| | Biomarker† | Molecular basis for biomarker targeting in ovarian cancer | References |
| | M-CSF | Hematopoietic cytokine that stimulates differentiation, activation, and proliferation of monocyte and macrophages; can also act as an autocrine or paracrine growth factor for some epithelial cancers; promotes vasculogenesis; modulates CSCs, and can thus be targeted in OCSCs to induce immune-mediated tumor cell lysis; a phase II trial with GM-CSF and recombinant interferon gamma 1b (rIFN-γ1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer produced reasonable OS. | [14, 16, 33, 34, 59, 275] |
| | HNF-1β | Overexpressed in ovarian clear cell adenocarcinoma (OCCC); reduction of HNF-1β expression by RNA interference induces apoptotic cell death in ovarian OCCC cells; HNF-1β is hypomethylated in OCCC and can thus be targeted in ovarian cancers. | [276–280] |
| | HE4 | A glycoprotein highly expressed in ovarian cancers that might have a role in ovarian carcinogenesis; HE4 expression is highest in endometrioid and serous ovarian cancer | [214, 281, 282] |
| | OPN | A glycophosphoprotein cytokine secreted by activated T-lymphocytes, macrophages, and leukocytes at the inflammation site; higher levels occur in patients with ovarian cancer versus normal control; correlates significantly with tumor response to surgery, chemotherapy, and disease recurrence; implicated in tumorigenesis, tumor invasion, metastasis, and poor prognosis; binding of OPN as an ECM component to integrin and CD44 receptors in the tumor microenvioronment regulates signaling cascades associated with adhesion, migration, invasion, chemotaxis, and cell survival; alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc; the latter possess ovarian protumorigenic properties mediated by PI3K/Akt signaling pathway which serves as a critical cancer molecular target. | [14, 111, 283–285] |
| | MES | Binding of MUC16 to MES, a GPI-anchored glycoprotein, is thought to facilitate cell adhesion and peritoneal metastasis of ovarian tumors; this function can be exploited as a molecular targeting strategy, for example, anti-MES antibodies, to limit the metastatic spread of the tumor; MES is an attractive candidate for adenoviruses-mediated gene therapy of ovarian cancers; diffuse mesothelin expression is associated with prolonged survival in patients with high-grade ovarian serous carcinoma. | [224, 225, 286, 287] |
| | HP-α | Glycoprotein synthesized in the liver, but also present in ascites and serum of ovarian cancer patients; proteomic profiling identified HP-α as a potential biomarker with high specificity for ovarian cancer; high levels of this acute phase protein correlate with poor prognosis, but attenuate with chemotherapy—this mechanism should be explored further. | [14, 71, 288–291] |
| | BIK | This glycosylated protease suppresses ovarian tumor cell invasion and metastasis by downregulating PI3K and Ca2+-dependent TGF-β signaling pathways; plasma BIK is a strong prognostic indicator of ovarian cancer; a combination of BIK and paclitaxel significantly reduced tumor burden and ascites in a mouse model of ovarian cancer; BIK overexpression has been shown to suppress TNF-induced apoptosis in ovarian cancer cells; BIK also downregulates uPA/R and HBP gene expression in ovarian cancer cells; other target genes of BIK include transcriptional regulators, oncogenes/tumor suppressor genes, signaling molecules, growth/cell cycle, invasion/metastasis, cytokines, apoptosis, ion channels, and ECM proteins; the evidence cited here underlines the applicability of BIK in therapeutic strategies targeting the inhibition of peritoneal invasion and dissemination of ovarian cancer. | [14, 292–299] |
| | FRα | This protein is an alternative folate transporter which may confer an increased DNA synthesis and growth advantage on tumor cells; ovarian cancer patients have elevated blood levels of this protein, identified as a diagnostic marker and molecular target in high-grade, high-stage serous tumors; the status of FRα apparently does not change in response to chemotherapy and has no effect on overall patient survival; however, farletuzumab, a humanized monoclonal antibody against FRα, demonstrated anticancer efficacy in patients with platinum-refractory/resistant EOC; FRα expression is preserved on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may have therapeutic potential for the majority of women with newly diagnosed or recurrent ovarian cancer. | [300–304] |
