomic routes, which is associated with cell detachment from the primary tumor site and dissemination as single cells or spheroids, where alterations in cell-cell and cell-extracellular matrix adhesion play a critical role [3, 4, 5]. Among the transmembrane adhesion molecules that have altered expression and function in many cancers, including in ovarian cancer, are integrins [6]. In humans, 24 different integrins are formed by specific combinations of 18 α and 8 β non-covalently bound heterodimer subunits [7, 8]. The large extracellular domains of integrins recognize specific amino acid sequences that are found on extracellular matrix (ECM) proteins such as fibronectin, collagen, laminin, and vitronectin. The short cytoplasmic tails in the c-terminus of integrins are linked to the actin cytoskeleton [7, 9]. Upon binding to ligands, integrins cluster to form adhesion complexes, which are comprised of proteins and enzymes that play roles in maintaining bidirectional signaling activities [10, 11]. In “outside-in” signaling, integrins that are bound to ECM ligands activate signaling pathways that lead to cellular responses, including survival and differentiation. Via this physical link, integrins can also transduce signals in a force-dependent manner, when the cell is exposed to mechanical stimuli. In “inside-out” signaling, intracellular conformational changes modulate the affinity of the integrins to ECM ligands [9, 10, 11, 12, 13]. Therefore, in addition to cell adhesion, a variety of cellular behaviors including differentiation, growth, and migration, can be mediated by integrins [7, 11]. In cancer, the expression and activation of integrins can be aberrant [14]. Additionally, since the ECM of solid tumors is usually disorganized and the crosslinking of ECM proteins is increased, integrin-mediated signaling is also altered, leading to the progression and drug resistance of the disease [15, 16]. Specifically in ovarian cancer, integrins play a key role in cancer cell detachment, migration, spheroid formation, and invasion, including as a result of the movement of fluid that accumulates within the peritoneal cavity, known as ascites (Figure 1) [5].

Figure 1.

Integrins play a key role in ovarian cancer progression including cell detachment from primary sites, spheroid formation, migration, adhesion to secondary sites, and invasion.

This review describes the role of integrins in ovarian cancer and discusses the current literature in integrin-targeted approaches for ovarian cancer, including photochemistry-based imaging and therapy.

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2. Integrins in ovarian cancer and the significance of ascites

2.1 Integrins and integrin-associated survival pathways in ovarian cancer

The potential role of integrins in critical processes leading to ovarian cancer progression, including the detachment of cancer cells from primary sites, spheroid formation, migration, adhesion to secondary sites, and invasion has been reported by multiple groups [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. The clustering of collagen-binding integrins α2β1 and α3β1 is associated with increased expression and activity of matrix metalloproteinase-9 (MMP-9). An increase in activated MMP-9 is associated with the shedding of E-cadherin, a transmembrane glycoprotein that regulates cell-to-cell adhesion, and increased epithelial-mesenchymal transition (EMT), changes that are indicative of an invasive and metastatic phenotype in ovarian cancer cells [17, 18, 19, 20]. The αvβ6 integrin has also been associated with protease secretion and ECM degradation in ovarian cancer cell lines, both of which are indicators of invasive potential [21, 22, 23]. Collagen-binding integrins, including heterodimer α4β1, have also been implicated in ovarian cancer migration by Slack-Davis et al., who showed that transmigration of SKOV3 cells through a mesothelial monolayer model decreased significantly upon blocking of α4 integrin, β1 integrin, or vascular cell adhesion protein-1 (VCAM-1). VCAM-1 is a glycoprotein that is predominantly expressed on endothelial cells, but, under high levels of inflammation and in chronic pathological conditions, is also expressed on other cell types, including macrophages and cancer cells [29]. The aforementioned findings by Slack-Davis et al. suggest that the VCAM-1-α4β1 integrin interaction is involved in ovarian cancer cell metastasis and invasion through the mesothelium [24]. In addition to migration and invasive potential, studies have found that α5 and β1 integrins are critical for ovarian cancer cell spheroid formation as well as their adhesion to different ligands including fibronectin, laminin and collagen IV, further implicating integrins in ovarian cancer progression [25, 26, 27, 28].

In the context of integrins, disease progression, and drug resistance in ovarian cancer, cell signaling pathways, including PI3K/Akt, Ras/Raf/MEK/ERK, Wnt, YAP/TAZ, as well as crosstalk between integrins and the epidermal growth factor receptor (EGFR), have been most commonly investigated (Figure 2) [30, 31, 32, 33, 34, 35]. A key player in the activation of the aforementioned pathways is focal adhesion kinase (FAK), a tyrosine kinase that localizes to focal adhesions [34, 36, 37, 38, 39, 40]. The overexpression of FAK is frequently associated with advanced-stage ovarian cancer and with increased invasiveness [41], thus FAK inhibition has been investigated as a treatment approach for ovarian cancer [42, 43]. The following subsections describe the current state of the literature on integrin-mediated activation of key molecules and survival pathways that contribute to ovarian cancer progression.

Figure 2.

Integrin activation can influence cell survival pathways: (1) the PI3K/Akt survival pathway involves the recruitment of FAK to focal adhesions. FAK can propagate the PI3K/Akt pathway, either directly or through Src kinase. (2) Shc phosphorylation by both Src and FAK, which initiates the Shc-Grb2-Sos-Ras cascade may lead to ERK phosphorylation. (3) FAK activation by integrins may also lead to the activation of Wnt/β-catenin pathway. Crosstalk between EGFR and integrins can potentiate signaling and cooperatively stimulate intracellular pathways that contribute to cell survival and drug resistance.