| | TTR | This is a highly sensitive biomarker used in the screening of prostate, lung, colorectal, and ovarian (PLCO) cancers; was found to be downregulated in grade 3 ovarian tumors; and has been validated for its high specificity and sensitivity in early-stage ovarian cancer; further research on TTR is needed to explore its molecular targeting possibilities. | [58, 71, 305–307] |
| | IαI | The expression of this protein is reportedly upregulated in ovarian cancer patients and it is used mainly to complement MUC16/CA125 in the screening for EOC; however, proteomic analysis showed its levels to be significantly reduced in the urine of patients with ovarian carcinoma. | [14, 125, 308] |
| | CRP | Is one of a panel of plasma biomarkers used for the identification of women with ovarian cancer and to significantly increase diagnostic performance compared to MUC16/CA125 used singly; raised serum levels of CRP is associated with high levels of Il-6 and haptoglobin, considered as adverse prognostic factors in ovarian cancer; CRP are also a marker of high-grade inflammation in advanced-stage ovarian cancer and anemia in EOC (i.e., CRP correlates negatively with hemoglobin levels); high levels of prediagnostic CRP may indicate an inflammation stage that precedes ovarian cancer development and might denote increased risk. | [235, 291, 309–313] |
| | PRSS | This channel-activating serine protease is overexpressed in EOC; it is localized to the apical surface of normal epithelial cells and suppresses cancer cell invasion in vitro; in various cancer cell lines, PRSS downregulates EGFR signaling by cleaving its extracellular domain and hence interferes with cell proliferation and tumor expansion; this property should be investigated as a molecular target. | [14, 71, 72, 314–316] |
| | CLDNs | Large family of integral membrane proteins essential for tight junction formation and function; CLDN3 and CLDN4 expression levels are upregulated in EOCs of all subtypes and correlate with MMP-2 activity; CLDNs may promote ovarian cancer invasion and metastasis; CLDN upregulation in ovarian carcinoma effusions is associated with poor survival; cells that overexpress CLDN4 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN4 promoter region, while the converse is true for cells that do not overexpress it; CLDN4-expressing EOC cells secrete proangiogenic factors (e.g., IL-8) and downregulate genes of the angiostatic IFN pathway; CLDN5 overexpression is associated with aggressive behavior in serous ovarian adenocarcinoma; CLDNs are, therefore, suitable biomarkers for different types of ovarian cancer and promising molecular targets for ovarian cancer therapy. | [317–326] |
| | APOA1 | Is the protein component of HDL; the APOA1 gene is upregulated in chemoresistant EOC and has an established role in tumorigenesis; algorithmic proteomic profiling of postdiagnostic/pretreatment sera of women with ovarian cancer revealed that the ApoA1 and TTR combination yield high specifity, but low sensitivity as tumor markers; further investigations into the mechanistic roles of APOA1 in ovarian tumorigenesis are crucial for its consideration as a molecular target in ovarian cancer. | [306, 327] |
| | LPA | Generated by the action of the enzyme, lysophospholipase; LPA is the ligand for GPCRs (LPAR2 and LPAR3) which are upregulated during ovarian tumorigenesis; LPA is a bioactive lipid central to the initiation and progression of ovarian cancer; LPA is preferable to MUC16/CA125 as a biomarker for the diagnosis, but not the prognosis of EOC; in human EOC tissues obtained from patients, LPA-induced POSTN (an ECM constituent, see the following) expression in cancer-associated stromal fibroblasts correlates with poor survival and recurrence; remarkably, LPA also regulates IL-6 expression and STAT3 phosphorylation via the Gi/PI3K-Akt/NF-κB pathway in ovarian cancer cells; LPA enhances growth and invasion of ovarian cancer cells and tumor angiogenesis; active RTK and EGFR signaling is required for LPA-mediated Gi-dependent cellular responses in ovarian cancer cells; LPA antibodies, LPA antagonists, and LPAR gene silencing may thus be useful molecular targeting strategies in ovarian cancer. | [2, 268, 328–339] |