2.1.1 PI3K/Akt pathway

The PI3K/Akt pathway transduces signals from the cell membrane to the cytoplasm and mediates fundamental cellular functions including proliferation and survival [44, 45]. Upon activation by a growth factor, receptor tyrosine kinases (RTKs) activate PI3K and trigger its conversion from phosphatidylinositol-4, 5-bisphosphate (PIP2) to phosphatidylinositol-3, 4, 5-triphosphate (PIP3). The serine/threonine kinase Akt interacts with PIP3, which causes its translocation to the plasma inner membrane, where it is phosphorylated by phosphatidylinositide-dependent kinase 1 (PDK1) and PDK2, known as Ser473-phosphorylated Akt kinase. The phosphorylated and activated Akt may interact with substrates that regulate cell growth and survival, including mTOR, Glycogen synthase kinase-3 (GSK3), Bad, and caspase-9. The PI3K/Akt pathway can also be activated by other cell surface receptors such as cytokine receptors and integrins. A recent study Zheng et al., found that α2β1 overexpressing (α2β1+) ovarian cancer cells, and ovarian cancer patient tissue samples that were resistant to microtubule-directed chemotherapeutic drugs, including paclitaxel and vincristine, had enhanced PI3K and Akt phosphorylation, as well as Akt translocation into the nucleus [30]. This suggests that α2β1 integrins activate the PI3K/AKT pathway to promote resistance to microtubule-directed chemotherapeutic drugs.

Integrin-mediated activation of PI3K/Akt survival pathway involves the recruitment of FAK to the adhesion complex [36]. FAK interacts with the cytoplasmic tail of β-subunits on integrins and forms a dual kinase complex with c-Src. FAK can activate the PI3K/Akt pathway, either directly or through Src kinase. The relationship between FAK signaling and PI3K/Akt pathway-mediated resistance to taxane-based therapy has been demonstrated in a study Kang et al. The authors found that VS-6063, a FAK inhibitor, synergized with paclitaxel in HeyA8-MDR cells and showed an additive inhibitory effect with paclitaxel in the taxane resistant cell lines SKOV3-TR and SKOV3ip1 [42]. Decreased tumor weight was also reported in the same study in mouse models of these cell lines after treatment with paclitaxel and VS-6063 compared to paclitaxel alone. Others have also explored the effectiveness of VS-6063 in ovarian cancer growth inhibition [43]. Xu et al. screened combinations of VS-6063 with 30 potent inhibitors and found that JQ1, an inhibitor of the Myc oncogenic network, synergized with VS-6063. Although the efficacy was dependent on the cell line, using VS-6063 and JQ1 caused an additive or synergistic inhibition effect in proliferation and viability of ovarian cancer cells by inhibiting active FAK and c-Myc, as well as their signaling, through the PI3K/Akt pathway.

2.1.2 Ras/Raf/MEK/ERK pathway

The Ras/Raf/MEK/ERK pathway, one of the major signaling cascades of the mitogen-activated protein kinase (MAPK) family, plays a key role in cell proliferation, differentiation, motility, and survival [46], and is dysregulated in one-third of human tumors [47]. Activation of this pathway can occur through a variety of mechanisms, including integrin-mediated cell adhesion or activation of membrane RTKs by extracellular stimuli such as growth factors, hormones, cytokines, and mitogens [48]. Although this pathway can be activated by either cell adhesion or growth factors, strong and sustainable ERK activation results from cooperative signaling by both RTKs and integrins [38, 49]. In RTK-mediated signaling, the activation of RTKs leads to the activation of the small GTP-binding protein Ras. Ras recruits Raf kinases to the cell membrane, which in turn activate MEK1 and MEK2, leading to the phosphorylation of ERK1 and ERK2, catalyzed by MEK. Phosphorylated ERK1 and ERK2 translocate to the nucleus and initiate phosphorylation of transcription factors, such as c-Myc, c-fos, Ets, and Elk1 [47]. In contrast to RTK signaling cascades, integrin-mediated signal transduction in this pathway is less dependent on Ras and is instead initiated by autophosphorylation of FAK and the formation of FAK-Src complexes [39]. According to the model for adhesion-mediated ERK activation suggested by Yee et al., Shc is phosphorylated by both Src and FAK, which initiates the Shc-Grb2-Sos-Ras cascade, leading to ERK phosphorylation [38].

As mentioned above, Shc phosphorylation by FAK and Src is an important step in integrin-mediated activation of the Ras/Raf/MEK/ERK pathway because only some integrins, including α1β1, α5β1, α6β4, and αvβ3, can recruit Shc to the FAK-Src complex [50]. Similarly, certain integrins, like αvβ6 integrin, play key roles in MEK/ERK activation which can lead to cancer-associated changes in the Ras/Raf/MEK/ERK pathway [31, 32]. Studies have shown that ERK activation, induced by thyroid hormone administration, in high αvβ3-expressing ovarian cancer cells enhances cell proliferation and survival, while inhibition of the Ras/Raf/MEK/ERK pathway increased ovarian cancer cell susceptibility to treatment in both chemosensitive and chemoresistant lines [51, 52, 53, 54]. In summary, integrin overexpression, notably that of αvβ3 and αvβ6 integrins, may contribute to ovarian cancer progression and resistance to therapies by promoting activation of the Ras/Raf/MEK/ERK pathway cooperatively with RTK-mediated signaling.

2.1.3 Wnt pathway

Wnt signaling cascades regulate multiple cellular processes including cell polarity, migration, adhesion, proliferation, and developmental events, such as embryogenesis and tissue morphogenesis [33, 55]. The two main Wnt pathways, non-canonical and canonical, are characterized by the involvement of β-catenin, which is one of the key components in cell-cell adhesion and cell migration, in addition to its role in Wnt-mediated gene transcription. In non-canonical signaling, small GTPases of the Rho family or heterotrimeric G proteins, independently from β-catenin, are activated to control cell polarity and calcium signaling, respectively [56, 57]. The Wnt/β-catenin pathway (a.k.a. canonical pathway) is initiated via the activation of the frizzled receptor by Wnt proteins [58]. Activated receptors recruit and activate the cytoplasmic protein Disheveled, which inactivates the β-catenin destruction complex that is composed of proteins, including Axin, Adenomatous Polyposis Coli (APC) and GSK-3β. Since β-catenin levels are kept low by the destruction complex, the inactivation of the complex enables cytoplasmic accumulation of β-catenin. Accumulated β-catenin then translocates to the nucleus and interacts with the TCF/LEF family proteins to control transcription [55, 56].

In cancer, Wnt signaling becomes dysregulated and Wnt target genes can regulate tumor progression and drug resistance [55, 58, 59]. The Wnt/β-catenin pathway is associated with poor prognosis in ovarian tumors and has been shown to be a key regulator of chemoresistance in different cancer types including ovarian, colon, prostate, and pancreatic [60, 61, 62, 63]. In a study by Viscarra et al., transcriptomic sequencing analysis of parental and carboplatin-resistant A2780 cells revealed 156 differentially expressed genes, among which those related to the Wnt/β-catenin pathway and integrin signaling were the most enriched (15.2 and 10.9%, respectively) [64]. Upregulation of one of the integrin signaling pathway members, COL11A1, in carboplatin-resistant A2780 cells is important to note because COL11A1 overexpression has been reported to be an indicator of poor prognosis, metastasis, and drug resistance in ovarian cancer. Interestingly, Viscarra et al. also reported that, compared to carboplatin-resistant A2780 cells, parental A2780 cells showed significant increases in caspase-3/7 cleavage, which are indicators of apoptosis. Together these findings suggest that integrins and the Wnt/β-catenin pathway can synergistically regulate carboplatin resistance in A2780 cells [64, 65]. In accordance with these findings, a study by Crampton et al. revealed that integrin-mediated signals can synergize with the Wnt pathway through the adapter protein growth factor Grb2 [33]. Additionally, Burkhalter et al. found that integrin clustering and binding to collagen increased nuclear β-catenin levels, thereby promoting transcriptional activation of Wnt/β-catenin pathway target genes [66].

2.1.4 YAP/TAZ transcriptional regulators

Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ) are two transcriptional regulators that play an important role in mechanotransduction, i.e., converting external mechanical inputs to cellular responses [67]. YAP and TAZ (YAP/TAZ) are known as coactivators in the Hippo pathway, a signaling pathway that plays a role in homeostasis, organ size control, cell differentiation, and the progression of various types of human cancer, including ovarian cancer [68, 69]. Active YAP/TAZ translocates to the nucleus to interact with TEA domain family member (TEAD) transcription factors, where the YAP/TAZ-TEAD protein complex transcribes genes that control cell proliferation and apoptosis [70]. In addition to their role in the Hippo pathway, YAP/TAZ also interact with the Wnt pathway and mediate Wnt signaling [68, 71]. Research has shown that integrins and other components in adhesion complexes, including FAK and Src, can also activate YAP/TAZ to maintain mechanotransduction [40, 72]. The overexpression and activation of YAP/TAZ have been shown to be correlated with poor prognosis in ovarian cancer [73, 74, 75, 76, 77, 78, 79]. Specifically, YAP was shown to play an important role in ovarian cancer tumorigenesis, cell proliferation, invasion, and resistance to therapy in vitro and in vivo [74, 76]. Expression and activation of YAP [76] and TAZ [79] were also associated with poor prognosis and resistance to chemotherapy in tissue samples from ovarian cancer patients. As a result of these findings, the therapeutic potential of YAP/TAZ inhibition in ovarian cancer has become a topic of recent research [75, 80, 81, 82]. In summary, the studies discussed above reveal that Wnt signaling pathway and YAP/TAZ, which can be activated by integrins, are key regulators in ovarian cancer invasion and drug resistance.

2.1.5 Epidermal growth factor receptor-integrin crosstalk

EGFR is a cell surface RTK, the activation of which initiates cell proliferation and survival pathways including PI3K/Akt and Ras/Raf/MEK/ERK [83]. High expression of EGFR is associated with an aggressive and invasive phenotype in multiple cancer types including ovarian cancer [84, 85, 86, 87, 88]. Interestingly, integrin-mediated ECM adhesion can induce tyrosine phosphorylation of EGFR in the absence of EGF, and if both EGF and activated integrins are present, they can promote sustained EGFR signaling [89, 90]. For example, EGFR expression in OV-MZ-6 cells is correlated with αvβ3 integrin levels [34]. In the same cells, the activity of MAPK and FAK was increased upon stimulation of αvβ3 integrins and EGFR by vitronectin and EGF, respectively, demonstrating that both MAPK and FAK play key roles in αvβ3-mediated regulation of EGFR activity. A cooperative effect of EGFR and integrins has also been reported in JAK2/STAT3 signaling, which is associated with EMT in cancer [91]. Colomiere et al. reported that EGF exposure initiates an EMT-associated increase in N-cadherin and vimentin levels, as well as cell motility in OVCA 433 and SKOV3 cells. Ovarian cancer cells also showed increased activation of JAK2/STAT3 and expression of α2, α6, and β1 integrin subunits when treated with EGF. Blocking integrin subunits α6 and β1 significantly inhibited EGF-induced migration, suggesting an interaction between EGFR, α6β1 integrins, and JAK2/STAT3 signaling in ovarian cancer cells that increases EMT and cell motility. The crosstalk between EGFR and β1 integrin was also studied by Lau et al. in the context of invasion and metastasis in ovarian cancer [35]. The authors found that EGF stimulation induces β1 expression in OVCAR5 and SKOV3 cells, and that blocking the MAPK/ERK pathway inhibited EGF-enhanced β1 expression. β1 is downstream of the MAPK/ERK pathway and EGF-induced β1 expression is mediated by MAPK/ERK signaling. In summary, EGFR plays a key role in multiple cell survival pathways and its overexpression is associated with a poor prognosis in ovarian cancer [84, 85, 86, 87, 88]. These studies suggest that EGFR-integrin crosstalk can lead to the potentiation and cooperative stimulation of intracellular pathways that contribute to cell survival and drug resistance.