| | POSTN | POSTN is an ECM protein which normally functions as a homophilic adhesion molecule in bone formation; 5 isoforms have so far been identified; targeted comparative glycotranscriptome analyses of ovarian cancer and normal ovarian tissues have shown that POSTN and thrombospondin may be useful biomarkers for specific tumor-specific glycan changes in benign ovarian adenomas, borderline ovarian adenocarcinomas, as well as malignant ovarian adenocarcinomas; POSTN binds to numerous cell-surface receptors, predominantly integrins, and signals effectively via the PI3K/Akt and other pathways to promote cancer cell survival, EMT, invasion, metastasis, and angiogenesis; ovarian cancer cells actively secrete the protein; interaction of the ligand, POSTN, with integrins facilitates ovarian cancer cell motility; antibodies directed against POSTN have been shown to inhibit growth and metastasis of subcutaneous and ovarian tumors derived from a POSTN-expressing ovarian cancer cell line; thus, POSTN represents a novel molecular-targeted therapy for ovarian cancer. | [330, 340–345] |
| | KLK | Largest family of flanking proteases in the human genome, comprising at least 15 members; KLKs are secreted serine proteases that stimulate or inhibit tumor progression; KLK5-11 levels are typically elevated in sera of ovarian cancer patients and regarded as predictors of poor disease prognosis; aberrant KLK gene expressions in different types of ovarian cancers may complicate generalizations; for example, high tumor KLK6 protein expression correlates with inferior patient outcome in ovarian cancer, while raised KLK8 is an independent marker of favorable prognosis in ovarian cancer, whereas KLK5 levels are low in serum of patients with benign ovarian tumors; elevated KLK5 antigen in serum and ascitic fluid of ovarian cancer patients is a prognostic factor for PFS; KLK5-specific antibodies have been detected in patients with benign masses, borderline tumors, and ovarian carcinomas compared with healthy controls; the presence of KLK5 antibodies suggests that KLK5 might represent a possible target for immune-based therapies; KLK6 exemplifies the altered glycosylation hallmark of ovarian cancer; KLK7 is associated with negative characteristics of ovarian cancer, but is not considered an independent prognosticator for the disease; a combined panel of KLK6, KLK13, and MUC16/CA125 affords improved sensitivity in the detection of early stage ovarian cancer than MUC16/CA125 alone; KLKs have recently been shown to be subject to posttranscriptional control by multiple miRNAs which can be exploited in the differential diagnosis of ovarian cancer and as a molecular targeting opportunity. | [60, 346–365] |
| | AGR2 | This is a mucinous metastasis-inducing protein detectable in the plasma of ovarian cancer patients; elevated AGR2 levels in ovarian cancer patients are associated with disease stages II and III in both serous and nonserous tumors; AGR2 is thought to promote cell proliferation and migration; it is currently being validated for its diagnostic and prognostic significance in ovarian cancers. | [67, 366–368] |