2.2 The role of FAK, a critical mediator of integrin signaling, in ovarian cancer

As a key player in cell adhesion, motility, and integrin-mediated cell signaling, FAK plays an important role in invasiveness and drug resistance in ovarian cancer. A study by Sood et al. reported that FAK is overexpressed in a panel of ovarian cancer cell lines, including SKOV3, EG, and 222, as well as in tissue samples from patients with invasive epithelial ovarian cancer, as compared to normal human ovarian surface epithelial cells and benign ovarian tissue samples [41]. The study showed that the dephosphorylation of FAK by FAK-related nonkinase (FRNK), decreased the invasion and migration of ovarian cancer cells in vitro. To evaluate the role of FAK degradation in cisplatin-mediated apoptosis in a cisplatin-sensitive ovarian cancer cell line, Sasaki et al. [92] treated OV2008 cells with varying concentrations of cisplatin (0–10 μM) then analyzed FAK expression in detached cells. Relative to the small number of cells that remained attached following cisplatin treatment, the detached cells expressed low levels of FAK and an increased accumulation of FAK cleavage fragments. Further, morphological investigations on detached cells showed incidence of apoptotic nuclear condensation and fragmentation after 12-hours of incubation with cisplatin. Therefore, the results of this study suggest that cisplatin causes apoptosis in OV2008 cells by caspase-3-mediated FAK cleavage and cell detachment, which can be inhibited by either synthetic or endogenous caspase-3 inhibitors. In another study assessing the mechanism of taxane-based chemotherapeutic agent-mediated apoptosis, Halder et al. [93] reported an increase in FAK cleavage and caspase-3 activity in docetaxel-sensitive parental SKOV3 and HeyA8 ovarian cancer cell lines in response to docetaxel treatment. Both FAK cleavage and caspase-3 activity remained unchanged in resistant ovarian cancer cell lines SKOV3-TR and HeyA8-MDR. Furthermore, inhibiting caspase-3 by the caspase blocker, DEVD-fmk, decreased docetaxel-mediated FAK cleavage and apoptosis in parental cells. Similarly, silencing FAK by siRNA transfection increased docetaxel effectiveness in both parental and resistant cell lines.

2.3 Malignant ascites in integrin-mediated invasiveness in ovarian cancer

Malignant ascites, the abnormal accumulation of fluid containing malignant cells in the peritoneum [92, 93], is more frequently associated with advanced-stage ovarian cancer than any other peritoneal malignancy, and represents a barrier to treatment [94, 95]. As shown in Figure 3, there are a variety of cellular and acellular factors in malignant ascites that contribute to disease progression, immune evasion, and even chemoresistance in ovarian cancer [92, 96]. Acellular factors include integrins, which play a role in the formation of a tumor-promoting microenvironment. Although these adhesion-regulating factors are normally involved in cell differentiation, growth, and migration [11, 97, 98], aberrant integrin signaling frequently observed in cancers can influence cell invasiveness, drug resistance, and metastasis [14].

Figure 3.

Malignant ascites has been shown to affect integrin expression and localization. Specifically, cellular and acellular factors in malignant ascites can promote increased integrin expression, leading to the upregulation of integrin-related survival pathways. Factors within malignant ascites can also promote integrin delocalization, which leads to cell clustering.

There are a multitude of integrins that are known to play a role in ovarian cancer. In the normal tumor microenvironment, activation of apoptosis by death receptors plays a key role in immune surveillance against tumor cells [99]. A study performed by Lane et al. demonstrated that malignant ascites protects against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through activation of the PI3K/Akt pathway in ovarian cancer cells. Normally, OVCAR3 and Caov-3 cell lines are sensitive to TRAIL-induced apoptosis and when exposed to TRAIL in the absence of ascites, only about 10% of cells remained viable. In contrast, Caov-3 cells exposed to TRAIL and patient-derived malignant ascites displayed a significant decrease in TRAIL-induced cell death. Similarly, OVCAR3 cells exposed to TRAIL and patient-derived malignant ascites demonstrated significantly increased cell viability compared to those treated only with TRAIL. A follow-up study performed by Lane et al. showed that ascites protects against TRAIL-induced apoptosis through αvβ5 integrin-mediated FAK and Akt activation [100]. Tumor cells in ascites from ovarian cancer often have higher expression of Akt compared to cells found in benign effusions, which suggests the role of ascites in the activation of the Akt pathway [101]. Akt activation may also occur due to the interactions between ECM proteins and cell surface integrins, integrin-mediated recruitment of FAK, or αvβ3 and αvβ5 integrin ligation [102, 103, 104]. In the study described above by Lane et al., the use of αvβ3 and αvβ5 integrin-blocking antibodies on Caov-3 cells in the presence of ascites demonstrated a 50% reduction in the protective effect of ascites on TRAIL-induced apoptosis [100]. The addition of αvβ5 integrin-blocking antibody also prevented FAK phosphorylation, demonstrating that ascites-induced FAK phosphorylation is αvβ5-dependent and that survival factors present in malignant ascites can promote resistance to TRAIL-induced apoptosis through Akt activation in an αvβ5-dependent manner [99, 100].

Factors within ascites that engage αvβ5 integrins may include vitronectin and periostin, which are ECM proteins secreted by malignant ovarian epithelial cells [100, 103, 105]. Adhesion of ovarian cancer cells to the ECM is controlled by integrin-dependent and independent mechanisms, therefore changes in the ECM composition as well as integrin expression allow for the alteration of cancer cell adhesion and motility [26, 105, 106, 107, 108]. Periostin is overexpressed in, and secreted by, epithelial ovarian cancer cells, and as a result, periostin accumulates in the malignant ascites [105, 109]. In a study by Gillan et al., ~95% of ascites samples from ovarian cancer patients contained periostin [105]. Exploring the role of periostin in cell adhesion, Gillan et al. found that periostin-coated surfaces supported HOSE and SKOV3 cell attachment in a concentration-dependent manner. SKOV3 cell adhesion was enhanced after adding manganese, which increases the ligand-binding affinity of integrin αvβ3; however, adhesion was inhibited by anti-αvβ3 and anti-αvβ5 antibodies. When examining the role of periostin on ovarian cancer cell motility, Gillan et al. further showed that ovarian cancer cells grown on periostin formed less stress fibers and focal adhesion plaques than those grown on vitronectin or fibronectin. Based on these findings, Gillan et al. concluded that αvβ3 and αvβ5 integrin play important roles in periostin-induced effects on cell adhesion and motility, which could promote intraperitoneal dissemination of ovarian cancer.

Similar to periostin, vitronectin and fibronectin are also important in shaping the tumor-promoting microenvironment of malignant ascites. Specifically, fibronectin has been shown to promote cell migration and spheroid formation, anchorage, and disaggregation in ovarian cancer [25, 27, 110, 111], while vitronectin has been found to play key roles in cancer cell adhesion, proliferation, and migration [112, 113, 114, 115]. Fibronectin and vitronectin can also enhance metastasis when they are cleaved into smaller fragments by matrix metalloproteinase-2 (MMP-2) [111, 116]. A study by Carduner et al. found that, in 14 patient-derived ascites samples, both vitronectin and fibronectin were detected. When cells were grown on patient-derived ascites, their morphology changed to clusters of rounded cells varying in thickness [111]. Purified vitronectin and fibronectin from patient-derived ascites also supported the adhesion and migration of ovarian cancer cells alongside altered integrin organization. Vitronectin-exposed IGROV1, OVCAR3, and SKOV3 cells displayed altered localization and/or organization patterns of αv and β1 integrins. In fibronectin-exposed cells, co-localization between β1 integrin and fibronectin fibrils was observed, suggesting a role for integrins in fibrillation.

Since EMT behavior can also be modulated by ascites in an integrin-dependent manner, Carduner et al. examined the EMT status of cells based on cell-cell contact, modification of cell-matrix adhesion, elongation of cell shape, and cell migration [117]. After treatment with ascites, cell shape was altered in IGROV1, SKOV3, and OVCAR3 cells, as cells become clustered, spindle-like, and heterogenous, respectively. Ascites also induced changes in localization and the expression of epithelial and mesenchymal markers that differed by cell line, but were nonetheless associated with an ascites-associated shift towards an intermediate epithelial or mesenchymal phenotype. In IGROV1 and SKOV3 cells, Carduner et al. reported that αv integrins were involved in the observed shift towards a mesenchymal phenotype, since ascites induced the partial delocalization of αv integrins to favor the formation of IGROV1 aggregates and SKOV3 migration. Overall, this study found that exposure to ascites stimulates integrin trafficking and is associated with a shift towards a mesenchymal phenotype in ovarian cancer cells.

Additional studies have implicated αv integrins in ovarian cancer progression by promoting an ascites-associated invasive and mesenchymal phenotype. For example, αvβ6 integrin has been correlated with increased urokinase plasminogen (uPA) expression, MMP-2 and MMP-9 secretion, and protease-dependent matrix degradation [23, 32]. Increased uPA and MMP-9 expression are associated with a poor prognosis because they contribute to ovarian cancer progression and enhanced metastatic potential [23, 118, 119]. uPA and its receptor (uPAR) are often found at high concentrations in both the tumors and ascitic fluid of advanced-stage ovarian cancer patients [120, 121]. It has been shown that increased uPAR expression in cancer cells is maintained by Erk MAP kinase pathway activity, which is associated with tumor cell growth and proliferation [122, 123, 124, 125]. The Erk MAP kinase pathway, a downstream target of the Ras pathway, is often activated upon integrin binding and activation [122, 123]. Since integrins, uPA, and MMPs are all present in malignant ascites, and are associated with a poor prognosis, Ahmed et al. examined the role of ascites in regulating integrin-mediated changes in ovarian cancer growth and function [122]. Results showed that, in the presence of ascites, α6 integrin expression was enhanced in OVHS1, PEO.36, OVCA 433 and HEY cell lines while uPAR expression was only enhanced in invasive OVCA 433 and HEY cell lines. Additionally, while malignant and high-grade tumors displayed epithelial uPAR staining, uPAR expression was absent in normal and benign tumor samples. α6 integrin staining was also much lower in benign and grade I tumors. Confirming the role of integrins in ovarian cancer cell progression, decreased ascites-induced and basal proliferation were observed in OVHS1 and HEY cell lines incubated with α6 and β1 antibodies. Similarly, decreased ascites-induced invasiveness was reported in OVCA 433 and HEY cell lines incubated with α6, β1, and uPAR antibodies.

Overall, acellular factors, such as integrins, play critical roles in shaping the ascitic tumor microenvironment of ovarian cancer and contribute to tumor growth, invasion, and metastasis. Since aberrant integrin signaling can increase invasiveness, chemoresistance, and metastasis of cancer cells, understanding the role of ascites and integrin expression in ovarian cancer is crucial for the development of targeted therapies.

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3. Integrins in ovarian cancer treatment

The current standard of care for ovarian cancer involves surgical debulking followed by treatment with multiple cycles of platinum- and taxane-based chemotherapy [3]. While this treatment regimen is often effective initially, the rapid development of resistance to these drugs is one of the main challenges in the treatment of ovarian cancer [126]. This has led researchers to seek new treatment strategies, such as targeting cell surface receptors that are overexpressed in cancer and tumor endothelial cells [127, 128]. Since research has shown integrins play an important role in vascular development and mediate the adhesion of disseminated cancer cells [28, 129, 130, 131, 132, 133], targeting integrins could be a rational treatment approach in ovarian cancer.