| | HDACs | Posttranslational modification of histones by HATs results in acetylation of the histone structure which exposes chromatin of transcriptionally active genes; the acetylation status of histones governs access of transcription factors to DNA and determines levels of gene expression; HDACs catalyze the removal of acetyl groups from histone tails and thus suppress transcription; accordingly, homeostatic control of HATs and HDACs activities is essential for maintaining nuclear and genomic stability; HDACs also act on various other transcription factors such as p53, Rb, and E2F1; HDACs are often activated or mutated in human cancers; in ovarian tumors, type-specific overexpression and roles for these enzymes have been delineated; for example, HDAC1 promotes cell proliferation whereas HDAC3 induces cell migration by downregulating E-cadherin; HDACs have become critical drug targets for cancer therapy and HDACi shows tremendous promise in preclinical and clinical trials (www.clinicaltrials.gov); SAHA (vorinostat, Zolinza) has been approved by the FDA for treatment of cutaneous T-cell lymphoma; HDACi promotes cell cycle arrest by inducing CDK inhibitor p21 (WAF1/CIP1); moreover, HDACi has pleiotropic actions, including the upregulation of proapoptotic proteins of Bcl-2 family (Bim, Bmf, Bax, Bak, and Bik) and downregulation of antiapoptotic proteins of Bcl-2 family (Bcl-2, Bcl-XL, Bcl-w, Mcl-1) and XIAP and survivin which may be significant in apoptosis targeting approaches [369, 370]; HDACi, such as NaB, SAHA, and TSA, enhanced in vitro ovarian cancer cell killing with concomitant increased mRNA expression of MDR1 but decreased mRNA expression of MRP1 and MRP2; the novel hydroxamic acid-derived HDACi, MHY218, has been shown to be more potent than SAHA in suppressing ovarian tumor cell viability and transplanted tumor growth in an in vivo tumor carcinomatosis model; MHY218 also raised expression levels of the cell cycle inhibitor, p21WAF1/CIP1, induced apoptosis via caspase-3 activation, and increased release of cytochrome c and Bax/Bcl-2 ratio; previously, similar results have been reported for another novel HDACi, apicidin; in view of the above, it is clear that HDACi is an emerging molecular-targeted approach to the management of ovarian cancer, but prudent forethought should be given to specific targeting of different HDAC family members, for example, HDAC1 and HDAC2 coregulator complexes, and more especially since acetylated HDAC1 can transregulate HDAC2 through heterodimerization. | [327, 371–386] |
| | miRNAs‡ | MicroRNAs belong to a family of endogenous, small RNAs (~22 nucleotides); these noncoding, yet functional RNAs are key regulators of coding genes in the human genome; microarray analysis of altered expression of miRNAs provides useful information on the ontogeny and differentiation status of various cancers; genomic and epigenetic modifications are known to deregulate miRNA expression in human EOC; a recent study showed that several miRNAs (let-7e, miR-30c, miR-125b, miR-130a, and miR-335) were differentially expressed and upregulated in paclitaxel- and cisplatin-resistant ovarian cancer cell lines and concluded that the development of drug resistance in ovarian cancer may be linked to distinct miRNA fingerprints that could be used as biomarkers to monitor disease prognosis; deregulation of miRNA-27a may correlate with the development of drug resistance by regulating the expression of MDR1/P-glycoprotein targeting HIPK2 in ovarian cancer cells; deregulation of miR-214, miR-199a, miR-200a, and miR-100 has also been demonstrated to occur in ovarian cancers; miR-214 promotes cell survival and cisplatin resistance by targeting the PTEN/Akt pathway; lack of miRNA-31 expression has been linked to a defective p53 pathway in serous ovarian cancer patients, raising hopes that treatment with miRNA-31 may offer an efficacious strategy in the management of such patients; miRNA-125a is a negative regulator of EMT since it induces reversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial histotype; this finding represents a landmark in ovarian cancer therapeutics since overexpression of EGFR is coupled to EMT in ovarian cancer cells which correlates with poor prognosis; the expression of miRNA-200 family members in ovarian tumors obtained from patients correlated with raised levels of β-tubulin and poor PFS to paclitaxel-based treatment; some miRNAs have been identified as putative tumor suppressor genes in ovarian tumors; thus specific miRNA signatures may be exploited as biomarkers for progression and recurrence of advanced stage ovarian carcinoma patients, and as molecular targets in ovarian cancer. | [68, 387–396] |
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