One integrin expressed in proliferating vascular endothelial cells, and some tumor cells, is the αvβ3 integrin [134]. In an in ovo study from 1994, blocking αvβ3 integrin led to the disruption of angiogenesis on a chick chorioallantoic membrane (CAM) and the regression of human melanoma tumors grown on the CAM through the induction of apoptosis in associated angiogenic vascular cells [135]. More recently, the cancer-promoting role of αvβ3 integrin was demonstrated in vitro in a panel of cancer cell lines, including in ovarian cancer cells [136, 137, 138, 139, 140, 141]. These efforts led to preclinical in vivo studies using the humanized monoclonal antibody, etaracizumab, to inhibit angiogenesis by blocking αvβ3 integrin. The efficacy of etaracizumab in ovarian cancer was explored by Landen et al., who generated orthotopic mouse models of ovarian cancer using three chemotherapy sensitive ovarian cancer cell lines: HeyA8, SKOV3ip1, and A2780ip2 (the “ip” cell lines were generated by injecting parental lines into the peritoneum of a mouse, then harvesting, isolating, and re-culturing the tumor cells) [142]. The authors reported that, after injection of etaracizumab, tumor size was significantly reduced in SKOV3ip1 and HeyA8 models, but not in A2780ip2 models. The underlying reason for this may be poor αvβ3 integrin expression in A2780ip2 cells, which was confirmed after flow cytometry and Western Blot analysis. Interestingly, when etaracizumab was combined with paclitaxel, A2780ip2 tumors were reduced in size by 72.8% compared to paclitaxel alone. These findings suggest that while etaracizumab alone did not reduce the size of A2780ip2 tumors, etaracizumab in combination with paclitaxel led to a synergistic reduction in A2780ip2 tumor size. The same synergism was not observed in HeyA8 tumors even though it was effective as a monotherapy, which the authors suggest may be due to the varied roles of the Akt pathway in the three cell lines. Proliferation in HeyA8 cells is driven, in significant part, by the Mek/Erk pathway and not the Akt pathway, while the other two cell lines have constitutive activation of Akt, potentially explaining the observed discrepancies in the efficacy of tumor reduction.

A follow-up study from the same research group assessed the efficacy of combining etaracizumab with the clinically approved VEGF receptor antibody, bevacizumab [143]. Taxane-sensitive (SKOV3ip1 and HeyA8), and -resistant (SKOV3TRip2) tumors were treated with single-agent therapies or with a cocktail of the two antibodies. Additionally, the individual antibodies, or the cocktail, were tested in combination with paclitaxel. In the SKOV3ip1 model, both individual agents as well as the etaracizumab-bevacizumab cocktail reduced tumor size, with the cocktail proving more effective than single agents alone. Furthermore, paclitaxel efficacy was increased in combination with bevacizumab or the cocktail, but not with etaracizumab, in the SKOV3ip1 model. In SKOV3TRip2 cells, bevacizumab or etaracizumab individually sensitized cells to paclitaxel. In HeyA8 cells, while bevacizumab alone significantly reduced tumor weight, neither etaracizumab alone, nor in combination with bevacizumab or paclitaxel, led to significant tumor size reduction, consistent with the findings reported above. Despite the literature supporting the anti-tumor activity of αvβ3 inhibition, there is also evidence that αvβ3 expression in ovarian cancer cells may inhibit tumor progression and reduce metastasis [144, 145], warranting further investigation into the value of targeting this integrin pair for ovarian cancer treatment.

Another drug that has been evaluated in preclinical and clinical studies for integrin-targeted treatment of ovarian cancer is the humanized α5β1 antibody volociximab. As previously mentioned, α5 and β1 integrins have been implicated in ovarian cancer cell adhesion and migration [28, 146]; however, α5β1 integrin is also associated with endothelial cell proliferation and survival [147, 148]. Kim et al. [131] blocked α5β1 integrins in human tumors grown on CAMs and found that that α5β1 regulates angiogenesis through the same pathway as αvβ3 integrin. Blocking α5β1 integrin using volociximab also proved successful in a cynomolgus monkey model of choroidal neovascularization [147], leading to a phase I clinical trial assessing volociximab in 21 patients with pathologically confirmed solid malignancies in 2008 [149]. After demonstrating safety in phase I trials, volociximab was tested in a single-arm, multi-institutional, phase II study. 14 patients with platinum-resistant, advanced stage epithelial ovarian cancer or primary peritoneal cancer received weekly intravenous volociximab at a dose of 15 mg/kg until progression or unacceptable toxicity. Among the patients whose responses were evaluable, only one patient remained in a stable condition, while the disease of the other 13 patients progressed. Although volociximab did not progress clinically for the treatment of ovarian cancer, the inhibition of neovascularization using the anti-VEGF receptor bevacizumab was approved in 2018 for the treatment of women with advanced (stage III or IV) ovarian cancer in combination with chemotherapy following initial surgical resection [150, 151, 152]. Unlike bevacizumab, α1β5 and αvβ3 integrins can block multiple growth factor pathways and cause apoptosis of proliferating endothelial cells, thus targeting angiogenesis from multiple routes. Although this strategy seems promising, integrin inhibitor drugs have not been recognized clinically because of inconsistent results and insufficient clinical activity.

Targeting integrins for selective drug delivery is another strategy of interest in the context of ovarian cancer treatment. The arginine-glycine-aspartic acid (RGD) tripeptide motif is found in many ECM proteins including collagen, fibronectin, and vitronectin. Since this motif is recognized by many integrins, chemotherapy agents can be coupled with RGD to deliver them selectively to ovarian cancer cells that overexpress certain integrins. This was shown by Pilkington-Miksa et al. who synthesized an αvβ3 integrin-binding RGD-paclitaxel conjugate that was more effective than unconjugated paclitaxel at decreasing tumor volume in a xenograft ovarian cancer model [153]. RGD-modified liposomes containing paclitaxel (RGD-SSL-PXT) have also been synthesized and tested in in vitro and in vivo ovarian cancer cell models [154]. Zhao et al. reported that the intracellular uptake of RGD-SSL-PXTs by SKOV3 cells was more than 6-fold higher, relative to non-targeted liposomes, and the tumor inhibition efficacy of RGD-SSL-PXTs was superior to both paclitaxel and non-targeted liposomes containing paclitaxel. In summary, there are a variety of ways that integrins can be targeted to reduce tumor burden in ovarian cancer. Thus far, as demonstrated in Figure 4, researchers have explored integrin inhibition in the context of vascular development as well as the selective delivery of RGD-modified cancer therapeutics; however, further research is needed to fully understand the potential value of targeting integrins in ovarian cancer treatment.

Figure 4.

Integrins as therapeutic targets in ovarian cancer. Integrin-targeted drugs, or anti-integrin antibodies, can be directly toxic to tumor cells that overexpress integrins (left) or can inhibit tumor vasculature (right), thereby decreasing tumor size.

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4. Targeting integrins for fluorescence imaging and photochemical/photothermal treatment in ovarian cancer

Photodynamic therapy (PDT) is a photochemical treatment modality involving the activation of a photosensitive molecule, a photosensitizer (PS), with light of an appropriate wavelength leading to the generation of reactive molecular species at the site of PS localization [155, 156, 157]. PSs can be conjugated to proteins or peptides, or formulated in delivery systems, to enhance selectivity or to improve photochemical potency [158, 159, 160, 161]. As discussed previously, integrins play an important role in ovarian cancer progression, but targeting integrins for selective drug delivery remains challenging. There are a limited number of studies that focus on integrin targeting in photochemistry-based applications. This section serves as a comprehensive review of the studies that have evaluated the effects of photosensitization on integrins, as well as the studies that target integrins to improve selectivity for fluorescence imaging and PDT of ovarian cancer. One photothermal therapy (PTT) study is also discussed at the end of this section to cover light-based practices that target integrins in ovarian cancer [162].

The effect of PDT on integrin expression and reorganization has been studied in the context of ovarian cancer by Runnels et al. [163]. In this study, OVCAR3 cells were maintained in monolayer or injected intraperitoneally into nude mice. In vitro and in vivo PDT treatments were carried out using a 690 nm argon ion pumped dye laser at 0.5 J/cm2 energy density following a 3-hour incubation of the cells with 0.092 μmol/L benzoporphyrin derivative monoacid (BPD). Subsequently, the cells were harvested and re-seeded on surfaces coated with ECM proteins: collagen IV, fibronectin, laminin, and vitronectin. Low-dose PDT (~ 85% cell survival) was shown to decrease the adhesion of OVCAR3 cells to collagen IV, fibronectin, laminin, and vitronectin-coated substrates in vitro and in vivo. The authors further reported that the binding of OVCAR3 cells to collagen IV and laminin, but not fibronectin, was inhibited by the presence of an anti-β1 antibody, suggesting that the β1 subunit plays a role in the adhesion of OVCAR3 cells to select ECM proteins. It was also noted that BPD localized in and around mitochondria and caused intracellular damage upon irradiation, mainly mediated by singlet oxygen rather than other reactive molecular species. In this study, BPD-PDT-mediated photodamage was shown to impact integrin function and the integrity of focal adhesion plaques.

A limited number of studies have explored integrins as targets for selective delivery of imaging agents and PSs. In a recent study, Li and colleagues linked an RGD-peptide and IRDye 700 DX (IR700) to human serum albumin [164]. Compared to the untargeted nanoconjugate, cell delivery of the targeted nanoconjugate (cRGD-PEG-HSA-IR700) increased by 121-fold in αvβ3-expressing TOV21G cells. Cells were also treated using a 660 nm LED light source at an irradiance of 3.5 mW/cm2 for 20 minutes [a fluence of 4.2 J/cm2, not specified in the report]. PDT effectively killed the αvβ3-expressing TOV21G cells but did not affect αvβ3-negative NIH/3 T3 cells. The nanoconjugates were also tested on spheroids of SKOV3 cells grown in ultra-low attachment wells. Confocal microscopy images and live/dead staining assays revealed that cRGD-PEG-HSA-IR700 successfully penetrated the spheroids, generated cell killing, and caused long-term tumor suppression. An RGD peptide with EtNBS as the PS and a 5 kDa polyethylene glycol (PEG) chain has also been explored in the context of ovarian cancer [165]. Using this construct, cellular uptake was increased in genetically modified, α5 integrin-overexpressing OVCAR5 cells relative to wild-type OVCAR5 cells. PEGylated constructs aggregated less and generated more reactive molecular species compared to their non-PEGylated analogs. Dai et al. synthesized a compound called TTB, which exhibits aggregation-induced near infrared (NIR) fluorescence and generates reactive oxygen species when excited by white light [166]. TTB was integrated into an amphiphilic polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (MPD) and conjugated with RGD peptide to target αvβ3 integrins. Efficacy of the construct for PDT and fluorescence imaging was evaluated in vitro and in animal models of prostate, cervical, and ovarian cancer. The integrin-targeted construct was shown to selectively accumulate in tumors, leading to cancer cell death in vitro and reduction of tumor size in tumor-bearing mice, compared to controls.

Fluorescence imaging of cancer relies on the selective accumulation of fluorescent agents in cancer cells. αvβ3 integrins are the most common targets in integrin-targeted fluorescent imaging studies. For instance, the fluorescent probe squaraine was covalently attached to one (monovalent) and two (divalent) cyclic RGD peptides by Shaw and colleagues to target ovarian cancer cells that overexpress αvβ3 integrins [167]. Uptake of the divalent probe in OVCAR4 cells was 2.2-fold higher than the monovalent probe, based on fluorescence imaging. Consistently, tumors grown in nude mice and imaged with the divalent probe were almost three times more fluorescent compared to tumors given the monovalent probe, and six times more fluorescent than tumors that received non-conjugated squaraine. To explore the potential of integrin-targeted, fluorescence-guided resection in ovarian cancer, Alvero et al. created a PLGA-PEG nanoparticle to target αvβ3 integrins in OCSC1-F2 ovarian cancer cells using an RGD peptide and three different fluorescent dyes: DIR, C6, and ICG [168]. The resulting conjugates enabled the investigators to visualize both the tumor-associated vasculature and intraperitoneal ovarian cancer micrometastases as small as 100 μm in a xenograft model. These studies demonstrate the potential of using αvβ3-targeted agents for fluorescence guided resection in ovarian cancer. An additional important consideration for this approach is the accuracy of tumor detection. This concern was addressed in a study by Harlaar et al., who found that the diagnostic accuracy of an αvβ3-targeted agent in combination with an NIR fluorescence intra-operative imaging system was 96.5%, with a sensitivity of 95% and a specificity of 88% [169].

In comparison to RGD peptides that have been relatively widely used to target integrins, less commonly used peptides, such as “OA02”, have been synthesized to bind an α3 integrin subunit [170]. An in vivo study by Aina et al. used nude mice bearing ES-2 tumors to evaluate three different forms of this peptide: OA02-biotin-Cy5.5, OA02-Cy5.5, and OA02-AlexaFluo 680. Results showed that OA02-Cy5.5 and OA02-AlexaFluo 680 exhibited fast and specific tumor uptake that sustained a fluorescence signal for approximately 70 minutes. Although the cellular uptake of OA02-biotin-Cy5.5 was slower than other peptide variants, the duration of the fluorescence signal was 24 hours. To confirm that α3 integrins were mediating the binding of OA02 peptides to ES-2 tumors, mice were injected with an anti-α3 monoclonal antibody, which blocked binding of the peptides to the tumors.

The value of targeting integrins has also been explored in the context of PTT, which involves the interaction of electromagnetic radiation (typically NIR light) with a photothermal agent to generate heat, leading to tissue hyperthermia. In a study by Zhou et al., the selectivity of silica-coated gold nanorods for ovarian cancer cells increased using hyaluronic acid and an RGD peptide that bind to CD44 and αvβ3 integrin, respectively [171]. The targeted nanoparticle showed high selectivity for SKOV3 cells but not for non-cancerous HOSEpiC cells. The nanorods were also loaded with doxorubicin (DOX) to increase cytotoxicity. PTT using the dual-targeted, DOX-loaded gold nanorods, and irradiation with an 808 nm laser at a high-power density (2 W/cm2), exhibited the highest cytotoxicity to SKOV3 cells among all experimental groups. Subsequent experiments have revealed that the release of DOX is pH-sensitive and triggered by NIR irradiation. Dox release may be influenced by hyaluronidase-mediated degradation of hyaluronic acid in low pH environments, and the disruption of the interaction between DOX and silica, respectively. An overview of photochemistry-based studies that focus on modulating or targeting integrins in the context of ovarian cancer is presented in Figure 5.

Figure 5.

Integrins as targets for fluorescence imaging and photochemical or photothermal treatment in ovarian cancer. Current research focuses on using RGD tripeptide-conjugated PS or PTT agents to target ovarian cancer cells that overexpress integrins (left), or to modulate integrin activity and inhibit cancer cell adhesion to secondary sites by low level cellular photodamage (right).

In summary, targeting integrins is a promising strategy for both anti-cancer PDT and fluorescence imaging. Since most PSs also have fluorescent properties, novel nanocarriers with integrin-targeting molecules can be used in theranostic applications and in real-time image-guided PDT of ovarian cancer. The potential of integrin-targeted PDT warrants further evaluation.

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5. Conclusion

Integrins are key players in cell adhesion and cell-ECM interactions that mediate important cell functions, such as survival, differentiation, and migration. In cancer, the aberrant expression, or reorganization, of integrins are associated with critical steps in tumor progression. Studies assessing the role of integrins in the context of ovarian cancer revealed that integrins are involved in ovarian cancer cell survival, migration, adhesion, and invasion of secondary sites. Despite this, integrin-targeted drugs for the treatment of ovarian cancer have displayed limited clinical success and have largely been evaluated in pre-clinical studies. Targeting integrins that are overexpressed in cancer cells for imaging or treatment purposes, using photochemical strategies, is a promising research area. Integrin function can be manipulated by PDT or a PS can be conjugated to target ovarian cancer cells that overexpress certain integrins for fluorescence imaging or toxicity via photodamage. Due to the role that integrins play during critical steps in ovarian cancer progression, integrin targeting may be promising for inhibition of tumor vasculature, drug delivery and photochemistry-based applications in ovarian cancer.

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Acknowledgments

This work was supported, in part, by the National Institutes of Health (NIH), a pre-doctoral traineeship from (National Research Service Award T32 ES007126 to BPR) from National Institute of Environmental Health Sciences (NIEHS), an NIH T32 award to the Certificate in Translational Medicine Program at UNC-Chapel Hill: grant number GM122741 (to BPR), as well as funding from the NC Translational and Clinical Sciences Institute (NC TraCS) at UNC-Chapel Hill supported by the National Center for Advancing Translational Sciences (NCATS), NIH through Grant Award Number UL1TR002489 (to WJP and IR), the Center for Environmental Health and Susceptibility (CEHS) at UNC-Chapel Hill supported by the NIEHS through Grant Award Number P30ES010126 (to IR), and UNC-NC State Joint Department of Biomedical Engineering Startup Funds (to WJP and IR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Written By

Mustafa Kemal Ruhi, Brittany P. Rickard, William J. Polacheck and Imran Rizvi

Submitted: 10 July 2022 Reviewed: 22 July 2022 Published: 22 August 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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